TY - GEN
A1 - Wicha, Sebastian G.
A1 - Kees, Martin G.
A1 - Solms, Alexander Maximilian
A1 - Minichmayr, Iris K.
A1 - Kratzer, Alexander
A1 - Kloft, Charlotte
T1 - TDMx: A novel web-based open-access support tool for optimising antimicrobial dosing regimens in clinical routine
T2 - International journal of antimicrobial agents
Y1 - 2015
U6 - https://doi.org/10.1016/j.ijantimicag.2014.12.010
SN - 0924-8579
SN - 1872-7913
VL - 45
IS - 4
SP - 442
EP - 444
PB - Elsevier
CY - Amsterdam
ER -
TY - JOUR
A1 - Minichmayr, Iris K.
A1 - Roberts, Jason A.
A1 - Frey, Otto R.
A1 - Roehr, Anka C.
A1 - Kloft, Charlotte
A1 - Brinkmann, Alexander
T1 - Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model
JF - Journal of Antimicrobial Chemotherapy
N2 - Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients. Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function. Methods: A population pharmacokinetic model was developed in NONMEM (R) 7.3 based on steady-state meropenem concentrations (C-ss) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRcG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (C-ss >= 8 mg/L) and potentially increased likelihood of adverse drug reactions (C-ss >32 mg/L). Results: In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P-0.05 - P-0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/ 3940 mg were required to reach a target C-ss = 8 mg/L in 90% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5%) was associated with these doses. Conclusions: A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.
Y1 - 2018
U6 - https://doi.org/10.1093/jac/dkx526
SN - 0305-7453
SN - 1460-2091
VL - 73
IS - 5
SP - 1330
EP - 1339
PB - Oxford Univ. Press
CY - Oxford
ER -
TY - JOUR
A1 - Melin, Johanna Stina Elisabet
A1 - Hartung, Niklas
A1 - Parra-Guillen, Zinnia Patricia
A1 - Whitaker, Martin J.
A1 - Ross, Richard J.
A1 - Kloft, Charlotte
T1 - The circadian rhythm of corticosteroid-binding globulin has little impact on cortisol exposure after hydrocortisone dosing
JF - Clinical endocrinology
N2 - Context Optimization of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm. Objective A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure after hydrocortisone administration. Design and Methods CBG was measured over 24 hours in 14 healthy individuals and, employing a modelling and simulation approach using a semi-mechanistic hydrocortisone pharmacokinetic model, we evaluated the impact on cortisol exposure (area under concentration-time curve and maximum concentration of total cortisol) of hydrocortisone administration at different clock times and of the changing CBG concentrations. Results The circadian rhythm of CBG was well described with two cosine terms added to the baseline of CBG: baseline CBG was 21.8 mu g/mL and interindividual variability 11.9%; the amplitude for the 24 and 12 hours cosine functions were relatively small (24 hours: 5.53%, 12 hours: 2.87%) and highest and lowest CBG were measured at 18:00 and 02:00, respectively. In simulations, the lowest cortisol exposure was observed after administration of hydrocortisone at 23:00-02:00, whereas the highest was observed at 15:00-18:00. The differences between the highest and lowest exposure were minor (<= 12.2%), also regarding the free cortisol concentration and free fraction (<= 11.7%). Conclusions Corticosteroid-binding globulin has a circadian rhythm but the difference in cortisol exposure is <= 12.2% between times of highest and lowest CBG concentrations; therefore, hydrocortisone dose adjustment based on time of dosing to adjust for the CBG concentrations is unlikely to be of clinical benefit.
KW - circadian rhythm
KW - hydrocortisone
KW - pharmacokinetics
KW - transcortin
Y1 - 2019
U6 - https://doi.org/10.1111/cen.13969
SN - 0300-0664
SN - 1365-2265
VL - 91
IS - 1
SP - 33
EP - 40
PB - Wiley
CY - Hoboken
ER -
TY - JOUR
A1 - Scharf, Christina
A1 - Weinelt, Ferdinand Anton
A1 - Schroeder, Ines
A1 - Paal, Michael
A1 - Weigand, Michael
A1 - Zoller, Michael
A1 - Irlbeck, Michael
A1 - Kloft, Charlotte
A1 - Briegel, Josef
A1 - Liebchen, Uwe
T1 - Does the cytokine adsorber CytoSorb (R) reduce vancomycin exposure in critically ill patients with sepsis or septic shock?
BT - a prospective observational study
JF - Annals of intensive care
N2 - Background:
Hemadsorption of cytokines is used in critically ill patients with sepsis or septic shock. Concerns have been raised that the cytokine adsorber CytoSorb (R) unintentionally adsorbs vancomycin. This study aimed to quantify vancomycin elimination by CytoSorb (R) .
Methods:
Critically ill patients with sepsis or septic shock receiving continuous renal replacement therapy and CytoSorb (R) treatment during a prospective observational study were included in the analysis. Vancomycin pharmacokinetics was characterized using population pharmacokinetic modeling. Adsorption of vancomycin by the CytoSorb (R) was investigated as linear or saturable process. The final model was used to derive dosing recommendations based on stochastic simulations.
Results:
20 CytoSorb (R) treatments in 7 patients (160 serum samples/24 during CytoSorb (R)-treatment, all continuous infusion) were included in the study. A classical one-compartment model, including effluent flow rate of the continuous hemodialysis as linear covariate on clearance, best described the measured concentrations (without CytoSorb (R)). Significant adsorption with a linear decrease during CytoSorb (R) treatment was identified (p <0.0001) and revealed a maximum increase in vancomycin clearance of 291% (initially after CytoSorb (R) installation) and a maximum adsorption capacity of 572 mg. For a representative patient of our cohort a reduction of the area under the curve (AUC) by 93 mg/L*24 h during CytoSorb (R) treatment was observed. The additional administration of 500 mg vancomycin over 2 h during CytoSorb (R) attenuated the effect and revealed a negligible reduction of the AUC by 4 mg/L*24h.
Conclusion:
We recommend the infusion of 500 mg vancomycin over 2 h during CytoSorb (R) treatment to avoid subtherapeutic concentrations.
KW - Vancomycin
KW - Critically ill patients
KW - CytoSorb (R)
KW - Sepsis;
KW - Pharmacokinetics
KW - Adsorption
Y1 - 2022
U6 - https://doi.org/10.1186/s13613-022-01017-5
SN - 2110-5820
VL - 12
IS - 1
PB - Springer
CY - Heidelberg
ER -
TY - JOUR
A1 - Falkenhagen, Undine
A1 - Knöchel, Jane
A1 - Kloft, Charlotte
A1 - Huisinga, Wilhelm
T1 - Deriving mechanism-based pharmacodynamic models by reducing quantitative systems pharmacology models
BT - an application to warfarin
JF - CPT: Pharmacometrics & Systems Pharmacology
N2 - Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitative knowledge about pharmacologically relevant processes. We previously proposed a first approach to leverage the knowledge in QSP models to derive simpler, mechanism-based pharmacodynamic (PD) models. Their complexity, however, is typically still too large to be used in the population analysis of clinical data. Here, we extend the approach beyond state reduction to also include the simplification of reaction rates, elimination of reactions, and analytic solutions. We additionally ensure that the reduced model maintains a prespecified approximation quality not only for a reference individual but also for a diverse virtual population. We illustrate the extended approach for the warfarin effect on blood coagulation. Using the model-reduction approach, we derive a novel small-scale warfarin/international normalized ratio model and demonstrate its suitability for biomarker identification. Due to the systematic nature of the approach in comparison with empirical model building, the proposed model-reduction algorithm provides an improved rationale to build PD models also from QSP models in other applications.
Y1 - 2023
U6 - https://doi.org/10.1002/psp4.12903
SN - 2163-8306
VL - 12
IS - 4
SP - 432
EP - 443
PB - Wiley
CY - Hoboken
ER -
TY - JOUR
A1 - Stübler, Sabine
A1 - Kloft, Charlotte
A1 - Huisinga, Wilhelm
T1 - Cell-level systems biology model to study inflammatory bowel diseases and their treatment options
JF - CPT: pharmacometrics & systems pharmacology
N2 - To help understand the complex and therapeutically challenging inflammatory bowel diseases (IBDs), we developed a systems biology model of the intestinal immune system that is able to describe main aspects of IBD and different treatment modalities thereof. The model, including key cell types and processes of the mucosal immune response, compiles a large amount of isolated experimental findings from literature into a larger context and allows for simulations of different inflammation scenarios based on the underlying data and assumptions. In the context of a large and diverse virtual IBD population, we characterized the patients based on their phenotype (in contrast to healthy individuals, they developed persistent inflammation after a trigger event) rather than on a priori assumptions on parameter differences to a healthy individual. This allowed to reproduce the enormous diversity of predispositions known to lead to IBD. Analyzing different treatment effects, the model provides insight into characteristics of individual drug therapy. We illustrate for anti-TNF-alpha therapy, how the model can be used (i) to decide for alternative treatments with best prospects in the case of nonresponse, and (ii) to identify promising combination therapies with other available treatment options.
Y1 - 2023
U6 - https://doi.org/10.1002/psp4.12932
SN - 2163-8306
VL - 12
IS - 5
SP - 690
EP - 705
PB - Nature Publ. Group
CY - London
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 - 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 - 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 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - JOUR
A1 - Liebchen, Uwe
A1 - Weinelt, Ferdinand
A1 - Scharf, Christina
A1 - Schröder, Ines
A1 - Paal, Michael
A1 - Zoller, Michael
A1 - Kloft, Charlotte
A1 - Jung, Jette
A1 - Michelet, Robin
T1 - Combination of pharmacokinetic and pathogen susceptibility information to optimize meropenem treatment of Gram-negative infections in critically iII patients
JF - Antimicrobial Agents and Chemotherapy
N2 - Meropenem is one of the most frequently used antibiotics to treat life-threatening infections in critically ill patients.
This study aimed to develop a meropenem dosing algorithm for the treatment of Gram-negative infections based on intensive care unit (ICU)-specific resistance data. Antimicrobial susceptibility testing of Gram-negative bacteria obtained from critically ill patients was carried out from 2016 to 2020 at a tertiary care hospital.
Based on the observed MIC distribution, stochastic simulations (n = 1,000) of an evaluated pharmacokinetic meropenem model, and a defined pharmacokinetic/pharmacodynamic target (100%T->4xMIC while minimum concentrations were <44.5 mg/L), dosing recommendations for patients with varying renal function were derived.
Pathogen-specific MIC distributions were used to calculate the cumulative fraction of response (CFR), and the overall MIC distribution was used to calculate the local pathogen-independent mean fraction of response (LPIFR) for the investigated dosing regimens.
A CFR/LPIFR of >90% was considered adequate. The observed MIC distribution significantly differed from the EUCAST database. Based on the 6,520 MIC values included, a three-level dosing algorithm was developed.
If the pathogen causing the infection is unknown (level 1), known (level 2), known to be neither Pseudomonas aeruginosa nor Acinetobacrer baumannii, or classified as susceptible (level 3), a continuous infusion of 1.5 g daily reached sufficient target attainment independent of renal function.
In all other cases, dosing needs to be adjusted based on renal function. ICU-specific susceptibility data should be assessed regularly and integrated into dosing decisions. The presented workflow may serve as a blueprint for other antimicrobial settings.
KW - meropenem
KW - critically ill
KW - antimicrobial susceptibility testing
KW - Gram negative
KW - dosing algorithm
Y1 - 2022
U6 - https://doi.org/10.1128/aac.01831-21
SN - 0066-4804
SN - 1098-6596
VL - 66
IS - 2
PB - American Society for Microbiology
CY - Washington
ER -