Mitsuhiro Nishihara1, Hitomi Yamasaki2, Richard Czerniak3, Helen Jenkins4. 1. Global Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA, 02139, USA. mitsuhiro.nishihara@takeda.com. 2. Drug Disposition and Analysis, Research Division, Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan. 3. Quantitative Clinical Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, MA, USA. 4. d3 Medicine, A Certara Company, London, UK.
Abstract
BACKGROUND AND OBJECTIVES: It was recently proposed that CYP-mediated drug-drug interactions (DDIs) of vonoprazan with clopidogrel and prasugrel can attenuate the antiplatelet actions of the latter two drugs. Clopidogrel is metabolized to the pharmacologically active metabolite H4 and its isomers by multiple CYPs, including CYP2C19 and CYP3A4. Therefore, to investigate the possibility of CYP-based DDIs, in vitro metabolic inhibition studies using CYP probe substrates or radiolabeled clopidogrel and human liver microsomes (HLMs) were conducted in this work. METHODS: Reversible inhibition studies focusing on the effects of vonoprazan on CYP marker activities and the formation of the [14C]clopidogrel metabolite H4 were conducted with and without pre-incubation using HLMs. Time-dependent inhibition (TDI) kinetics were also measured. RESULTS: It was found that vonoprazan is not a significant direct inhibitor of any CYP isoforms (IC50 ≥ 16 μM), but shows the potential for TDI of CYP2B6, CYP2C19, and CYP3A4/5. This TDI was weaker than the inhibition induced by the corresponding reference inhibitors ticlopidine, esomeprazole, and verapamil, based on the measured potencies (kinact/KI ratio and the R2 value). In a more direct in vitro experiment, vonoprazan levels of up to 10 µM (a 100-fold higher concentration than the plasma Cmax of 75.9 nM after taking 20 mg once daily for 7 days) did not suppress the formation of the active metabolite H4 or other oxidative metabolites of [14C]clopidogrel in a reversible or time-dependent manner. Additionally, an assessment of clinical trials and post-marketing data suggested no evidence of a DDI between vonoprazan and clopidogrel. CONCLUSIONS: The body of evidence shows that the pharmacodynamic DDI reported between vonoprazan and clopidogrel is unlikely to be caused by the inhibition of CYP2B6, CYP2C19, or CYP3A4/5 by vonoprazan.
BACKGROUND AND OBJECTIVES: It was recently proposed that CYP-mediated drug-drug interactions (DDIs) of vonoprazan with clopidogrel and prasugrel can attenuate the antiplatelet actions of the latter two drugs. Clopidogrel is metabolized to the pharmacologically active metabolite H4 and its isomers by multiple CYPs, including CYP2C19 and CYP3A4. Therefore, to investigate the possibility of CYP-based DDIs, in vitro metabolic inhibition studies using CYP probe substrates or radiolabeled clopidogrel and human liver microsomes (HLMs) were conducted in this work. METHODS: Reversible inhibition studies focusing on the effects of vonoprazan on CYP marker activities and the formation of the [14C]clopidogrel metabolite H4 were conducted with and without pre-incubation using HLMs. Time-dependent inhibition (TDI) kinetics were also measured. RESULTS: It was found that vonoprazan is not a significant direct inhibitor of any CYP isoforms (IC50 ≥ 16 μM), but shows the potential for TDI of CYP2B6, CYP2C19, and CYP3A4/5. This TDI was weaker than the inhibition induced by the corresponding reference inhibitors ticlopidine, esomeprazole, and verapamil, based on the measured potencies (kinact/KI ratio and the R2 value). In a more direct in vitro experiment, vonoprazan levels of up to 10 µM (a 100-fold higher concentration than the plasma Cmax of 75.9 nM after taking 20 mg once daily for 7 days) did not suppress the formation of the active metabolite H4 or other oxidative metabolites of [14C]clopidogrel in a reversible or time-dependent manner. Additionally, an assessment of clinical trials and post-marketing data suggested no evidence of a DDI between vonoprazan and clopidogrel. CONCLUSIONS: The body of evidence shows that the pharmacodynamic DDI reported between vonoprazan and clopidogrel is unlikely to be caused by the inhibition of CYP2B6, CYP2C19, or CYP3A4/5 by vonoprazan.
Authors: Miia Turpeinen; Ari Tolonen; Jouko Uusitalo; Jorma Jalonen; Olavi Pelkonen; Kari Laine Journal: Clin Pharmacol Ther Date: 2005-06 Impact factor: 6.875
Authors: Scott W Grimm; Heidi J Einolf; Steven D Hall; Kan He; Heng-Keang Lim; Kah-Hiing John Ling; Chuang Lu; Amin A Nomeir; Eleanore Seibert; Konstantine W Skordos; George R Tonn; Robert Van Horn; Regina W Wang; Y Nancy Wong; Tian J Yang; R Scott Obach Journal: Drug Metab Dispos Date: 2009-04-09 Impact factor: 3.922