Data‐driven personalization of a physiologically based pharmacokinetic model for caffeine: A systematic assessment
CPT Pharmacometrics & Systems Pharmacology, vol. 10, pp. 782–793
Abstract
Physiologically based pharmacokinetic (PBPK) models have been proposed as a tool for more accurate individual pharmacokinetic (PK) predictions and model-informed precision dosing, but their application in clinical practice is still rare. This study systematically assesses the benefit of using individual patient information to improve PK predictions. A PBPK model of caffeine was stepwise personalized by using individual data on (1) demography, (2) physiology, and (3) cytochrome P450 (CYP) 1A2 phenotype of 48 healthy volunteers participating in a single-dose clinical study. Model performance was benchmarked against a caffeine base model simulated with parameters of an average individual. In the first step, virtual twins were generated based on the study subjects' demography (height, weight, age, sex), which implicated the rescaling of average organ volumes and blood flows. The accuracy of PK simulations improved compared with the base model. The percentage of predictions within 0.8-fold to 1.25-fold of the observed values increased from 45.8% (base model) to 57.8% (Step 1). However, setting physiological parameters (liver blood flow determined by magnetic resonance imaging, glomerular filtration rate, hematocrit) to measured values in the second step did not further improve the simulation result (59.1% in the 1.25-fold range). In the third step, virtual twins matching individual demography, physiology, and CYP1A2 activity considerably improved the simulation results. The percentage of data within the 1.25-fold range was 66.15%. This case study shows that individual PK profiles can be predicted more accurately by considering individual attributes and that personalized PBPK models could be a valuable tool for model-informed precision dosing approaches in the future.
Authors 12
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Rebekka Fendt Aachen Institute of Applied Microbiology Aachen Biology and Biotechnology Rheinisch‐Westfaelische Technische Hochschule Aachen University Aachen Germany Institute of Applied Microbiology
Bayer (Germany) · RWTH Aachen University
Affiliation as printed
Institute of Applied Microbiology Aachen Biology and Biotechnology Rheinisch‐Westfaelische Technische Hochschule Aachen University Aachen Germany
Systems Pharmacology & Medicine Bayer AG Leverkusen Germany
Institute of Applied Microbiology, Aachen Biology and Biotechnology, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany
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Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology · University of Tübingen
Affiliation as printed
Dr. Margarete Fischer‐Bosch‐Institute of Clinical Pharmacology Stuttgart Germany
University of Tuebingen Tuebingen Germany
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
University of Tuebingen, Tuebingen, Germany
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Annika R. P. Schneider Aachen Institute of Applied Microbiology Aachen Biology and Biotechnology Rheinisch‐Westfaelische Technische Hochschule Aachen University Aachen Germany Institute of Applied Microbiology
Bayer (Germany) · RWTH Aachen University
Affiliation as printed
Institute of Applied Microbiology Aachen Biology and Biotechnology Rheinisch‐Westfaelische Technische Hochschule Aachen University Aachen Germany
Systems Pharmacology & Medicine Bayer AG Leverkusen Germany
Institute of Applied Microbiology, Aachen Biology and Biotechnology, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany
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Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology · University of Tübingen
Affiliation as printed
Dr. Margarete Fischer‐Bosch‐Institute of Clinical Pharmacology Stuttgart Germany
University of Tuebingen Tuebingen Germany
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
University of Tuebingen, Tuebingen, Germany
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Affiliation as printed
Systems Pharmacology & Medicine Bayer AG Leverkusen Germany
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Affiliation as printed
Department of Cardiology I University Hospital Muenster Münster Germany
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Lars M. Blank Aachen Institute of Applied Microbiology Aachen Biology and Biotechnology Rheinisch‐Westfaelische Technische Hochschule Aachen University Aachen Germany Institute of Applied Microbiology
Affiliation as printed
Institute of Applied Microbiology Aachen Biology and Biotechnology Rheinisch‐Westfaelische Technische Hochschule Aachen University Aachen Germany
Institute of Applied Microbiology, Aachen Biology and Biotechnology, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany
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Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology · University of Tübingen
Affiliation as printed
Dr. Margarete Fischer‐Bosch‐Institute of Clinical Pharmacology Stuttgart Germany
University of Tuebingen Tuebingen Germany
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
University of Tuebingen, Tuebingen, Germany
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Affiliation as printed
Systems Pharmacology & Medicine Bayer AG Leverkusen Germany
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Affiliation as printed
Systems Pharmacology & Medicine Bayer AG Leverkusen Germany
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Matthias Georg Schwab corresponding
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology · University of Tübingen
Affiliation as printed
Departments of Clinical Pharmacology and Biochemistry and Pharmacy University of Tuebingen Tuebingen Germany
Dr. Margarete Fischer‐Bosch‐Institute of Clinical Pharmacology Stuttgart Germany
Departments of Clinical Pharmacology and Biochemistry and Pharmacy, University of Tuebingen, Tuebingen, Germany
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
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Universitätsklinikum Aachen · Bayer (Germany) · RWTH Aachen University
Affiliation as printed
Institute for Systems Medicine With Focus on Organ Interactions University Hospital RWTH Aachen Aachen Germany
Systems Pharmacology & Medicine Bayer AG Leverkusen Germany
Institute for Systems Medicine With Focus on Organ Interactions, University Hospital RWTH Aachen, Aachen, Germany
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