Recommendations for the Design of Clinical Drug-Drug Interaction Studies With Itraconazole Using a Mechanistic Physiologically-Based Pharmacokinetic Model

被引：36

作者：

Chen, Yuan ^{[1
,2
]}

Cabalu, Tamara D. ^{[3
]}

Callegari, Ernesto ^{[4
]}

Einolf, Heidi ^{[5
]}

Liu, Lichuan ^{[6
]}

Parrott, Neil ^{[7
]}

Peters, Sheila Annie ^{[8
]}

Schuck, Edgar ^{[9
]}

Sharma, Pradeep ^{[10
]}

Tracey, Helen ^{[11
]}

Upreti, Vijay V. ^{[12
]}

Zheng, Ming ^{[13
]}

Zhu, Andy Z. X. ^{[14
]}

Hall, Stephen D. ^{[15
]}

机构：

[1] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[2] Roche Grp, San Francisco, CA 94080 USA

[3] Merck & Co Inc, Dept Pharmacokinet Pharmacodynam & Drug Metab, Kenilworth, NJ USA

[4] Pfizer Inc, Pharmacokinet Dynam & Metab, Groton, CT 06340 USA

[5] Novartis Inst Biomed Res, Modeling & Simulat PK Sci, E Hanover, NJ USA

[6] Genentech Inc, San Francisco, CA 94080 USA

[7] F Hoffmann La Roche Ltd, Roche Innovat Ctr, Pharmaceut Res & Early Dev, Pharmaceut Sci, Basel, Switzerland

[8] Merck KGaA, Translat Quantitat Pharmacol, Darmstadt, Germany

[9] Eisai Inc, Clin Pharmacol Sci, MDC, Modeling & Simulat, Woodcliff Lake, NJ USA

[10] AstraZeneca R&D, Mechanist Safety & ADME Sci Drug Safety & Metab, Innovat Med IMED Biotech Unit, Cambridge, England

[11] GlaxoSmithKline, Dept Mechanist Safety & Disposit, Stevenage, Herts, England

[12] Amgen Inc, Clin Pharmacol Modeling & Simulat, San Francisco, CA USA

[13] Bristol Myers Squibb Co, Clin Pharmacol & Pharmacometr, Princeton, NJ USA

[14] Takeda Pharmaceut Int Co, Dept Drug Metab & Pharmacokinet, Cambridge, MA USA

[15] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY | 2019年 / 8卷 / 09期

关键词：

SYSTEMIC ANTIMYCOTICS KETOCONAZOLE; STEADY-STATE PHARMACOKINETICS; FOOD INTERACTION; PROTEIN-BINDING; PHARMACODYNAMICS; MIDAZOLAM; METABOLITES; INHIBITION; PREDICTION; CAPSULES;

D O I：

10.1002/psp4.12449

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Regulatory agencies currently recommend itraconazole (ITZ) as a strong cytochrome P450 3A (CYP3A) inhibitor for clinical drug-drug interaction (DDI) studies. This work by an International Consortium for Innovation and Quality in Pharmaceutical Development working group (WG) is to develop and verify a mechanistic ITZ physiologically-based pharmacokinetic model and provide recommendations for optimal DDI study design based on model simulations. To support model development and verification, in vitro and clinical PK data for ITZ and its metabolites were collected from WG member companies. The model predictions of ITZ DDIs with seven different CYP3A substrates were within the guest criteria for 92% of area under the concentration-time curve ratios and 95% of maximum plasma concentration ratios, thus verifying the model for DDI predictions. The verified model was used to simulate various clinical DDI study scenarios considering formulation, duration of dosing, dose regimen, and food status to recommend the optimal design for maximal inhibitory effect by ITZ.

引用

页码：685 / 695

页数：11

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