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 - 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 - 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 - 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 - 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 - 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.
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 - 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 -
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 - 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.
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.
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.
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 - 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 -