TY  - JOUR
A1  - Knöchel, Jane
A1  - Kloft, Charlotte
A1  - Huisinga, Wilhelm
T1  - Understanding and reducing complex systems pharmacology models based on a novel input-response index
JF  - Journal of pharmacokinetics and pharmacodynamics
N2  - A growing understanding of complex processes in biology has led to large-scale mechanistic models of pharmacologically relevant processes. These models are increasingly used to study the response of the system to a given input or stimulus, e.g., after drug administration. Understanding the input–response relationship, however, is often a challenging task due to the complexity of the interactions between its constituents as well as the size of the models. An approach that quantifies the importance of the different constituents for a given input–output relationship and allows to reduce the dynamics to its essential features is therefore highly desirable. In this article, we present a novel state- and time-dependent quantity called the input–response index that quantifies the importance of state variables for a given input–response relationship at a particular time. It is based on the concept of time-bounded controllability and observability, and defined with respect to a reference dynamics. In application to the brown snake venom–fibrinogen (Fg) network, the input–response indices give insight into the coordinated action of specific coagulation factors and about those factors that contribute only little to the response. We demonstrate how the indices can be used to reduce large-scale models in a two-step procedure: (i) elimination of states whose dynamics have only minor impact on the input–response relationship, and (ii) proper lumping of the remaining (lower order) model. In application to the brown snake venom–fibrinogen network, this resulted in a reduction from 62 to 8 state variables in the first step, and a further reduction to 5 state variables in the second step. We further illustrate that the sequence, in which a recursive algorithm eliminates and/or lumps state variables, has an impact on the final reduced model. The input–response indices are particularly suited to determine an informed sequence, since they are based on the dynamics of the original system. In summary, the novel measure of importance provides a powerful tool for analysing the complex dynamics of large-scale systems and a means for very efficient model order reduction of nonlinear systems.
KW  - Control theory
KW  - Model order reduction
KW  - Blood coagulation network
KW  - Nonlinear systems
Y1  - 2017
U6  - https://doi.org/10.1007/s10928-017-9561-x
SN  - 1567-567X
SN  - 1573-8744
VL  - 45
IS  - 1
SP  - 139
EP  - 157
PB  - Springer Science + Business Media B.V.
CY  - New York
ER  - 
TY  - JOUR
A1  - Démaris, Alix
A1  - Widigson, Ella S. K.
A1  - Ilvemark, Johan F. K. F.
A1  - Steenholdt, Casper
A1  - Seidelin, Jakob B.
A1  - Huisinga, Wilhelm
A1  - Michelet, Robin
A1  - Aulin, Linda B. S.
A1  - Kloft, Charlotte
T1  - Ulcerative colitis and acute severe ulcerative colitis patients are overlooked in infliximab population pharmacokinetic models
BT  - results from a comprehensive review
JF  - Pharmaceutics / Molecular Diversity Preservation International
N2  - Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis alpha monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.
KW  - infliximab
KW  - inflammatory bowel disease
KW  - ulcerative colitis
KW  - acute severe
KW  - disease activity
KW  - pharmacokinetic
KW  - pharmacometrics
Y1  - 2022
U6  - https://doi.org/10.3390/pharmaceutics14102095
SN  - 1999-4923
VL  - 14
IS  - 10
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Wicha, Sebastian G.
A1  - Huisinga, Wilhelm
A1  - Kloft, Charlotte
T1  - Translational pharmacometric evaluation of typical antibiotic broad-spectrum combination therapies against staphylococcus aureus exploiting in vitro information
JF  - CPT: pharmacometrics & systems pharmacology
N2  - Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.
Y1  - 2017
U6  - https://doi.org/10.1002/psp4.12197
SN  - 2163-8306
VL  - 6
SP  - 512
EP  - 522
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - GEN
A1  - Weisser, Karin
A1  - Stübler, Sabine
A1  - Matheis, Walter
A1  - Huisinga, Wilhelm
T1  - Towards toxicokinetic modelling of aluminium exposure from adjuvants in medicinal products
T2  - Regulatory toxicology and pharmacology : official journal of the International Society for Regulatory Toxicology and Pharmacology
N2  - As a potentially toxic agent on nervous system and bone, the safety of aluminium exposure from adjuvants in vaccines and subcutaneous immune therapy (SCIT) products has to be continuously reevaluated, especially regarding concomitant administrations. For this purpose, knowledge on absorption and disposition of aluminium in plasma and tissues is essential. Pharmacokinetic data after vaccination in humans, however, are not available, and for methodological and ethical reasons difficult to obtain. To overcome these limitations, we discuss the possibility of an in vitro-in silico approach combining a toxicokinetic model for aluminium disposition with biorelevant kinetic absorption parameters from adjuvants. We critically review available kinetic aluminium-26 data for model building and, on the basis of a reparameterized toxicokinetic model (Nolte et al., 2001), we identify main modelling gaps. The potential of in vitro dissolution experiments for the prediction of intramuscular absorption kinetics of aluminium after vaccination is explored. It becomes apparent that there is need for detailed in vitro dissolution and in vivo absorption data to establish an in vitro-in vivo correlation (IVIVC) for aluminium adjuvants. We conclude that a combination of new experimental data and further refinement of the Nolte model has the potential to fill a gap in aluminium risk assessment. (C) 2017 Elsevier Inc. All rights reserved.
KW  - Aluminium
KW  - Aluminium adjuvants
KW  - Absorption kinetics
KW  - Toxicokinetic modelling
KW  - In vitro dissolution
Y1  - 2017
U6  - https://doi.org/10.1016/j.yrtph.2017.02.018
SN  - 0273-2300
SN  - 1096-0295
VL  - 88
SP  - 310
EP  - 321
PB  - Elsevier
CY  - San Diego
ER  - 
TY  - JOUR
A1  - Mueller-Schoell, Anna
A1  - Groenland, Stefanie L.
A1  - Scherf-Clavel, Oliver
A1  - van Dyk, Madele
A1  - Huisinga, Wilhelm
A1  - Michelet, Robin
A1  - Jaehde, Ulrich
A1  - Steeghs, Neeltje
A1  - Huitema, Alwin D. R.
A1  - Kloft, Charlotte
T1  - Therapeutic drug monitoring of oral targeted antineoplastic drugs
JF  - European journal of clinical pharmacology
N2  - Purpose This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. Methods A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. Results OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. Conclusion Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.
KW  - targeted antineoplastic drugs
KW  - tyrosine kinase inhibitors
KW  - therapeutic
KW  - drug monitoring
KW  - oral anticancer drugs
KW  - personalised medicine
Y1  - 2020
U6  - https://doi.org/10.1007/s00228-020-03014-8
SN  - 0031-6970
SN  - 1432-1041
VL  - 77
IS  - 4
SP  - 441
EP  - 464
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Moldenhawer, Ted
A1  - Moreno, Eduardo
A1  - Schindler, Daniel
A1  - Flemming, Sven
A1  - Holschneider, Matthias
A1  - Huisinga, Wilhelm
A1  - Alonso, Sergio
A1  - Beta, Carsten
T1  - Spontaneous transitions between amoeboid and keratocyte-like modes of migration
JF  - Frontiers in Cell and Developmental Biology
N2  - The motility of adherent eukaryotic cells is driven by the dynamics of the actin cytoskeleton. Despite the common force-generating actin machinery, different cell types often show diverse modes of locomotion that differ in their shape dynamics, speed, and persistence of motion. Recently, experiments in Dictyostelium discoideum have revealed that different motility modes can be induced in this model organism, depending on genetic modifications, developmental conditions, and synthetic changes of intracellular signaling. Here, we report experimental evidence that in a mutated D. discoideum cell line with increased Ras activity, switches between two distinct migratory modes, the amoeboid and fan-shaped type of locomotion, can even spontaneously occur within the same cell. We observed and characterized repeated and reversible switchings between the two modes of locomotion, suggesting that they are distinct behavioral traits that coexist within the same cell. We adapted an established phenomenological motility model that combines a reaction-diffusion system for the intracellular dynamics with a dynamic phase field to account for our experimental findings.
KW  - cell migration
KW  - amoeboid motility
KW  - keratocytle-like motility
KW  - modes of
KW  - migration
KW  - D. discoideum
KW  - actin dynamics
Y1  - 2022
U6  - https://doi.org/10.3389/fcell.2022.898351
SN  - 2296-634X
VL  - 10
PB  - Frontiers Media
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Henrich, Andrea
A1  - Joerger, Markus
A1  - Kraff, Stefanie
A1  - Jaehde, Ulrich
A1  - Huisinga, Wilhelm
A1  - Kloft, Charlotte
A1  - Parra-Guillen, Zinnia Patricia
T1  - Semimechanistic Bone Marrow Exhaustion Pharmacokinetic/Pharmacodynamic Model for Chemotherapy-Induced Cumulative Neutropenia
JF  - Journal of Pharmacology and Experimental Therapeutics
N2  - Paclitaxel is a commonly used cytotoxic anticancer drug with potentially life-threatening toxicity at therapeutic doses and high interindividual pharmacokinetic variability. Thus, drug and effect monitoring is indicated to control dose-limiting neutropenia. Joerger et al. (2016) developed a dose individualization algorithm based on a pharmacokinetic (PK)/pharmacodynamic (PD) model describing paclitaxel and neutrophil concentrations. Furthermore, the algorithm was prospectively compared in a clinical trial against standard dosing (Central European Society for Anticancer Drug Research Study of Paclitaxel Therapeutic Drug Monitoring; 365 patients, 720 cycles) but did not substantially improve neutropenia. This might be caused by misspecifications in the PK/PD model underlying the algorithm, especially without consideration of the observed cumulative pattern of neutropenia or the platinum-based combination therapy, both impacting neutropenia. This work aimed to externally evaluate the original PK/PD model for potential misspecifications and to refine the PK/PD model while considering the cumulative neutropenia pattern and the combination therapy. An underprediction was observed for the PK (658 samples), the PK parameters, and these parameters were re-estimated using the original estimates as prior information. Neutrophil concentrations (3274 samples) were over-predicted by the PK/PD model, especially for later treatment cycles when the cumulative pattern aggravated neutropenia. Three different modeling approaches (two from the literature and one newly developed) were investigated. The newly developed model, which implemented the bone marrow hypothesis semiphysiologically, was superior. This model further included an additive effect for toxicity of carboplatin combination therapy. Overall, a physiologically plausible PK/PD model was developed that can be used for dose adaptation simulations and prospective studies to further improve paclitaxel/ carboplatin combination therapy.
Y1  - 2017
U6  - https://doi.org/10.1124/jpet.117.240309
SN  - 0022-3565
SN  - 1521-0103
VL  - 362
IS  - 2
SP  - 347
EP  - 358
PB  - American Society for Pharmacology and Experimental Therapeutics
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Ehmann, Lisa
A1  - Zoller, Michael
A1  - Minichmayr, Iris K.
A1  - Scharf, Christina
A1  - Maier, Barbara
A1  - Schmitt, Maximilian V.
A1  - Hartung, Niklas
A1  - Huisinga, Wilhelm
A1  - Vogeser, Michael
A1  - Frey, Lorenz
A1  - Zander, Johannes
A1  - Kloft, Charlotte
T1  - Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients
BT  - a prospective observational study
JF  - Critical care
N2  - Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. Methods: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100% T->MIC, 50% T->4xMIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment. Results: Large inter-and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100% T->MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50% T->4xMIC. A hyperbolic relationship between CLCRCG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C-8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment). Conclusions: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy-and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.
KW  - beta-Lactam
KW  - Intensive care
KW  - Pharmacokinetics/Pharmacodynamics
KW  - Target attainment
KW  - Renal function
KW  - Risk assessment tool
KW  - Continuous renal replacement therapy
Y1  - 2017
U6  - https://doi.org/10.1186/s13054-017-1829-4
SN  - 1466-609X
SN  - 1364-8535
VL  - 21
PB  - BioMed Central
CY  - London
ER  - 
TY  - CHAP
A1  - Steenholdt, Casper
A1  - Edlund, Helena
A1  - Ainsworth, Mark A.
A1  - Brynskov, Jorn
A1  - Thomsen, Ole Ostergaard
A1  - Huisinga, Wilhelm
A1  - Kloft, Charlotte
T1  - Relationship between measures of infliximab exposure and clinical outcome of infliximab intensification at therapeutic failure in Crohn's  disease
T2  - JOURNAL OF CROHNS & COLITIS
Y1  - 2015
SN  - 1873-9946
SN  - 1876-4479
VL  - 9
SP  - S330
EP  - S330
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Grisic, Ana-Marija
A1  - Eser, Alexander
A1  - Huisinga, Wilhelm
A1  - Reinisch, Walter
A1  - Kloft, Charlotte
T1  - Quantitative relationship between infliximab exposure and inhibition of C-reactive protein synthesis to support inflammatory bowel disease management
JF  - British journal of clinical pharmacology
N2  - Aim Quantitative and kinetic insights into the drug exposure-disease response relationship might enhance our knowledge on loss of response and support more effective monitoring of inflammatory activity by biomarkers in patients with inflammatory bowel disease (IBD) treated with infliximab (IFX). This study aimed to derive recommendations for dose adjustment and treatment optimisation based on mechanistic characterisation of the relationship between IFX serum concentration and C-reactive protein (CRP) concentration. <br /> Methods Data from an investigator-initiated trial included 121 patients with IBD during IFX maintenance treatment. Serum concentrations of IFX, antidrug antibodies (ADA), CRP, and disease-related covariates were determined at the mid-term and end of a dosing interval. Data were analysed using a pharmacometric nonlinear mixed-effects modelling approach. An IFX exposure-CRP model was generated and applied to evaluate dosing regimens to achieve CRP remission. <br /> Results The generated quantitative model showed that IFX has the potential to inhibit up to 72% (9% relative standard error [RSE]) of CRP synthesis in a patient. IFX concentration leading to 90% of the maximum CRP synthesis inhibition was 18.4 mu g/mL (43% RSE). Presence of ADA was the most influential factor on IFX exposure. With standard dosing strategy, >= 55% of ADA+ patients experienced CRP nonremission. Shortening the dosing interval and co-therapy with immunomodulators were found to be the most beneficial strategies to maintain CRP remission. <br /> Conclusions With the generated model we could for the first time establish a robust relationship between IFX exposure and CRP synthesis inhibition, which could be utilised for treatment optimisation in IBD patients.
KW  - C‐ reactive protein remission
KW  - inflammatory bowel disease
KW  - infliximab dosing
Y1  - 2020
U6  - https://doi.org/10.1111/bcp.14648
SN  - 0306-5251
SN  - 1365-2125
VL  - 87
IS  - 5
SP  - 2374
EP  - 2384
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - GEN
A1  - Weiße, Andrea Y.
A1  - Middleton, Richard H.
A1  - Huisinga, Wilhelm
T1  - Quantifying uncertainty, variability and likelihood for ordinary differential equation models
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Background
In many applications, ordinary differential equation (ODE) models are subject to uncertainty or variability in initial conditions and parameters. Both, uncertainty and variability can be quantified in terms of a probability density function on the state and parameter space.

Results
The partial differential equation that describes the evolution of this probability density function has a form that is particularly amenable to application of the well-known method of characteristics. The value of the density at some point in time is directly accessible by the solution of the original ODE extended by a single extra dimension (for the value of the density). This leads to simple methods for studying uncertainty, variability and likelihood, with significant advantages over more traditional Monte Carlo and related approaches especially when studying regions with low probability.

Conclusions
While such approaches based on the method of characteristics are common practice in other disciplines, their advantages for the study of biological systems have so far remained unrecognized. Several examples illustrate performance and accuracy of the approach and its limitations.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 894 
KW  - ordinary differential equation
KW  - Unscented Kalman Filter
KW  - global sensitivity analysis
KW  - Ordinary Differential Equation model
KW  - joint normal distribution
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-431340
SN  - 1866-8372
IS  - 894
ER  - 
TY  - JOUR
A1  - Weiße, Andrea Y.
A1  - Middleton, Richard H.
A1  - Huisinga, Wilhelm
T1  - Quantifying uncertainty, variability and likelihood for ordinary differential equation models
N2  - Background: In many applications, ordinary differential equation (ODE) models are subject to uncertainty or variability in initial conditions and parameters. Both, uncertainty and variability can be quantified in terms of a probability density function on the state and parameter space. Results: The partial differential equation that describes the evolution of this probability density function has a form that is particularly amenable to application of the well- known method of characteristics. The value of the density at some point in time is directly accessible by the solution of the original ODE extended by a single extra dimension (for the value of the density). This leads to simple methods for studying uncertainty, variability and likelihood, with significant advantages over more traditional Monte Carlo and related approaches especially when studying regions with low probability. Conclusions: While such approaches based on the method of characteristics are common practice in other disciplines, their advantages for the study of biological systems have so far remained unrecognized. Several examples illustrate performance and accuracy of the approach and its limitations.
Y1  - 2010
UR  - http://www.biomedcentral.com/1752-0509/
U6  - https://doi.org/10.1186/1752-0509-4-144
SN  - 1752-0509
ER  - 
TY  - JOUR
A1  - Makarava, Natallia
A1  - Menz, Stephan
A1  - Theves, Matthias
A1  - Huisinga, Wilhelm
A1  - Beta, Carsten
A1  - Holschneider, Matthias
T1  - Quantifying the degree of persistence in random amoeboid motion based on the Hurst exponent of fractional Brownian motion
JF  - Physical review : E, Statistical, nonlinear and soft matter physics
N2  - Amoebae explore their environment in a random way, unless external cues like, e. g., nutrients, bias their motion. Even in the absence of cues, however, experimental cell tracks show some degree of persistence. In this paper, we analyzed individual cell tracks in the framework of a linear mixed effects model, where each track is modeled by a fractional Brownian motion, i.e., a Gaussian process exhibiting a long-term correlation structure superposed on a linear trend. The degree of persistence was quantified by the Hurst exponent of fractional Brownian motion. Our analysis of experimental cell tracks of the amoeba Dictyostelium discoideum showed a persistent movement for the majority of tracks. Employing a sliding window approach, we estimated the variations of the Hurst exponent over time, which allowed us to identify points in time, where the correlation structure was distorted ("outliers"). Coarse graining of track data via down-sampling allowed us to identify the dependence of persistence on the spatial scale. While one would expect the (mode of the) Hurst exponent to be constant on different temporal scales due to the self-similarity property of fractional Brownian motion, we observed a trend towards stronger persistence for the down-sampled cell tracks indicating stronger persistence on larger time scales.
Y1  - 2014
U6  - https://doi.org/10.1103/PhysRevE.90.042703
SN  - 1539-3755
SN  - 1550-2376
VL  - 90
IS  - 4
PB  - American Physical Society
CY  - College Park
ER  - 
TY  - JOUR
A1  - Nassar, Yomna M.
A1  - Hohmann, Nicolas
A1  - Michelet, Robin
A1  - Gottwalt, Katharina
A1  - Meid, Andreas D.
A1  - Burhenne, Jürgen
A1  - Huisinga, Wilhelm
A1  - Haefeli, Walter E.
A1  - Mikus, Gerd
A1  - Kloft, Charlotte
T1  - Quantification of the Time Course of CYP3A Inhibition, Activation, and Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam Continuous Infusion
JF  - Clinical Pharmacokinetics
N2  - Background
Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. 

Objective
We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity.

Methods
Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM (R). CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. 

Results
Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, -70.6%, and -61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively.

Conclusions
We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected.
Y1  - 2022
U6  - https://doi.org/10.1007/s40262-022-01175-6
SN  - 0312-5963
SN  - 1179-1926
VL  - 61
IS  - 11
SP  - 1595
EP  - 1607
PB  - Springer
CY  - Northcote
ER  - 
TY  - GEN
A1  - Krippendorff, Ben-Fillippo
A1  - Oyarzún, Diego A.
A1  - Huisinga, Wilhelm
T1  - Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 958 
KW  - cell-level kinetics
KW  - pharmacokinetic models
KW  - therapeutic proteins
KW  - EGFR
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-431051
SN  - 1866-8372
IS  - 958
SP  - 125
EP  - 139
ER  - 
TY  - JOUR
A1  - Krippendorff, Ben-Fillippo
A1  - Oyarzún, Diego A.
A1  - Huisinga, Wilhelm
T1  - Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling
JF  - Journal of pharmacokinetics and pharmacodynamics
N2  - Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity.
KW  - Cell-level kinetics
KW  - Pharmacokinetic models
KW  - Therapeutic proteins
KW  - EGFR
Y1  - 2012
U6  - https://doi.org/10.1007/s10928-012-9243-7
SN  - 1567-567X
VL  - 39
IS  - 2
SP  - 125
EP  - 139
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Melin, Johanna
A1  - Parra-Guillen, Zinnia Patricia
A1  - Hartung, Niklas
A1  - Huisinga, Wilhelm
A1  - Ross, Richard J.
A1  - Whitaker, Martin J.
A1  - Kloft, Charlotte
T1  - Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults
JF  - Clinical Pharmacokinetics
N2  - Background and objective Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort (R) oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency. Methods Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort (R) or 20 mg of Infacort (R)/hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model. Results Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline (cort),15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing < 20 kg. Conclusions Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing < 20 kg.
Y1  - 2018
U6  - https://doi.org/10.1007/s40262-017-0575-8
SN  - 0312-5963
SN  - 1179-1926
VL  - 57
IS  - 4
SP  - 515
EP  - 527
PB  - Springer
CY  - Northcote
ER  - 
TY  - JOUR
A1  - Hethey, Christoph Philipp
A1  - Hartung, Niklas
A1  - Wangorsch, Gaby
A1  - Weisser, Karin
A1  - Huisinga, Wilhelm
T1  - Physiology-based toxicokinetic modelling of aluminium in rat and man
JF  - Archives of toxicology : official journal of EUROTOX
N2  - A sufficient quantitative understanding of aluminium (Al) toxicokinetics (TK) in man is still lacking, although highly desirable for risk assessment of Al exposure. Baseline exposure and the risk of contamination severely limit the feasibility of TK studies administering the naturally occurring isotope Al-27, both in animals and man. These limitations are absent in studies with Al-26 as a tracer, but tissue data are limited to animal studies. A TK model capable of inter-species translation to make valid predictions of Al levels in humans-especially in toxicological relevant tissues like bone and brain-is urgently needed. Here, we present: (i) a curated dataset which comprises all eligible studies with single doses of Al-26 tracer administered as citrate or chloride salts orally and/or intravenously to rats and humans, including ultra-long-term kinetic profiles for plasma, blood, liver, spleen, muscle, bone, brain, kidney, and urine up to 150 weeks; and (ii) the development of a physiology-based (PB) model for Al TK after intravenous and oral administration of aqueous Al citrate and Al chloride solutions in rats and humans. Based on the comprehensive curated Al-26 dataset, we estimated substance-dependent parameters within a non-linear mixed-effect modelling context. The model fitted the heterogeneous Al-26 data very well and was successfully validated against datasets in rats and humans. The presented PBTK model for Al, based on the most extensive and diverse dataset of Al exposure to date, constitutes a major advancement in the field, thereby paving the way towards a more quantitative risk assessment in humans.
KW  - PBTK
KW  - Toxicokinetics
KW  - Al-26
KW  - Aluminium
Y1  - 2021
U6  - https://doi.org/10.1007/s00204-021-03107-y
SN  - 0340-5761
SN  - 1432-0738
VL  - 95
IS  - 9
SP  - 2977
EP  - 3000
PB  - Springer
CY  - Berlin ; Heidelberg
ER  - 
TY  - CHAP
A1  - Andersson, H.
A1  - Keunecke, A.
A1  - Eser, A.
A1  - Huisinga, Wilhelm
A1  - Reinisch, W.
A1  - Kloft, Charlotte
T1  - Pharmacokinetic considerations for optimising dosing regimens of  a potsdam univ infliximab in patients with Crohn's disease
T2  - JOURNAL OF CROHNS & COLITIS
Y1  - 2014
U6  - https://doi.org/10.1016/S1873-9946(14)60086-6
SN  - 1873-9946
SN  - 1876-4479
VL  - 8
SP  - S44
EP  - S44
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Kluwe, Franziska
A1  - Michelet, Robin
A1  - Müller-Schöll, Anna
A1  - Maier, Corinna
A1  - Klopp-Schulze, Lena
A1  - van Dyk, Madele
A1  - Mikus, Gerd
A1  - Huisinga, Wilhelm
A1  - Kloft, Charlotte
T1  - Perspectives on model-informed precision dosing in the digital health era
BT  - challenges, opportunities, and recommendations
JF  - Clinical pharmacology & therapeutics
Y1  - 2020
U6  - https://doi.org/10.1002/cpt.2049
SN  - 0009-9236
SN  - 1532-6535
VL  - 109
IS  - 1
SP  - 29
EP  - 36
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - GEN
A1  - Müller-Schöll, A.
A1  - Klopp-Schulze, Lena
A1  - Huisinga, Wilhelm
A1  - Jörger, M.
A1  - Neven, P.
A1  - Koolen, S. L.
A1  - Mathijssen, R. H. J.
A1  - Schmidt, S.
A1  - Kloft, Charlotte
T1  - Patient-tailored tamoxifen dosing based on an increased quantitative understanding of its complex pharmacokinetics: A novel integrative modelling approach
T2  - Annals of Oncology
Y1  - 2019
SN  - 0923-7534
SN  - 1569-8041
VL  - 30
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - GEN
A1  - Grisic, Ana-Marija
A1  - Huisinga, Wilhelm
A1  - Reinisch, W.
A1  - Kloft, Charlotte
T1  - P485 Dosing infliximab in Crohn's disease
BT  - is adjustment for body size justified?
T2  - Journal of Crohn's and Colitis
N2  - Background: Infliximab (IFX), an anti-TNF monoclonal antibody approved for the treatment of inflammatory bowel disease, is dosed per kg body weight (BW). However, the rationale for body size adjustment has not been unequivocally demonstrated [1], and first attempts to improve IFX therapy have been undertaken [2]. The aim of our study was to assess the impact of different dosing strategies (i.e. body size-adjusted and fixed dosing) on drug exposure and pharmacokinetic (PK) target attainment. For this purpose, a comprehensive simulation study was performed, using patient characteristics (n=116) from an in-house clinical database.

Methods: IFX concentration-time profiles of 1000 virtual, clinically representative patients were generated using a previously published PK model for IFX in patients with Crohn's disease [3]. For each patient 1000 profiles accounting for PK variability were considered. The IFX exposure during maintenance treatment after the following dosing strategies was compared: i) fixed dose, and per ii) BW, iii) lean BW (LBW), iv) body surface area (BSA), v) height (HT), vi) body mass index (BMI) and vii) fat-free mass (FFM)). For each dosing strategy the variability in maximum concentration Cmax, minimum concentration Cmin (= C8weeks) and area under the concentration-time curve (AUC), as well as percent of patients achieving the PK target, Cmin=3 μg/mL [4] were assessed.

Results: For all dosing strategies the variability of Cmin (CV ≈110%) was highest, compared to Cmax and AUC, and was of similar extent regardless of dosing strategy. The proportion of patients reaching the PK target (≈⅓ was approximately equal for all dosing strategies.
Y1  - 2017
U6  - https://doi.org/10.1093/ecco-jcc/jjx002.609
SN  - 1873-9946
SN  - 1876-4479
VL  - 11
IS  - 1
SP  - S325
EP  - S326
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Hartung, Niklas
A1  - Wahl, Martin
A1  - Rastogi, Abhishake
A1  - Huisinga, Wilhelm
T1  - Nonparametric goodness-of-fit testing for parametric covariate models in pharmacometric analyses
JF  - CPT: pharmacometrics & systems pharmacology
N2  - The characterization of covariate effects on model parameters is a crucial step during pharmacokinetic/pharmacodynamic analyses. Although covariate selection criteria have been studied extensively, the choice of the functional relationship between covariates and parameters, however, has received much less attention. Often, a simple particular class of covariate-to-parameter relationships (linear, exponential, etc.) is chosen ad hoc or based on domain knowledge, and a statistical evaluation is limited to the comparison of a small number of such classes. Goodness-of-fit testing against a nonparametric alternative provides a more rigorous approach to covariate model evaluation, but no such test has been proposed so far. In this manuscript, we derive and evaluate nonparametric goodness-of-fit tests for parametric covariate models, the null hypothesis, against a kernelized Tikhonov regularized alternative, transferring concepts from statistical learning to the pharmacological setting. The approach is evaluated in a simulation study on the estimation of the age-dependent maturation effect on the clearance of a monoclonal antibody. Scenarios of varying data sparsity and residual error are considered. The goodness-of-fit test correctly identified misspecified parametric models with high power for relevant scenarios. The case study provides proof-of-concept of the feasibility of the proposed approach, which is envisioned to be beneficial for applications that lack well-founded covariate models.
Y1  - 2021
U6  - https://doi.org/10.1002/psp4.12614
SN  - 2163-8306
VL  - 10
IS  - 6
SP  - 564
EP  - 576
PB  - Nature Publ. Group
CY  - London
ER  - 
TY  - JOUR
A1  - Fronton, Ludivine
A1  - Pilari, Sabine
A1  - Huisinga, Wilhelm
T1  - Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models
JF  - Journal of pharmacokinetics and pharmacodynamics
N2  - The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two-compartment models for mAb disposition-identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)-is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3 and T84.66 in mice.
KW  - mAb disposition
KW  - PBPK
KW  - Extravasation rate-limited tissue model
KW  - Classical compartment model
Y1  - 2014
U6  - https://doi.org/10.1007/s10928-014-9349-1
SN  - 1567-567X
SN  - 1573-8744
VL  - 41
IS  - 2
SP  - 87
EP  - 107
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Michelet, Robin
A1  - Bindellini, Davide
A1  - Melin, Johanna
A1  - Neumann, Uta
A1  - Blankenstein, Oliver
A1  - Huisinga, Wilhelm
A1  - Johnson, Trevor N.
A1  - Whitaker, Martin J.
A1  - Ross, Richard
A1  - Kloft, Charlotte
T1  - Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach
JF  - Frontiers in Pharmacology
N2  - Introduction: 
Hydrocortisone is the standard of care in cortisol replacement therapy for congenital adrenal hyperplasia patients. Challenges in mimicking cortisol circadian rhythm and dosing individualization can be overcome by the support of mathematical modelling. Previously, a non-linear mixed-effects (NLME) model was developed based on clinical hydrocortisone pharmacokinetic (PK) pediatric and adult data. Additionally, a physiologically-based pharmacokinetic (PBPK) model was developed for adults and a pediatric model was obtained using maturation functions for relevant processes. In this work, a middle-out approach was applied. The aim was to investigate whether PBPK-derived maturation functions could provide a better description of hydrocortisone PK inter-individual variability when implemented in the NLME framework, with the goal of providing better individual predictions towards precision dosing at the patient level.

Methods:
Hydrocortisone PK data from 24 adrenal insufficiency pediatric patients and 30 adult healthy volunteers were used for NLME model development, while the PBPK model and maturation functions of clearance and cortisol binding globulin (CBG) were developed based on previous studies published in the literature.

Results:
Clearance (CL) estimates from both approaches were similar for children older than 1 year (CL/F increasing from around 150 L/h to 500 L/h), while CBG concentrations differed across the whole age range (CBG(NLME) stable around 0.5 mu M vs. steady increase from 0.35 to 0.8 mu M for CBG (PBPK)). PBPK-derived maturation functions were subsequently included in the NLME model. After inclusion of the maturation functions, none, a part of, or all parameters were re-estimated. However, the inclusion of CL and/or CBG maturation functions in the NLME model did not result in improved model performance for the CL maturation function (& UDelta;OFV > -15.36) and the re-estimation of parameters using the CBG maturation function most often led to unstable models or individual CL prediction bias.

Discussion:
Three explanations for the observed discrepancies could be postulated, i) non-considered maturation of processes such as absorption or first-pass effect, ii) lack of patients between 1 and 12 months, iii) lack of correction of PBPK CL maturation functions derived from urinary concentration ratio data for the renal function relative to adults. These should be investigated in the future to determine how NLME and PBPK methods can work towards deriving insights into pediatric hydrocortisone PK.
KW  - hydrocortisone
KW  - congenital adrenal hyperplasia
KW  - population pharmacokinetics
KW  - middle-out approach
KW  - pediatrics
KW  - physiologically-based pharmacokinetics (PBPK)
KW  - non-linear mixed effects modelling (NLME);
KW  - maturation
Y1  - 2023
U6  - https://doi.org/10.3389/fphar.2022.1090554
SN  - 1663-9812
VL  - 13
PB  - Frontiers Media
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Fuhrmann, Saskia
A1  - Kloft, Charlotte
A1  - Huisinga, Wilhelm
T1  - Impact of altered endogenous IgG on unspecific mAb clearance
JF  - Journal of pharmacokinetics and pharmacodynamics
N2  - Immunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data. We used a PBPK modelling approach to elucidate the influence of altered endogenous IgG concentrations on unspecific mAb clearance. To this end, we used PK data in immunodeficient mice, i.e. nude and severe combined immunodeficiency mice. To avoid impact of target-mediated clearance processes, we focussed on mAbs without affinity to a target antigen in these mice. In addition, intravenous immunoglobulin (IVIG) data of immunocompetent mice was used to study the impact of increased total IgG concentrations on unspecific therapeutic antibody clearance. The unspecific clearance is linear, whenever therapeutic IgG concentrations, i.e. mAb and IVIG concentrations are lower than FcRn; it can be non-linear if therapeutic IgG concentrations are larger than FcRn and endogenous IgG concentrations (e.g., under IVIG therapy). Unspecific mAb clearance of immunodeficient mice is effectively linear (under mAb doses as typically used in human). Studying the impact of reduced endogenous IgG concentrations on unspecific mAb clearance is of great relevance for the extrapolation to clinical species, e.g., when predicting mAb PK in immunosuppressed cancer patients.
KW  - mAb disposition
KW  - PBPK
KW  - FcRn salvage mechanism
KW  - Immunodeficient mice models
KW  - Unspecific antibody clearance
Y1  - 2017
U6  - https://doi.org/10.1007/s10928-017-9524-2
SN  - 1567-567X
SN  - 1573-8744
VL  - 44
SP  - 351
EP  - 374
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Menz, Stephan
A1  - Latorre, Juan C.
A1  - Schütte, Christof
A1  - Huisinga, Wilhelm
T1  - Hybrid stochastic-deterministic solution of the chemical master equation
JF  - Multiscale modeling & simulation : a SIAM interdisciplinary journal
N2  - The chemical master equation (CME) is the fundamental evolution equation of the stochastic description of biochemical reaction kinetics. In most applications it is impossible to solve the CME directly due to its high dimensionality. Instead, indirect approaches based on realizations of the underlying Markov jump process are used, such as the stochastic simulation algorithm (SSA). In the SSA, however, every reaction event has to be resolved explicitly such that it becomes numerically inefficient when the system's dynamics include fast reaction processes or species with high population levels. In many hybrid approaches, such fast reactions are approximated as continuous processes or replaced by quasi-stationary distributions in either a stochastic or a deterministic context. Current hybrid approaches, however, almost exclusively rely on the computation of ensembles of stochastic realizations. We present a novel hybrid stochastic-deterministic approach to solve the CME directly. Our starting point is a partitioning of the molecular species into discrete and continuous species that induces a partitioning of the reactions into discrete-stochastic and continuous-deterministic processes. The approach is based on a WKB (Wentzel-Kramers-Brillouin) ansatz for the conditional probability distribution function (PDF) of the continuous species (given a discrete state) in combination with Laplace's method of integral approximation. The resulting hybrid stochastic-deterministic evolution equations comprise a CME with averaged propensities for the PDF of the discrete species that is coupled to an evolution equation of the related expected levels of the continuous species for each discrete state. In contrast to indirect hybrid methods, the impact of the evolution of discrete species on the dynamics of the continuous species has to be taken into account explicitly. The proposed approach is efficient whenever the number of discrete molecular species is small. We illustrate the performance of the new hybrid stochastic-deterministic approach in an application to model systems of biological interest.
KW  - chemical master equation
KW  - hybrid model
KW  - multiscale analysis
KW  - partial averaging
KW  - asymptotic approximation
KW  - WKB ansatz
Y1  - 2012
U6  - https://doi.org/10.1137/110825716
SN  - 1540-3459
VL  - 10
IS  - 4
SP  - 1232
EP  - 1262
PB  - Society for Industrial and Applied Mathematics
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - von Kleist, Max
A1  - Menz, Stephan
A1  - Stocker, Hartmut
A1  - Arasteh, Keikawus
A1  - Schuette, Christof
A1  - Huisinga, Wilhelm
T1  - HIV quasispecies dynamics during pro-active treatment switching impact on multi-drug resistance and resistance archiving in latent reservoirs
JF  - PLoS one
N2  - The human immunodeficiency virus (HIV) can be suppressed by highly active anti-retroviral therapy (HAART) in the majority of infected patients. Nevertheless, treatment interruptions inevitably result in viral rebounds from persistent, latently infected cells, necessitating lifelong treatment. Virological failure due to resistance development is a frequent event and the major threat to treatment success. Currently, it is recommended to change treatment after the confirmation of virological failure. However, at the moment virological failure is detected, drug resistant mutants already replicate in great numbers. They infect numerous cells, many of which will turn into latently infected cells. This pool of cells represents an archive of resistance, which has the potential of limiting future treatment options. The objective of this study was to design a treatment strategy for treatment-naive patients that decreases the likelihood of early treatment failure and preserves future treatment options. We propose to apply a single, pro-active treatment switch, following a period of treatment with an induction regimen. The main goal of the induction regimen is to decrease the abundance of randomly generated mutants that confer resistance to the maintenance regimen, thereby increasing subsequent treatment success. Treatment is switched before the overgrowth and archiving of mutant strains that carry resistance against the induction regimen and would limit its future re-use. In silico modelling shows that an optimal trade-off is achieved by switching treatment at & 80 days after the initiation of antiviral therapy. Evaluation of the proposed treatment strategy demonstrated significant improvements in terms of resistance archiving and virological response, as compared to conventional HAART. While continuous pro-active treatment alternation improved the clinical outcome in a randomized trial, our results indicate that a similar improvement might also be reached after a single pro-active treatment switch. The clinical validity of this finding, however, remains to be shown by a corresponding trial.
Y1  - 2011
U6  - https://doi.org/10.1371/journal.pone.0018204
SN  - 1932-6203
VL  - 6
IS  - 3
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Busse, David
A1  - Simon, Philipp
A1  - Petroff, David
A1  - El-Najjar, Nahed
A1  - Schmitt, Lisa
A1  - Bindellini, Davide
A1  - Dietrich, Arne
A1  - Zeitlinger, Markus
A1  - Huisinga, Wilhelm
A1  - Michelet, Robin
A1  - Wrigge, Hermann
A1  - Kloft, Charlotte
T1  - High-dosage fosfomycin results in adequate plasma and target-site exposure in morbidly obese and nonobese nonhyperfiltration patients
JF  - Antimicrobial agents and chemotherapy
N2  - The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT(>= MIC) (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC(0-24h)/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m(2)) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC <= 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of,130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement beta-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status.
KW  - population pharmacokinetics
KW  - pharmacodynamics
KW  - fosfomycin
KW  - obesity
KW  - adipose tissue
KW  - interstitial space fluid
KW  - microdialysis
KW  - anti-infective
KW  - probability of target attainment
Y1  - 2022
U6  - https://doi.org/10.1128/aac.02302-21
SN  - 0066-4804
SN  - 1098-6596
VL  - 66
IS  - 6
PB  - American Society for Microbiology
CY  - Washington
ER  - 
TY  - JOUR
A1  - Pilari, Sabine
A1  - Preusse, Cornelia
A1  - Huisinga, Wilhelm
T1  - Gestational influences on the pharmacokinetics of gestagenic drugs a combined in silico, in vitro and in vivo analysis
JF  - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, EUFEPS
N2  - During preclinical development of a gestagenic drug, a significant increase of the total plasma concentration was observed after multiple dosing in pregnant rabbits, but not in (non-pregnant) rats or monkeys. We used a PBPK modeling approach in combination with in vitro and in vivo data to address the question to what extent the pharmacologically active free drug concentration is affected by pregnancy induced processes. In human, a significant increase in sex hormone binding globulin (SHBG), and an induction of hepatic CYP3A4 as well as plasma esterases is observed during pregnancy. We find that the observed increase in total plasma trough levels in rabbits can be explained as a combined result of (i) drug accumulation due to multiple dosing, (ii) increase of the binding protein SHBG, and (iii) clearance induction. For human, we predict that free drug concentrations in plasma would not increase during pregnancy above the steady state trough level for non-pregnant women.
KW  - PBPK
KW  - Pregnancy
KW  - Gestagenic drug
KW  - Protein binding
KW  - SHBG
KW  - Clearance induction
Y1  - 2011
U6  - https://doi.org/10.1016/j.ejps.2010.12.003
SN  - 0928-0987
VL  - 42
IS  - 4
SP  - 318
EP  - 331
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Stachanow, Viktoria
A1  - Neumann, Uta
A1  - Blankenstein, Oliver
A1  - Bindellini, Davide
A1  - Melin, Johanna
A1  - Ross, Richard
A1  - Whitaker, Martin J. J.
A1  - Huisinga, Wilhelm
A1  - Michelet, Robin
A1  - Kloft, Charlotte
T1  - Exploring dried blood spot cortisol concentrations as an alternative for monitoring pediatric adrenal insufficiency patients
BT  - a model-based analysis
JF  - Frontiers in pharmacology
N2  - Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. 

Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. 

In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions. 

In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples.
KW  - adrenal insufficiency
KW  - cortisol
KW  - dried blood spots
KW  - pediatrics
KW  - pharmacokinetics
KW  - binding
KW  - association
KW  - red blood cells
Y1  - 2022
U6  - https://doi.org/10.3389/fphar.2022.819590
SN  - 1663-9812
VL  - 13
PB  - Frontiers Media
CY  - Lausanne
ER  - 
TY  - CHAP
A1  - Démaris, Alise
A1  - Grišić, Ana-Marija
A1  - Huisinga, Wilhelm
A1  - Walter, Reinisch
A1  - Kloft, Charlotte
T1  - Evaluation of dosing strategies of anti-TNF alpha monoclonal antibodies using pharmacokinetic modelling and simulation
T2  - Journal of Crohn's and Colitis
N2  - Background:
Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed.

Methods:
A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy.

Results:
For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing.

Conclusion:
By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively).
KW  - linical databases
KW  - crohn's disease
KW  - regimen
KW  - monoclonal antibodies
KW  - body surface area
KW  - infliximab
KW  - fat-free mass
KW  - certolizumab pegol
KW  - body mass index procedure
Y1  - 2020
U6  - https://doi.org/10.1093/ecco-jcc/jjz203.201
SN  - 1873-9946
SN  - 1876-4479
VL  - 14
IS  - Supp. 1
SP  - S171
EP  - S172
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Weinelt, Ferdinand Anton
A1  - Stegemann, Miriam Songa
A1  - Theloe, Anja
A1  - Pfäfflin, Frieder
A1  - Achterberg, Stephan
A1  - Weber, Franz
A1  - Dübel, Lucas
A1  - Mikolajewska, Agata
A1  - Uhrig, Alexander
A1  - Kiessling, Peggy
A1  - Huisinga, Wilhelm
A1  - Michelet, Robin
A1  - Hennig, Stefanie
A1  - Kloft, Charlotte
T1  - Evaluation of a meropenem and piperacillin monitoring program in intensive care unit patients calls for the regular assessment of empirical targets and easy-to-use dosing decision tools
JF  - Antibiotics : open access journal
N2  - The drug concentrations targeted in meropenem and piperacillin/tazobactam therapy also depend on the susceptibility of the pathogen. Yet, the pathogen is often unknown, and antibiotic therapy is guided by empirical targets. To reliably achieve the targeted concentrations, dosing needs to be adjusted for renal function. We aimed to evaluate a meropenem and piperacillin/tazobactam monitoring program in intensive care unit (ICU) patients by assessing (i) the adequacy of locally selected empirical targets, (ii) if dosing is adequately adjusted for renal function and individual target, and (iii) if dosing is adjusted in target attainment (TA) failure. In a prospective, observational clinical trial of drug concentrations, relevant patient characteristics and microbiological data (pathogen, minimum inhibitory concentration (MIC)) for patients receiving meropenem or piperacillin/tazobactam treatment were collected. If the MIC value was available, a target range of 1-5 x MIC was selected for minimum drug concentrations of both drugs. If the MIC value was not available, 8-40 mg/L and 16-80 mg/L were selected as empirical target ranges for meropenem and piperacillin, respectively. A total of 356 meropenem and 216 piperacillin samples were collected from 108 and 96 ICU patients, respectively. The vast majority of observed MIC values was lower than the empirical target (meropenem: 90.0%, piperacillin: 93.9%), suggesting empirical target value reductions. TA was found to be low (meropenem: 35.7%, piperacillin 50.5%) with the lowest TA for severely impaired renal function (meropenem: 13.9%, piperacillin: 29.2%), and observed drug concentrations did not significantly differ between patients with different targets, indicating dosing was not adequately adjusted for renal function or target. Dosing adjustments were rare for both drugs (meropenem: 6.13%, piperacillin: 4.78%) and for meropenem irrespective of TA, revealing that concentration monitoring alone was insufficient to guide dosing adjustment. Empirical targets should regularly be assessed and adjusted based on local susceptibility data. To improve TA, scientific knowledge should be translated into easy-to-use dosing strategies guiding antibiotic dosing.
KW  - meropenem
KW  - piperacillin/tazobactam
KW  - antimicrobial stewardship
KW  - critically ill
KW  - antibiotics
KW  - pharmacokinetic/pharmacodynamic
Y1  - 2022
U6  - https://doi.org/10.3390/antibiotics11060758
SN  - 2079-6382
VL  - 11
IS  - 6
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Gopalakrishnan, Sathej
A1  - Montazeri, Hesam
A1  - Menz, Stephan
A1  - Beerenwinkel, Niko
A1  - Huisinga, Wilhelm
T1  - Estimating HIV-1 fitness characteristics from cross-sectional genotype data
JF  - PLoS Computational Biology : a new community journal
N2  - Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success. Assessing in vivo viral fitness is a challenging task and yet one that has significant clinical relevance. Here, we present a new computational modelling approach for estimating viral fitness that relies on common sparse cross-sectional clinical data by combining statistical approaches to learn drug-specific mutational pathways and resistance factors with viral dynamics models to represent the host-virus interaction and actions of drug mechanistically. We estimate in vivo fitness characteristics of mutant genotypes for two antiretroviral drugs, the reverse transcriptase inhibitor zidovudine (ZDV) and the protease inhibitor indinavir (IDV). Well-known features of HIV-1 fitness landscapes are recovered, both in the absence and presence of drugs. We quantify the complex interplay between fitness costs and resistance by computing selective advantages for different mutants. Our approach extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. The combined statistical and dynamical modelling approach may help in dissecting the effects of fitness costs and resistance with the ultimate aim of assisting the choice of salvage therapies after treatment failure.
Y1  - 2014
U6  - https://doi.org/10.1371/journal.pcbi.1003886
SN  - 1553-734X
SN  - 1553-7358
VL  - 10
IS  - 11
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Weiss, Andrea Y.
A1  - Huisinga, Wilhelm
T1  - Error-controlled global sensitivity analysis of ordinary differential equations
JF  - Journal of computational physics
N2  - We propose a novel strategy for global sensitivity analysis of ordinary differential equations. It is based on an error-controlled solution of the partial differential equation (PDE) that describes the evolution of the probability density function associated with the input uncertainty/variability. The density yields a more accurate estimate of the output uncertainty/variability, where not only some observables (such as mean and variance) but also structural properties (e.g., skewness, heavy tails, bi-modality) can be resolved up to a selected accuracy. For the adaptive solution of the PDE Cauchy problem we use the Rothe method with multiplicative error correction, which was originally developed for the solution of parabolic PDEs. We show that, unlike in parabolic problems, conservation properties necessitate a coupling of temporal and spatial accuracy to avoid accumulation of spatial approximation errors over time. We provide convergence conditions for the numerical scheme and suggest an implementation using approximate approximations for spatial discretization to efficiently resolve the coupling of temporal and spatial accuracy. The performance of the method is studied by means of low-dimensional case studies. The favorable properties of the spatial discretization technique suggest that this may be the starting point for an error-controlled sensitivity analysis in higher dimensions.
KW  - ODE with random initial conditions
KW  - Global sensitivity analysis
KW  - Cauchy problem
KW  - Error control/adaptivity
KW  - Rothe method
KW  - Approximate approximations
Y1  - 2011
U6  - https://doi.org/10.1016/j.jcp.2011.05.011
SN  - 0021-9991
VL  - 230
IS  - 17
SP  - 6824
EP  - 6842
PB  - Elsevier
CY  - San Diego
ER  - 
TY  - GEN
A1  - Ehmann, Lisa
A1  - Zoller, Michael
A1  - Minichmayr, Iris K.
A1  - Schmitt, Maximilian V.
A1  - Hartung, Niklas
A1  - Huisinga, Wilhelm
A1  - Zander, Johannes
A1  - Kloft, Charlotte
T1  - Development of a tool to identify intensive care patients at risk of meropenem therapy failure
T2  - International Journal of Clinical Pharmacy
Y1  - 2018
SN  - 2210-7703
SN  - 2210-7711
VL  - 40
IS  - 1
SP  - 317
EP  - 317
PB  - Springer
CY  - Dordrecht
ER  - 
TY  - JOUR
A1  - Ehmann, Lisa
A1  - Zoller, Michael
A1  - Minichmayr, Iris K.
A1  - Scharf, Christina
A1  - Huisinga, Wilhelm
A1  - Zander, Johannes
A1  - Kloft, Charlotte
T1  - Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis
JF  - International journal of antimicrobial agents
N2  - Effective antibiotic dosing is vital for therapeutic success in critically ill patients. This work aimed to develop an algorithm to identify appropriate meropenem dosing in critically ill patients. Population pharma-cokinetic (PK) modelling was performed in NONMEM (R) 7.3 based on densely sampled meropenem serum samples (n(patients) = 48; n(samples) =1376) and included a systematic analysis of 27 pre-selected covariates to identify factors influencing meropenem exposure. Using Monte Carlo simulations newly considering the uncertainty of PK parameter estimates, standard meropenem dosing was evaluated with respect to attainment of the pharmacokinetic/pharmacodynamic (PK/PD) target and was compared with alternative infusion regimens (short-term, prolonged, continuous; daily dose, 2000-6000 mg). Subsequently, a dosing algorithm was developed to identify appropriate dosing regimens. The two-compartment population PK model included three factors influencing meropenem pharmacokinetics: the Cockcroft-Gault creatinine clearance (CLCRCG ) on meropenem clearance; and body weight and albumin on the central and peripheral volume of distribution, respectively; of these, only CLCRCG was identified as a vital influencing factor on PK/PD target attainment. A three-level dosing algorithm was developed (considering PK parameter uncertainty), suggesting dosing regimens depending on renal function and the level (L) of knowledge about the infecting pathogen (L1, pathogen unknown; L2, pathogen known; L3((-MIC)), pathogen and susceptibility known; L3((+MIC)), MIC known). Whereas patients with higher CLCRCG and lower pathogen susceptibility required mainly intensified dosing regimens, lower than standard doses appeared sufficient for highly susceptible pathogens. In conclusion, a versatile meropenem dosing algorithm for critically ill patients is proposed, indicating appropriate dosing regimens based on patient- and pathogen-specific information. (C) 2019 Published by Elsevier B.V.
KW  - beta-Lactams
KW  - Intensive care
KW  - Pharmacokinetics/pharmacodynamics
KW  - Renal function
KW  - Dosing algorithm
Y1  - 2019
U6  - https://doi.org/10.1016/j.ijantimicag.2019.06.016
SN  - 0924-8579
SN  - 1872-7913
VL  - 54
IS  - 3
SP  - 309
EP  - 317
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - GEN
A1  - Krause, Andreas
A1  - Kloft, Charlotte
A1  - Huisinga, Wilhelm
A1  - Karlsson, Mats
A1  - Pinheiro, José
A1  - Bies, Robert
A1  - Rogers, James
A1  - Mentré, France
A1  - Musser, Bret J.
T1  - Comment on Jaki et al., A proposal for a new PhD level curriculum on quantitative methods for drug development
T2  - Pharmaceutical statistics : the journal of applied statistics in the pharmaceutical industry
Y1  - 2019
SN  - 1539-1604
SN  - 1539-1612
VL  - 18
IS  - 3
SP  - 278
EP  - 281
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Maier, Corinna
A1  - Hartung, Niklas
A1  - de Wiljes, Jana
A1  - Kloft, Charlotte
A1  - Huisinga, Wilhelm
T1  - Bayesian Data Assimilation to Support Informed Decision Making in Individualized Chemotherapy
JF  - CPT: Pharmacometrics & Systems Pharmacology
N2  - An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity. Bayesian data assimilation (DA) methods overcome these limitations by providing a comprehensive uncertainty quantification. We compare DA methods with MAP-based approaches and show how probabilistic statements about key markers related to chemotherapy-induced neutropenia can be leveraged for more informative decision support in individualized chemotherapy. Sequential Bayesian DA proved to be most computationally efficient for handling interoccasion variability and integrating TDM data. For new digital monitoring devices enabling more frequent data collection, these features will be of critical importance to improve patient care decisions in various therapeutic areas.
KW  - Induced neutropenia
KW  - Model
KW  - Myelosuppression
KW  - Prediction
Y1  - 2019
U6  - https://doi.org/10.1002/psp4.12492
SN  - 2163-8306
VL  - XX
PB  - Nature Publ. Group
CY  - London
ER  - 
TY  - GEN
A1  - Maier, Corinna
A1  - Hartung, Niklas
A1  - de Wiljes, Jana
A1  - Kloft, Charlotte
A1  - Huisinga, Wilhelm
T1  - Bayesian Data Assimilation to Support Informed Decision Making in Individualized Chemotherapy
T2  - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe
N2  - An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity. Bayesian data assimilation (DA) methods overcome these limitations by providing a comprehensive uncertainty quantification. We compare DA methods with MAP-based approaches and show how probabilistic statements about key markers related to chemotherapy-induced neutropenia can be leveraged for more informative decision support in individualized chemotherapy. Sequential Bayesian DA proved to be most computationally efficient for handling interoccasion variability and integrating TDM data. For new digital monitoring devices enabling more frequent data collection, these features will be of critical importance to improve patient care decisions in various therapeutic areas.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 827 
KW  - Induced neutropenia
KW  - Model
KW  - Myelosuppression
KW  - Prediction
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-445500
SN  - 1866-8372
IS  - 827
ER  - 
TY  - JOUR
A1  - Schindler, Daniel
A1  - Moldenhawer, Ted
A1  - Stange, Maike
A1  - Lepro, Valentino
A1  - Beta, Carsten
A1  - Holschneider, Matthias
A1  - Huisinga, Wilhelm
T1  - Analysis of protrusion dynamics in amoeboid cell motility by means of regularized contour flows
JF  - PLoS Computational Biology : a new community journal
N2  - Amoeboid cell motility is essential for a wide range of biological processes including wound healing, embryonic morphogenesis, and cancer metastasis. It relies on complex dynamical patterns of cell shape changes that pose long-standing challenges to mathematical modeling and raise a need for automated and reproducible approaches to extract quantitative morphological features from image sequences. Here, we introduce a theoretical framework and a computational method for obtaining smooth representations of the spatiotemporal contour dynamics from stacks of segmented microscopy images. Based on a Gaussian process regression we propose a one-parameter family of regularized contour flows that allows us to continuously track reference points (virtual markers) between successive cell contours. We use this approach to define a coordinate system on the moving cell boundary and to represent different local geometric quantities in this frame of reference. In particular, we introduce the local marker dispersion as a measure to identify localized membrane expansions and provide a fully automated way to extract the properties of such expansions, including their area and growth time. The methods are available as an open-source software package called AmoePy, a Python-based toolbox for analyzing amoeboid cell motility (based on time-lapse microscopy data), including a graphical user interface and detailed documentation. Due to the mathematical rigor of our framework, we envision it to be of use for the development of novel cell motility models. We mainly use experimental data of the social amoeba Dictyostelium discoideum to illustrate and validate our approach. <br /> Author summary Amoeboid motion is a crawling-like cell migration that plays an important key role in multiple biological processes such as wound healing and cancer metastasis. This type of cell motility results from expanding and simultaneously contracting parts of the cell membrane. From fluorescence images, we obtain a sequence of points, representing the cell membrane, for each time step. By using regression analysis on these sequences, we derive smooth representations, so-called contours, of the membrane. Since the number of measurements is discrete and often limited, the question is raised of how to link consecutive contours with each other. In this work, we present a novel mathematical framework in which these links are described by regularized flows allowing a certain degree of concentration or stretching of neighboring reference points on the same contour. This stretching rate, the so-called local dispersion, is used to identify expansions and contractions of the cell membrane providing a fully automated way of extracting properties of these cell shape changes. We applied our methods to time-lapse microscopy data of the social amoeba Dictyostelium discoideum.
Y1  - 2021
U6  - https://doi.org/10.1371/journal.pcbi.1009268
SN  - 1553-734X
SN  - 1553-7358
VL  - 17
IS  - 8
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Edlund, Helena
A1  - Grisic, Ana-Marija
A1  - Steenholdt, Casper
A1  - Ainsworth, Mark Andrew
A1  - Brynskov, Torn
A1  - Huisinga, Wilhelm
A1  - Kloft, Charlotte
T1  - Absence of Relationship Between Crohn's Disease Activity Index or C-Reactive Protein and Infliximab Exposure Calls for Objective Crohn's Disease Activity Measures for the Evaluation of Treatment Effects at Treatment Failure
JF  - Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology
N2  - Background: Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure-response relationship by linking the disease activity markers "Crohn's disease activity index" (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics.

Methods: Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure-response relationships. Metrics of exposure included area under the concentration-time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12.

Results: Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other.

Conclusions: No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure.
Y1  - 2019
U6  - https://doi.org/10.1097/FTD.0000000000000590
SN  - 0163-4356
SN  - 1536-3694
VL  - 41
IS  - 2
SP  - 235
EP  - 242
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Maier, Corinna Sabrina
A1  - Wiljes, Jana de
A1  - Hartung, Niklas
A1  - Kloft, Charlotte
A1  - Huisinga, Wilhelm
T1  - A continued learning approach for model-informed precision dosing
BT  - Updating models in clinical practice
JF  - CPT: pharmacometrics & systems pharmacology
N2  - Model-informed precision dosing (MIPD) is a quantitative dosing framework that combines prior knowledge on the drug-disease-patient system with patient data from therapeutic drug/ biomarker monitoring (TDM) to support individualized dosing in ongoing treatment. Structural models and prior parameter distributions used in MIPD approaches typically build on prior clinical trials that involve only a limited number of patients selected according to some exclusion/inclusion criteria. Compared to the prior clinical trial population, the patient population in clinical practice can be expected to also include altered behavior and/or increased interindividual variability, the extent of which, however, is typically unknown. Here, we address the question of how to adapt and refine models on the level of the model parameters to better reflect this real-world diversity. We propose an approach for continued learning across patients during MIPD using a sequential hierarchical Bayesian framework. The approach builds on two stages to separate the update of the individual patient parameters from updating the population parameters. Consequently, it enables continued learning across hospitals or study centers, because only summary patient data (on the level of model parameters) need to be shared, but no individual TDM data. We illustrate this continued learning approach with neutrophil-guided dosing of paclitaxel. The present study constitutes an important step toward building confidence in MIPD and eventually establishing MIPD increasingly in everyday therapeutic use.
Y1  - 2021
U6  - https://doi.org/10.1002/psp4.12745
SN  - 2163-8306
VL  - 11
IS  - 2
SP  - 185
EP  - 198
PB  - London
CY  - Nature Publ. Group
ER  -