Physiologically Based Precision Dosing Approach for Drug-Drug-Gene Interactions: A Simvastatin Network Analysis.

Autor: Wojtyniak JG; Clinical Pharmacy, Saarland University, Saarbrücken, Germany.; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany., Selzer D; Clinical Pharmacy, Saarland University, Saarbrücken, Germany., Schwab M; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.; Departments of Clinical Pharmacology and Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC2180) 'Image-guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany., Lehr T; Clinical Pharmacy, Saarland University, Saarbrücken, Germany.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2021 Jan; Vol. 109 (1), pp. 201-211. Date of Electronic Publication: 2020 Dec 06.
DOI: 10.1002/cpt.2111
Abstrakt: Drug-drug interactions (DDIs) and drug-gene interactions (DGIs) are well known mediators for adverse drug reactions (ADRs), which are among the leading causes of death in many countries. Because physiologically based pharmacokinetic (PBPK) modeling has demonstrated to be a valuable tool to improve pharmacotherapy affected by DDIs or DGIs, it might also be useful for precision dosing in extensive interaction network scenarios. The presented work proposes a novel approach to extend the prediction capabilities of PBPK modeling to complex drug-drug-gene interaction (DDGI) scenarios. Here, a whole-body PBPK network of simvastatin was established, including three polymorphisms (SLCO1B1 (rs4149056), ABCG2 (rs2231142), and CYP3A5 (rs776746)) and four perpetrator drugs (clarithromycin, gemfibrozil, itraconazole, and rifampicin). Exhaustive network simulations were performed and ranked to optimize 10,368 DDGI scenarios based on an exposure marker cost function. The derived dose recommendations were translated in a digital decision support system, which is available at simvastatin.precisiondosing.de. Although the network covers only a fraction of possible simvastatin DDGIs, it provides guidance on how PBPK modeling could be used to individualize pharmacotherapy in the future. Furthermore, the network model is easily extendable to cover additional DDGIs. Overall, the presented work is a first step toward a vision on comprehensive precision dosing based on PBPK models in daily clinical practice, where it could drastically reduce the risk of ADRs.
(© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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