Publications by authors named "Stefan Willmann"

70 Publications

Dosing Regimen Prediction and Confirmation with Rivaroxaban for Thromboprophylaxis in Children after the Fontan Procedure: Insights from the Phase III UNIVERSE Study.

J Clin Pharmacol 2021 Sep 15. Epub 2021 Sep 15.

Janssen Research & Development, LLC, Raritan, NJ, USA.

Thrombosis remains an important complication for children with single ventricle physiology post-Fontan procedure and effective thromboprophylaxis is an important unmet medical need. To obviate conventional dose-finding studies and expedite clinical development, a rivaroxaban dose regimen for this indication was determined utilizing a model-informed drug development approach. A physiologically based pharmacokinetic (PBPK) rivaroxaban model was used to predict a pediatric dosing regimen that would produce drug exposures similar to that of 10 mg once daily in adults. This regimen was used in an open-label, multicenter Phase 3 study, which investigated the use of rivaroxaban for thromboprophylaxis in post-Fontan patients 2 to 8 years of age. The pharmacokinetics (PK) of rivaroxaban was assessed in Part A (n = 12) and in Part B (n = 64) of UNIVERSE. The safety and efficacy in the rivaroxaban group were compared to those in the acetylsalicylic acid group for 12 months. Pharmacodynamic endpoints were assessed in both parts of the study. Rivaroxaban exposures achieved in Part A and B were similar to the adult reference exposures. Prothrombin time also showed similarity to the adult reference. Exposure-response analysis did not identify a quantitative relationship between rivaroxaban exposures and efficacy/safety outcomes within the observed exposure ranges. A body-weight based dose regimen selected by PBPK modeling was shown in the UNIVERSE study to be appropriate for thromboprophylaxis in the post-Fontan pediatric population. Model-based dose selection can support pediatric drug development and bridge adult dose data to pediatrics, thereby obviating the need for dose-finding studies in pediatric programs. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jcph.1966DOI Listing
September 2021

Riociguat for the treatment of Phe508del homozygous adults with cystic fibrosis.

J Cyst Fibros 2021 Aug 19. Epub 2021 Aug 19.

University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Background: Riociguat is a first-in-class soluble guanylate cyclase stimulator for which preclinical data suggested improvements in cystic fibrosis transmembrane conductance regulator (CFTR) function.

Methods: This international, multicenter, two-part, Phase II study of riociguat enrolled adults with cystic fibrosis (CF) homozygous for Phe508del CFTR. Part 1 was a 28-day, randomized, double-blind, placebo-controlled study in participants not receiving CFTR modulator therapy. Twenty-one participants were randomized 1:2 to placebo or oral riociguat (0.5 mg three times daily [tid] for 14 days, increased to 1.0 mg tid for the subsequent 14 days). The primary and secondary efficacy endpoints were change in sweat chloride concentration and percent predicted forced expiratory volume in 1 second (ppFEV), respectively, from baseline to Day 14 and Day 28 with riociguat compared with placebo.

Results: Riociguat did not alter CFTR activity (change in sweat chloride) or lung function (change in ppFEV) at doses up to 1.0 mg tid after 28 days. The most common drug-related adverse event (AE) was headache occurring in three participants (21%); serious AEs occurred in one participant receiving riociguat (7%) and one participant receiving placebo (14%). This safety profile was consistent with the underlying disease and the known safety of riociguat for its approved indications.

Conclusions: The Rio-CF study was terminated due to lack of efficacy and the changing landscape of CF therapeutic development. The current study⁠, within its limits of a small sample size, did not provide evidence that riociguat could be a valid treatment option for CF.

Clinical Trial Registration Number: NCT02170025.
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http://dx.doi.org/10.1016/j.jcf.2021.07.015DOI Listing
August 2021

Population pharmacokinetic analysis of rivaroxaban in children and comparison to prospective physiologically-based pharmacokinetic predictions.

CPT Pharmacometrics Syst Pharmacol 2021 Jul 22. Epub 2021 Jul 22.

Research and Development, Pharmaceuticals, Bayer AG, Wuppertal/Leverkusen, Germany.

Rivaroxaban has been investigated in the EINSTEIN-Jr program for the treatment of acute venous thromboembolism (VTE) in children aged 0 to 18 years and in the UNIVERSE program for thromboprophylaxis in children aged 2 to 8 years with congenital heart disease after Fontan-procedure. Physiologically-based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) modeling were used throughout the pediatric development of rivaroxaban according to the learn-and-confirm paradigm. The development strategy was to match pediatric drug exposures to adult exposure proven to be safe and efficacious. In this analysis, a refined pediatric PopPK model for rivaroxaban based on integrated EINSTEIN-Jr data and interim PK data from part A of the UNIVERSE phase III study was developed and the influence of potential covariates and intrinsic factors on rivaroxaban exposure was assessed. The model adequately described the observed pediatric PK data. PK parameters and exposure metrics estimated by the PopPK model were compared to the predictions from a previously published pediatric PBPK model for rivaroxaban. Ninety-one percent of the individual post hoc clearance estimates were found within the 5th to 95th percentile of the PBPK model predictions. In patients below 2 years of age, however, clearance was underpredicted by the PBPK model. The iterative and integrative use of PBPK and PopPK modeling and simulation played a major role in the establishment of the bodyweight-adjusted rivaroxaban dosing regimen that was ultimately confirmed to be a safe and efficacious dosing regimen for children aged 0 to 18 years with acute VTE in the EINSTEIN-Jr phase III study.
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http://dx.doi.org/10.1002/psp4.12688DOI Listing
July 2021

Clinical investigation of the biopharmaceutical characteristics of nifurtimox tablets - Implications for quality control and application.

Eur J Pharm Sci 2021 Nov 12;166:105940. Epub 2021 Jul 12.

Bayer AG, Research & Development - Pharmaceuticals, Clinical PK CV, Building 0431 - 403, 42096 Wuppertal, Germany.

Nifurtimox is approved in Chagas disease and has been used in endemic countries since the 1960s. Nifurtimox, available as a 120 mg tablet, is administered with food typically three times daily, and dose is adjusted for age and bodyweight. Accurately or reproducibly fragmenting the 120 mg tablet for dose adjustment in young children and those with low bodyweight is problematic. Based on the existing tablet formulation, new nifurtimox 30 mg and 120 mg tablets have been developed in a format that can be divided accurately into 15 mg and 60 mg fragments. In adults with chronic Chagas disease, we investigated whether nifurtimox bioavailability is affected by tablet dissolution rate, and whether different diets affect nifurtimox bioavailability. In an open-label, three-period cross-over study (n=36; ClinicalTrials.gov, NCT03350295), patients randomly received three 30 mg tablet formulations (slow, medium, or fast dissolution; a 4 × 30 mg dose of one formulation per period). In an open-label, four-period cross-over study (n=24; ClinicalTrials.gov, NCT03334838) patients randomly fasted or received one of three meal types (high-fat/high-calorie, low-fat, dairy-based) before ingesting nifurtimox (a 4 × 30 mg dose per period). Acceptance criteria for no difference between groups were 90% confidence intervals (CIs) of exposure ratios in the range 0.8-1.25. Nifurtimox bioavailability was unaffected by tablet dissolution kinetics. Ratios of area under the curve at final assessment (AUC [90% CI]) were: fast/medium dissolution, 1.061 (0.990-1.137); slow/medium dissolution, 0.964 (0.900-1.033); fast/slow dissolution, 1.100 (1.027-1.179). Compared with a fasting state, nifurtimox bioavailability increased by 73% after a high-fat/high-calorie meal (AUC ratio [90% CI], 1.732 [1.581-1.898]); smaller increases were seen with the other meal types (low-fat: 1.602 [1.462-1.755]; dairy-based: 1.340 [1.222-1.468]). Although type of diet can affect bioavailability, taking nifurtimox with food is most important.
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http://dx.doi.org/10.1016/j.ejps.2021.105940DOI Listing
November 2021

Predictive Performance of Physiology-Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small-Molecule Compounds in Children.

J Clin Pharmacol 2021 Jun;61 Suppl 1:S70-S82

Pharmacometrics/Modeling and Simulation, Research and Development, Pharmaceuticals, Bayer, AG, Germany.

Development and guidance of dosing schemes in children have been supported by physiology-based pharmacokinetic (PBPK) modeling for many years. PBPK models are built on a generic basis, where compound- and system-specific parameters are separated and can be exchanged, allowing the translation of these models from adults to children by accounting for physiological differences. Owing to these features, PBPK modeling is a valuable approach to support clinical decision making for dosing in children. In this analysis, we evaluate pediatric PBPK models for 10 small-molecule compounds that were applied to support clinical decision processes at Bayer for their predictive power in different age groups. Ratios of PBPK-predicted to observed PK parameters for the evaluated drugs in different pediatric age groups were estimated. Predictive performance was analyzed on the basis of a 2-fold error range and the bioequivalence range (ie, 0.8 ≤ predicted/observed ≤ 1.25). For all 10 compounds, all predicted-to-observed PK ratios were within a 2-fold error range (n = 27), with two-thirds of the ratios within the bioequivalence range (n = 18). The findings demonstrate that the pharmacokinetics of these compounds was successfully and adequately predicted in different pediatric age groups. This illustrates the applicability of PBPK for guiding dosing schemes in the pediatric population.
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http://dx.doi.org/10.1002/jcph.1869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361729PMC
June 2021

PK/PD modeling of FXI antisense oligonucleotides to bridge the dose-FXI activity relation from healthy volunteers to end-stage renal disease patients.

CPT Pharmacometrics Syst Pharmacol 2021 Aug 23;10(8):890-901. Epub 2021 Jun 23.

Ionis Pharmaceuticals, Inc, Carlsbad, California, USA.

IONIS-FXI (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI (FXI) and has been investigated in healthy volunteers and patients with end-stage renal disease (ESRD). FXI-LICA (BAY2976217) shares the same RNA sequence as IONIS-FXI but contains a GalNAc-conjugation that facilitates asialoglycoprotein receptor (ASGPR)-mediated uptake into hepatocytes. FXI-LICA has been studied in healthy volunteers and is currently investigated in patients with ESRD on hemodialysis. We present a model-informed bridging approach that facilitates the extrapolation of the dose-exposure-FXI relationship from IONIS-FXI to FXI-LICA in patients with ESRD and, thus, supports the selection of FX-LICA doses being investigated in patients with ESRD. A two-compartment pharmacokinetic (PK) model, with mixed first- and zero-order subcutaneous absorption and first-order elimination, was combined with an indirect response model for the inhibitory effect on the FXI synthesis rate via an effect compartment. This PK/pharmacodynamic model adequately described the median trends, as well as the interindividual variabilities for plasma drug concentration and FXI activity in healthy volunteers of IONIS-FXI and FXI-LICA, and in patients with ESRD of IONIS-FXI . The model was then used to predict dose-dependent steady-state FXI activity following repeat once-monthly doses of FXI-LICA in a virtual ESRD patient population. Under the assumption of similar ASGPR expression in patients with ESRD and healthy volunteers, doses of 40 mg, 80 mg, and 120 mg FXI-LICA are expected to cover the target range of clinical interest for steady-state FXI activity in the phase IIb study of FXI-LICA in patients with ESRD undergoing hemodialysis.
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http://dx.doi.org/10.1002/psp4.12663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376138PMC
August 2021

Comparing Predictions of a PBPK Model for Cyclosporine With Drug Levels From Therapeutic Drug Monitoring.

Front Pharmacol 2021 14;12:630904. Epub 2021 May 14.

Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany.

This study compared simulations of a physiologically based pharmacokinetic (PBPK) model implemented for cyclosporine with drug levels from therapeutic drug monitoring to evaluate the predictive performance of a PBPK model in a clinical population. Based on a literature search model parameters were determined. After calibrating the model using the pharmacokinetic profiles of healthy volunteers, 356 cyclosporine trough levels of 32 renal transplant outpatients were predicted based on their biometric parameters. Model performance was assessed by calculating absolute and relative deviations of predicted and observed trough levels. The median absolute deviation was 6 ng/ml (interquartile range: 30 to 31 ng/ml, minimum = -379 ng/ml, maximum = 139 ng/ml). 86% of predicted cyclosporine trough levels deviated less than twofold from observed values. The high intra-individual variability of observed cyclosporine levels was not fully covered by the PBPK model. Perspectively, consideration of clinical and additional patient-related factors may improve the model's performance. In summary, the current study has shown that PBPK modeling may offer valuable contributions for pharmacokinetic research in clinical drug therapy.
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http://dx.doi.org/10.3389/fphar.2021.630904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161189PMC
May 2021

Applications of Physiologically Based Pharmacokinetic Modeling of Rivaroxaban-Renal and Hepatic Impairment and Drug-Drug Interaction Potential.

J Clin Pharmacol 2021 05 6;61(5):656-665. Epub 2021 Jan 6.

Clinical Pharmacokinetics Cardiovascular, Bayer AG, Wuppertal, Germany.

The non-vitamin K antagonist oral anticoagulant rivaroxaban is used in several thromboembolic disorders. Rivaroxaban is eliminated via both metabolic degradation and renal elimination as unchanged drug. Therefore, renal and hepatic impairment may reduce rivaroxaban clearance, and medications inhibiting these clearance pathways could lead to drug-drug interactions. This physiologically based pharmacokinetic (PBPK) study investigated the pharmacokinetic behavior of rivaroxaban in clinical situations where drug clearance is impaired. A PBPK model was developed using mass balance and bioavailability data from adults and qualified using clinically observed data. Renal and hepatic impairment were simulated by adjusting disease-specific parameters, and concomitant drug use was simulated by varying enzyme activity in virtual populations (n = 1000) and compared with pharmacokinetic predictions in virtual healthy populations and clinical observations. Rivaroxaban doses of 10 mg or 20 mg were used. Mild to moderate renal impairment had a minor effect on area under the concentration-time curve and maximum plasma concentration of rivaroxaban, whereas severe renal impairment caused a more pronounced increase in these parameters vs normal renal function. Area under the concentration-time curve and maximum plasma concentration increased with severity of hepatic impairment. These effects were smaller in the simulations compared with clinical observations. AUC and C increased with the strength of cytochrome P450 3A4 and P-glycoprotein inhibitors in simulations and clinical observations. This PBPK model can be useful for estimating the effects of impaired drug clearance on rivaroxaban pharmacokinetics. Identifying other factors that affect the pharmacokinetics of rivaroxaban could facilitate the development of models that approximate real-world pharmacokinetics more accurately.
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http://dx.doi.org/10.1002/jcph.1784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048900PMC
May 2021

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in patients with non-valvular atrial fibrillation.

J Thromb Thrombolysis 2020 Jul;50(1):20-29

Janssen Research & Development, LLC, Raritan, NJ, USA.

Rivaroxaban exposure and patient characteristics may affect the rivaroxaban benefit-risk balance. This study aimed to quantify associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in patients with non-valvular atrial fibrillation (NVAF), using data from the phase 3 ROCKET AF trial (NCT00403767). In ROCKET AF, 14,264 patients with NVAF were randomized to rivaroxaban (20 mg once daily [OD], or 15 mg OD if creatinine clearance was 30-49 mL/min) or dose-adjusted warfarin (median follow-up: 707 days); rivaroxaban plasma concentration was measured in a subset of 161 patients. In this post hoc exposure-response analysis, a multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event efficacy and safety outcomes in 7061 and 7111 patients, respectively. There was no significant association between model-predicted rivaroxaban trough plasma concentration (C) and efficacy outcomes. Creatinine clearance and history of stroke were significantly associated with efficacy outcomes. C was significantly associated with the composite of major or non-major clinically relevant (NMCR) bleeding (hazard ratio [95th percentile vs. median]: 1.26 [95% confidence interval 1.13-1.40]) but not with major bleeding alone. The exposure-response relationship for major or NMCR bleeding was shallow with no clear threshold for an acceleration in risk. History of gastrointestinal bleeding had a greater influence on safety outcomes than C. These results support fixed rivaroxaban 15 mg and 20 mg OD dosages in NVAF. Therapeutic drug monitoring is unlikely to offer clinical benefits in this indication beyond evaluation of patient characteristics.
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http://dx.doi.org/10.1007/s11239-020-02077-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293978PMC
July 2020

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism.

J Thromb Thrombolysis 2020 Jul;50(1):1-11

Bayer U.S., LLC, Research & Development, Pharmaceuticals, 100 Bayer Boulevard, Whippany, NJ, 07981, USA.

Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN-DVT and EINSTEIN-PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure-response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure-efficacy relationships were shallow. Exposure-safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.
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http://dx.doi.org/10.1007/s11239-020-02073-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293979PMC
July 2020

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the prevention of venous thromboembolism.

J Thromb Thrombolysis 2020 Jul;50(1):12-19

Bayer U.S., LLC, Research & Development, Pharmaceuticals, 100 Bayer Boulevard, Whippany, NJ, 07981, USA.

Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. The study objective was to assess the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism (VTE) prophylaxis (VTE-P) after hip/knee replacement surgery. Post hoc exposure-response analyses were conducted using data from the phase 3 RECORD1-4 studies, in which 12,729 patients were randomized to rivaroxaban 10 mg once daily or enoxaparin for ≤ 39 days. Multivariate regression approaches were used to correlate model-predicted individual rivaroxaban exposures and patient characteristics with outcomes. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and by making use of the known correlation between rivaroxaban plasma concentration and dynamics of PT. No significant associations between rivaroxaban exposure and total VTE or major bleeding were identified. A significant association between exposure and a composite of major or non-major clinically relevant (NMCR) bleeding from day 4 after surgery was observed. The relationship was shallow, with an approximate predicted absolute increase in a composite of major or NMCR bleeding from 1.08 [95% confidence interval (CI) 0.76-1.54] to 2.18% (95% CI 1.51-3.17) at the 5th and 95th percentiles of trough plasma concentration, respectively. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Hence, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-P.
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http://dx.doi.org/10.1007/s11239-020-02078-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293976PMC
July 2020

Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation.

J Thromb Haemost 2020 07 4;18(7):1672-1685. Epub 2020 Jun 4.

Bayer AG, Wuppertal, Germany.

Background: Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling.

Methods: Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to <30, and <12 kg, respectively. Previously, these regimens were confirmed for children weighing ≥20 kg but only predicted in those <20 kg. Based on sparse blood sampling, the daily area under the plasma concentration-time curve [AUC ] and trough [C ] and maximum [C ] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, repeat imaging outcomes, and bleeding or adverse events. A taste-and-texture questionnaire was collected for suspension-recipients.

Results: Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable.

Discussion: Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.
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http://dx.doi.org/10.1111/jth.14813DOI Listing
July 2020

Predictive Pediatric Modeling and Simulation Using Ontogeny Information.

J Clin Pharmacol 2019 09;59 Suppl 1:S95-S103

Clinical Pharmacometrics, Research & Development, Pharmaceuticals, Bayer AG, Germany.

Food and Drug Administration submissions of physiologically based pharmacokinetic (PBPK) modeling and simulation of small-molecule drugs document the relevance of pediatric drug development and, in particular, information on dosing strategies in children. The most relevant prerequisite for reliable PBPK-based translation of adult pharmacokinetics of a small molecule to children is knowledge of the drug-specific absorption, distribution, metabolism, and elimination (ADME) processes in adults together with existing information about ontogeny of ADME processes relevant for the drug. All mechanisms driving a drug's clearance are of specific importance. For other drug modalities, our knowledge of ADME processes and ontogeny is still limited. More research is required, for example, to understand why some therapeutic proteins show complex differences in pharmacokinetics between adults and children, whereas other proteins seem to follow simple allometric scaling rules. Ontogeny information originates from various sources, such as (semi)quantitative mRNA expression, in vitro activity data, and deconvolution of in vivo pharmacokinetic data. The workflow for pediatric predictions is well described in several articles documenting successful translation from adults to children. The technical hurdles for PBPK modeling are low. State-of-the-art PBPK modeling software tools provide integrated pediatric translation workflows. For example, PK-Sim and MoBi are freely available as fully transparent open-source software via Open Systems Pharmacology (OSP). With the latest 2019 software release, version 8.0, OSP even provides a fully integrated technical framework for the qualification (and requalification) of any specific intended PBPK use in line with Food and Drug Administration and European Medicines Agency PBPK guidance. Qualification packages for pediatric translation are available on the OSP platform.
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http://dx.doi.org/10.1002/jcph.1497DOI Listing
September 2019

Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies.

Lancet Haematol 2019 Oct 13;6(10):e500-e509. Epub 2019 Aug 13.

Bayer AG, Wuppertal, Germany.

Background: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents.

Methods: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843.

Findings: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events.

Interpretation: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism.

Funding: Bayer AG, Janssen Research and Development.
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http://dx.doi.org/10.1016/S2352-3026(19)30161-9DOI Listing
October 2019

Influence of model-predicted rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome.

Ther Adv Cardiovasc Dis 2019 Jan-Dec;13:1753944719863641

Janssen Research & Development, LLC, Raritan, NJ, USA.

Background: This analysis aimed to evaluate the impact of rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome (ACS) and to determine whether therapeutic drug monitoring might provide additional information regarding rivaroxaban dose, beyond what patient characteristics provide.

Methods: A exposure-response analysis was conducted using data from the phase III ATLAS ACS 2 Thrombolysis in Myocardial Infarction (TIMI) 51 study, in which 15,526 randomized ACS patients received rivaroxaban (2.5 mg or 5 mg twice daily) or placebo for a mean of 13 months (maximum follow up: 31 months). A multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event clinical outcomes.

Results: For the incidence of myocardial infarction (MI), ischemic stroke, or nonhemorrhagic cardiovascular death, hazard ratios (HRs) for steady-state maximum plasma concentration (C) in the 5th and 95th percentiles the median were statistically significant but close to 1 for both rivaroxaban doses. For TIMI major bleeding events, a statistically significant association was observed with C [HR, 1.08; 95% CI, 1.06-1.11 (95th percentile median, 2.5 mg twice daily)], sex [HR, 0.56; 95% CI, 0.38-0.84 (female male)], and previous revascularization [HR, 0.62; 95% CI, 0.44-0.87 (no yes)].

Conclusions: The shallow slopes of the exposure-response relationships and the lack of a clear therapeutic window render it unlikely that therapeutic drug monitoring in patients with ACS would provide additional information regarding rivaroxaban dose beyond that provided by patient characteristics.
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http://dx.doi.org/10.1177/1753944719863641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669848PMC
August 2019

Application of Physiologically-Based and Population Pharmacokinetic Modeling for Dose Finding and Confirmation During the Pediatric Development of Moxifloxacin.

CPT Pharmacometrics Syst Pharmacol 2019 09 7;8(9):654-663. Epub 2019 Aug 7.

Clinical Pharmacology, Research & Development, Pharmaceuticals Bayer AG, Wuppertal, Germany.

Moxifloxacin is a widely used fluoroquinolone for the treatment of complicated intra-abdominal infections. We applied physiologically-based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) modeling to support dose selection in pediatric patients. We scaled an existing adult PBPK model to children based on prior physiological knowledge. The resulting model proposed an age-dependent dosing regimen that was tested in a phase I study. Refined doses were then tested in a phase III study. A popPK analysis of all clinical pediatric data confirmed the PBPK predictions, including the proposed dosing schedule in children, and supported pharmacokinetics-related safety/efficacy questions. The pediatric PBPK model adequately predicted the doses necessary to achieve antimicrobial efficacy while maintaining safety in the phase I and III pediatric studies. Altogether, this study retroactively demonstrated the robustness and utility of modeling to support dose finding and confirmation in pediatric drug development for moxifloxacin.
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http://dx.doi.org/10.1002/psp4.12446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765696PMC
September 2019

Enhancing the Quality of Rivaroxaban Exposure Estimates Using Prothrombin Time in the Absence of Pharmacokinetic Sampling.

CPT Pharmacometrics Syst Pharmacol 2019 11 5;8(11):805-814. Epub 2019 Jul 5.

Clinical Pharmacometrics, Bayer AG, Wuppertal, Germany.

Prothrombin time (PT) is a measure of coagulation status and was assessed in the majority of patients in the rivaroxaban phase II and III clinical trials as a pharmacodynamic marker. In the absence of sufficient phase III pharmacokinetic (PK) data to provide individual exposure measures for input into rivaroxaban exposure-response analyses, the aim of the present study was to investigate the use of PT-adjustment approaches (i.e., the use of observed individual PT measurements) to enhance the prediction of individual rivaroxaban exposure metrics (derived using a previously developed integrated population PK model) based on the observed linear relationship between PT and rivaroxaban plasma concentrations. The PT-adjustment approaches were established using time-matched PK and PT measurements, which were available from 1,779 patients across four phase II trials and one phase III trial of rivaroxaban. PT-adjusted exposure estimates improved the identification of statistically significant effects when compared with covariate-only exposure estimates.
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http://dx.doi.org/10.1002/psp4.12444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875705PMC
November 2019

Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous Moxifloxacin in Pediatric Patients: Dose Optimization in a Phase 1 Study.

J Clin Pharmacol 2019 05 25;59(5):654-667. Epub 2019 Jan 25.

University of California, San Diego School of Medicine and Rady Children's Hospital San Diego, San Diego, CA, USA.

The pharmacokinetics, safety, and tolerability of a single dose of moxifloxacin were characterized in 31 pediatric patients already receiving antibiotics for a suspected or proven infection in an open-label phase 1 study. A dosing strategy for each age cohort (Cohort 1: ≥6 years to ≤14 years; Cohort 2: ≥2 years to <6 years; Cohort 3: >3 month to <2 years) was developed using physiology-based pharmacokinetic modeling combined with a stepwise dosing scheme to obtain a similar exposure to adults receiving 400 mg of moxifloxacin. Doses, adjusted to body weight and age, were gradually escalated from 5 mg/kg in Cohort 1 to 10 mg/kg in Cohort 3 based on interim analysis of the pharmacokinetic and safety data. Plasma and urine samples before and after the 60-minute infusion were collected for the analysis of moxifloxacin and its metabolites using a validated high-pressure liquid chromatography assay with tandem mass spectrometry. Moxifloxacin and metabolite concentrations in plasma were within the ranges observed in adults; however, clearance of all analytes was lower in pediatric patients compared with adults. Population pharmacokinetic analyses using the achieved exposure levels in the 3 age cohorts (with known body weight and clearance) predicted similar efficacy and safety profiles to adults. Moxifloxacin was well tolerated in all pediatric age cohorts. Adverse events related to moxifloxacin were mild or moderate in intensity and showed no correlation with increased weight-adjusted doses. Our findings guided the selection of age-appropriate clinical doses for a subsequent phase 3 clinical trial in pediatric patients with complicated intra-abdominal infections.
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http://dx.doi.org/10.1002/jcph.1358DOI Listing
May 2019

Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study.

Thromb J 2018 4;16:32. Epub 2018 Dec 4.

3Clinical Pharmacometrics, Bayer AG, Leverkusen, Germany.

Background: The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed.

Methods: We quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration-time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5-18 years who had completed treatment for VTE.

Results: PK data from 59 children were obtained. The observed plasma concentration-time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions.

Conclusions: These results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5-18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies.

Trial Registration: ClinicalTrials.gov number, NCT01145859; registration date: 17 June 2010.
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http://dx.doi.org/10.1186/s12959-018-0185-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278136PMC
December 2018

Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study.

Thromb J 2018 4;16:31. Epub 2018 Dec 4.

11Clinical Development, Bayer AG, Pharmaceuticals, Wuppertal, Germany.

Background: The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.

Methods: This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5-18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5-2 years, 2-6 years, 6-12 years and 12-18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.

Results: Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.

Conclusions: Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.

Trial Registration: ClinicalTrials.gov number, NCT01145859.
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http://dx.doi.org/10.1186/s12959-018-0186-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278122PMC
December 2018

A Physiologically-Based Pharmacokinetic Model to Describe Ciprofloxacin Pharmacokinetics Over the Entire Span of Life.

Clin Pharmacokinet 2018 12;57(12):1613-1634

Clinical Pharmacology, Bayer AG, Wuppertal, Germany.

Background: Physiologically-based pharmacokinetic (PBPK) modeling has received growing interest as a useful tool for the assessment of drug pharmacokinetics by continuous knowledge integration.

Objective: The objective of this study was to build a ciprofloxacin PBPK model for intravenous and oral dosing based on a comprehensive literature review, and evaluate the predictive performance towards pediatric and geriatric patients.

Methods: The aim of this report was to establish confidence in simulations of the ciprofloxacin PBPK model along the development process to facilitate reliable predictions outside of the tested adult age range towards the extremes of ages. Therefore, mean data of 69 published clinical trials were identified and integrated into the model building, simulation and verification process. The predictive performance on both ends of the age scale was assessed using individual data of 258 subjects observed in own clinical trials.

Results: Ciprofloxacin model verification demonstrated no concentration-related bias and accurate simulations for the adult age range, with only 4.8% of the mean observed data points for intravenous administration and 12.1% for oral administration being outside the simulated twofold range. Predictions towards the extremes of ages for the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (C) over the entire span of life revealed a reliable estimation, with only two pediatric AUC observations outside the 90% prediction interval.

Conclusion: Overall, this ciprofloxacin PBPK modeling approach demonstrated the predictive power of a thoroughly informed middle-out approach towards age groups of interest to potentially support the decision-making process.
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http://dx.doi.org/10.1007/s40262-018-0661-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267540PMC
December 2018

Integrated Population Pharmacokinetic Analysis of Rivaroxaban Across Multiple Patient Populations.

CPT Pharmacometrics Syst Pharmacol 2018 05 16;7(5):309-320. Epub 2018 Apr 16.

Clinical Pharmacometrics, Bayer AG, Wuppertal, Germany.

The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population-specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one-compartment disposition model with a first-order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest.
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http://dx.doi.org/10.1002/psp4.12288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980303PMC
May 2018

Moxifloxacin in Pediatric Patients With Complicated Intra-abdominal Infections: Results of the MOXIPEDIA Randomized Controlled Study.

Pediatr Infect Dis J 2018 08;37(8):e207-e213

Bayer AG, Berlin, Germany.

Background: This study was designed to evaluate primarily the safety and also the efficacy of moxifloxacin (MXF) in children with complicated intra-abdominal infections (cIAIs).

Methods: In this multicenter, randomized, double-blind, controlled study, 451 pediatric patients aged 3 months to 17 years with cIAIs were treated with intravenous/oral MXF (N = 301) or comparator (COMP, intravenous ertapenem followed by oral amoxicillin/clavulanate; N = 150) for 5 to 14 days. Doses of MXF were selected based on the results of a Phase 1 study in pediatric patients (NCT01049022). The primary endpoint was safety, with particular focus on cardiac and musculoskeletal safety; clinical and bacteriologic efficacy at test of cure was also investigated.

Results: The proportion of patients with adverse events (AEs) was comparable between the 2 treatment arms (MXF: 58.1% and COMP: 54.7%). The incidence of drug-related AEs was higher in the MXF arm than in the COMP arm (14.3% and 6.7%, respectively). No cases of QTc interval prolongation-related morbidity or mortality were observed. The proportion of patients with musculoskeletal AEs was comparable between treatment arms; no drug-related events were reported. Clinical cure rates were 84.6% and 95.5% in the MXF and COMP arms, respectively, in patients with confirmed pathogen(s) at baseline.

Conclusions: MXF treatment was well tolerated in children with cIAIs. However, a lower clinical cure rate was observed with MXF treatment compared with COMP. This study does not support a recommendation of MXF for children with cIAIs when alternative more efficacious antibiotics with better safety profile are available.
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http://dx.doi.org/10.1097/INF.0000000000001910DOI Listing
August 2018

A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim.

J Pharmacokinet Pharmacodyn 2018 04 12;45(2):235-257. Epub 2017 Dec 12.

Clinical Pharmacometrics, Bayer AG Pharmaceuticals, 42113, Wuppertal, Germany.

Proteins are an increasingly important class of drugs used as therapeutic as well as diagnostic agents. A generic physiologically based pharmacokinetic (PBPK) model was developed in order to represent at whole body level the fundamental mechanisms driving the distribution and clearance of large molecules like therapeutic proteins. The model was built as an extension of the PK-Sim model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc receptor (FcRn) mediated recycling as especially relevant for antibodies. For model development and evaluation, PK data was used for compounds with a wide range of solute radii. The model supports the integration of knowledge gained during all development phases of therapeutic proteins, enables translation from pre-clinical species to human and allows predictions of tissue concentration profiles which are of relevance for the analysis of on-target pharmacodynamic effects as well as off-target toxicity. The current implementation of the model replaces the generic protein PBPK model available in PK-Sim since version 4.2 and becomes part of the Open Systems Pharmacology Suite.
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http://dx.doi.org/10.1007/s10928-017-9559-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845054PMC
April 2018

Gestation-Specific Changes in the Anatomy and Physiology of Healthy Pregnant Women: An Extended Repository of Model Parameters for Physiologically Based Pharmacokinetic Modeling in Pregnancy.

Clin Pharmacokinet 2017 11;56(11):1303-1330

Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, Westfälische Wilhelm-University Münster, Münster, Germany.

Background: In the past years, several repositories for anatomical and physiological parameters required for physiologically based pharmacokinetic modeling in pregnant women have been published. While providing a good basis, some important aspects can be further detailed. For example, they did not account for the variability associated with parameters or were lacking key parameters necessary for developing more detailed mechanistic pregnancy physiologically based pharmacokinetic models, such as the composition of pregnancy-specific tissues.

Objectives: The aim of this meta-analysis was to provide an updated and extended database of anatomical and physiological parameters in healthy pregnant women that also accounts for changes in the variability of a parameter throughout gestation and for the composition of pregnancy-specific tissues.

Methods: A systematic literature search was carried out to collect study data on pregnancy-related changes of anatomical and physiological parameters. For each parameter, a set of mathematical functions was fitted to the data and to the standard deviation observed among the data. The best performing functions were selected based on numerical and visual diagnostics as well as based on physiological plausibility.

Results: The literature search yielded 473 studies, 302 of which met the criteria to be further analyzed and compiled in a database. In total, the database encompassed 7729 data. Although the availability of quantitative data for some parameters remained limited, mathematical functions could be generated for many important parameters. Gaps were filled based on qualitative knowledge and based on physiologically plausible assumptions.

Conclusion: The presented results facilitate the integration of pregnancy-dependent changes in anatomy and physiology into mechanistic population physiologically based pharmacokinetic models. Such models can ultimately provide a valuable tool to investigate the pharmacokinetics during pregnancy in silico and support informed decision making regarding optimal dosing regimens in this vulnerable special population.
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http://dx.doi.org/10.1007/s40262-017-0539-zDOI Listing
November 2017

Physiologically Based Pharmacokinetic Modeling of Renally Cleared Drugs in Pregnant Women.

Clin Pharmacokinet 2017 12;56(12):1525-1541

Department of Pharmaceutical and Medical Chemistry-Clinical Pharmacy, Westfälische Wilhelm-University Münster, 48149, Münster, Germany.

Background: Since pregnant women are considerably underrepresented in clinical trials, information on optimal dosing in pregnancy is widely lacking. Physiologically based pharmacokinetic (PBPK) modeling may provide a method for predicting pharmacokinetic changes in pregnancy to guide subsequent in vivo pharmacokinetic trials in pregnant women, minimizing associated risks.

Objectives: The goal of this study was to build and verify a population PBPK model that predicts the maternal pharmacokinetics of three predominantly renally cleared drugs (namely cefazolin, cefuroxime, and cefradine) at different stages of pregnancy. It was further evaluated whether the fraction unbound (f ) could be estimated in pregnant women using a proposed scaling approach.

Methods: Based on a recent literature review on anatomical and physiological changes during pregnancy, a pregnancy population PBPK model was built using the software PK-Sim/MoBi. This model comprised 27 compartments, including nine pregnancy-specific compartments. The PBPK model was verified by comparing the predicted maternal pharmacokinetics of cefazolin, cefuroxime, and cefradine with observed in vivo data taken from the literature. The proposed scaling approach for estimating the f in pregnancy was evaluated by comparing the predicted f with experimentally observed f values of 32 drugs taken from the literature.

Results: The pregnancy population PBPK model successfully predicted the pharmacokinetics of cefazolin, cefuroxime, and cefradine at all tested stages of pregnancy. All predicted plasma concentrations fell within a 2-fold error range and 85% of the predicted concentrations within a 1.25-fold error range. The f in pregnancy could be adequately predicted using the proposed scaling approach, although a slight underestimation was evident in case of drugs bound to α-acidic glycoprotein.

Conclusion: Pregnancy population PBPK models can provide a valuable tool to predict a priori the pharmacokinetics of predominantly renally cleared drugs in pregnant women. These models can ultimately support informed decision making regarding optimal dosing regimens in this vulnerable special population.
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http://dx.doi.org/10.1007/s40262-017-0538-0DOI Listing
December 2017

Addressing Adherence Using Genotype-Specific PBPK Modeling-Impact of Drug Holidays on Tamoxifen and Endoxifen Plasma Levels.

Front Pharmacol 2017 14;8:67. Epub 2017 Mar 14.

Computational Systems Biology, Bayer AG Leverkusen, Germany.

Tamoxifen is one of the most common treatment opportunities for hormonal positive breast cancer. Despite its good tolerability, patients demonstrate decreasing adherence over years impacting on therapeutic success. PBPK modeling was applied to demonstrate the impact of drug holidays on plasma levels of tamoxifen and its active metabolite endoxifen for different CYP2D6 genotypes. A virtual study with 24,000 patients was conducted in order to investigate the development of tamoxifen steady-state kinetics in patient groups of different CYP2D6 genotypes. The impact of drug holidays on steady-state kinetics was investigated assuming changing drug holiday scenarios. Drug holidays in CYP2D6 extensive and intermediate metabolizers (EMs, IMs) exceeding 1 month lead to a decrease of endoxifen steady-state trough levels below the 5th percentile of the control group. Assuming drug holidays of 1, 2, or 3 months and administering a fixed-dose combination of 20 mg tamoxifen and 3 mg endoxifen EMs demonstrated re-established endoxifen steady-state trough levels after 5, 8, and 9 days. IMs receiving the same fixed-dose combination demonstrated re-established endoxifen steady-state trough levels after 7, 10, and 11 days. The PBPK model impressively demonstrates the impact of drug holidays in different CYP2D6 genotypes on PK. Population simulation results indicate that drug holidays of more than 2 weeks cause a tremendous decrease of plasma levels despite the long half-life of tamoxifen. To improve therapeutic success, PBPK modeling allows identifying genotype-specific differences in PK following drug holidays and adequate treatment with loading doses.
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http://dx.doi.org/10.3389/fphar.2017.00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361661PMC
March 2017

Development of a Whole-Body Physiologically Based Pharmacokinetic Approach to Assess the Pharmacokinetics of Drugs in Elderly Individuals.

Clin Pharmacokinet 2016 12;55(12):1573-1589

Institute of Pharmacy, Clinical Pharmacy, University of Bonn, 53121, Bonn, Germany.

Background: Because of the vulnerability and frailty of elderly adults, clinical drug development has traditionally been biased towards young and middle-aged adults. Recent efforts have begun to incorporate data from paediatric investigations. Nevertheless, the elderly often remain underrepresented in clinical trials, even though persons aged 65 years and older receive the majority of drug prescriptions. Consequently, a knowledge gap exists with regard to pharmacokinetic (PK) and pharmacodynamic (PD) responses in elderly subjects, leaving the safety and efficacy of medicines for this population unclear.

Objectives: The goal of this study was to extend a physiologically based pharmacokinetic (PBPK) model for adults to encompass the full course of healthy aging through to the age of 100 years, to support dose selection and improve pharmacotherapy for the elderly age group.

Methods: For parameterization of the PBPK model for healthy aging individuals, the literature was scanned for anthropometric and physiological data, which were consolidated and incorporated into the PBPK software PK-Sim. Age-related changes that occur from 65 to 100 years of age were the main focus of this work. For a sound and continuous description of an aging human, data on anatomical and physiological changes ranging from early adulthood to old age were included. The capability of the PBPK approach to predict distribution and elimination of drugs was verified using the test compounds morphine and furosemide, administered intravenously. Both are cleared by a single elimination pathway. PK parameters for the two compounds in younger adults and elderly individuals were obtained from the literature. Matching virtual populations-with regard to age, sex, anthropometric measures and dosage-were generated. Profiles of plasma drug concentrations over time, volume of distribution at steady state (V ) values and elimination half-life (t ) values from the literature were compared with those predicted by PBPK simulations for both younger adults and the elderly.

Results: For most organs, the age-dependent information gathered in the extensive literature analysis was dense. In contrast, with respect to blood flow, the literature study produced only sparse data for several tissues, and in these cases, linear regression was required to capture the entire elderly age range. On the basis of age-informed physiology, the predicted PK profiles described age-associated trends well. The root mean squared prediction error for the prediction of plasma concentrations of furosemide and morphine in the elderly were improved by 32 and 49 %, respectively, by use of age-informed physiology. The majority of the individual V and t values for the two model compounds, furosemide and morphine, were well predicted in the elderly population, except for long furosemide half-lifes.

Conclusion: The results of this study support the feasibility of using a knowledge-driven PBPK aging model that includes the elderly to predict PK alterations throughout the entire course of aging, and thus to optimize drug therapy in elderly individuals. These results indicate that pharmacotherapy and safety-related control of geriatric drug therapy regimens may be greatly facilitated by the information gained from PBPK predictions.
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http://dx.doi.org/10.1007/s40262-016-0422-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107207PMC
December 2016

Modeling and Simulation of In Vivo Drug Effects.

Handb Exp Pharmacol 2016 ;232:313-29

Bayer Pharma AG, Aprather Weg 18a, 42113, Wuppertal, Germany.

The concept of a pharmacokinetics-pharmacodynamics (PK/PD) assessment of drug development candidates is well established in pharmaceutical research and development, and PK/PD modeling is common practice in all pharmaceutical companies. A recent analysis (Morgan et al., Drug Discov Today 17(9-10):419-424, 2012) revealed however that insufficient certainty in the integrity of the causal chain of fundamental pharmacological steps from drug dosing through systemic exposure, target tissue exposure, and engagement of molecular target to pharmacological response is still the major driver of failure in phase II of clinical drug development. Despite the rise of molecular biomarkers, ethical, scientific, and practical constraints very often still prevent a direct assessment of each necessary step ultimately leading to an intended drug effect or an unintended adverse reaction. Yet, incomplete investigation of the causality of drug responses is a major risk for translational assessments and the prediction of drug responses in different species or other populations. Mechanism-based modeling and simulation (M&S) offers a means to investigate complex physiological and pharmacological processes and to complement experimental data for non-accessible steps in the pharmacological causal chain. With the help of two examples, it is illustrated, what level of physiological detail, state-of-the-art models can represent, how predictive these models are and how mechanism-based approaches can be combined with empirical correlation-based concepts.
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http://dx.doi.org/10.1007/164_2015_21DOI Listing
June 2016
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