Physiologically‐Based Pharmacokinetic Modeling in Renal and Hepatic Impairment Populations: A Pharmaceutical Industry Perspective

Clinical Pharmacology and Therapeutics - Tập 110 Số 2 - Trang 297-310 - 2021
Tycho Heimbach1, Yuan Chen2, Jun Chen3, Vaishali Dixit4, Neil Parrott5, Sheila Annie Peters6, Italo Poggesi7, Pradeep Sharma8, Jan Snoeys9, Mohamad Shebley10, Guoying Tai11, Susanna Tse12, Vijay Upreti13, Ying‐Hong Wang14, Alice Tsai15, Binfeng Xia16, Ming Zheng17, Andy Z. X. Zhu18, Stephen D. Hall19
1Pharmaceutical Sciences, Merck & Co., Inc, Rahway, New Jersey, USA
2Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, California, USA
3Clinical Pharmacology, Alkermes Inc, Waltham, Massachusetts, USA
4Drug Metabolism and Pharmacokinetics, Kymera Therapeutics, Watertown, Massachusetts, USA
5Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
6Translational Medicine, Merck Healthcare KGaA, Darmstadt, Germany
7Clinical Pharmacology and Pharmacometrics, Janssen, Milan, Italy
8Clinical Pharmacology & Quantitative Pharmacology Clinical Pharmacology & Safety Sciences R&D, AstraZeneca Cambridge UK
9Department of Drug Metabolism and Pharmacokinetics Janssen R&D Beerse Belgium
10Clinical Pharmacology and Pharmacometrics, AbbVie Inc, North Chicago, Illinois, USA
11Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Plc, Collegeville, Pennsylvania, USA
12Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA
13Clinical Pharmacology, Modeling & Simulation, Amgen Inc, South San Francisco, California, USA
14Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Inc, Kenilworth, New Jersey, USA
15Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals Inc, Boston, Massachusetts, USA
16PK/PD Group, Pharmacokinetics, Dynamics and Metabolism, Sanofi, Bridgewater, New Jersey, USA
17Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA
18Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International, Co, Cambridge, Massachusetts, USA
19Department of Drug Disposition, Lilly, Indianapolis, Indiana, USA

Tóm tắt

The predictive performance of physiologically‐based pharmacokinetics (PBPK) models for pharmacokinetics (PK) in renal impairment (RI) and hepatic impairment (HI) populations was evaluated using clinical data from 29 compounds with 106 organ impairment study arms were collected from 19 member companies of the International Consortium for Innovation and Quality in Pharmaceutical Development. Fifty RI and 56 HI study arms with varying degrees of organ insufficiency along with control populations were evaluated. For RI, the area under the curve (AUC) ratios of RI to healthy control were predicted within twofold of the observed ratios for > 90% (N = 47/50 arms). For HI, > 70% (N = 43/56 arms) of the hepatically impaired to healthy control AUC ratios were predicted within twofold. Inaccuracies, typically overestimation of AUC ratios, occurred more in moderate and severe HI. PBPK predictions can help determine the need and timing of organ impairment study. It may be suitable for predicting the impact of RI on PK of drugs predominantly cleared by metabolism with varying contribution of renal clearance. PBPK modeling may be used to support mild impairment study waivers or clinical study design.

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Clinical Pharmacology and Therapeutics

Tập 110 Số 2

297-310

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