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

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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Copyright © 2021 Zapke, Willmann, Grebe, Menke, Thürmann and Schmiedl.

Déclaration de conflit d'intérêts

SW was employed by the company Bayer AG, Research and Development, Clinical Pharmacometrics, Wuppertal, Germany. KM was employed by the company Bayer AG, Research and Development, Systems Pharmacology and Medicine I, Leverkusen, Germany. For this study, the software PK-Sim® (Open Systems Pharmacology Suite/Leverkusen, Germany) was used. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.