Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole

Chirag G Patel, Li Li, Suzette Girgis, David M Kornhauser, Ernest U Frevert, David W BoultonBristol-Myers Squibb, Princeton, NJ, USABackground: Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin), antihypertensives (eg, diltiazem, nifedipine, verapamil), and a...

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Autores principales:	Patel C, Li L, Girgis S, Kornhauser D, Frevert E, Boulton D
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2011
Materias:	Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/245b79bc6e874bf6a7d03ee071325afe
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spelling	oai:doaj.org-article:245b79bc6e874bf6a7d03ee071325afe2021-12-02T01:21:25ZTwo-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole1179-1438https://doaj.org/article/245b79bc6e874bf6a7d03ee071325afe2011-06-01T00:00:00Zhttp://www.dovepress.com/two-way-pharmacokinetic-interaction-studies-between-saxagliptin-and-cy-a7707https://doaj.org/toc/1179-1438Chirag G Patel, Li Li, Suzette Girgis, David M Kornhauser, Ernest U Frevert, David W BoultonBristol-Myers Squibb, Princeton, NJ, USABackground: Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin), antihypertensives (eg, diltiazem, nifedipine, verapamil), and antifungals (eg, ketoconazole) are metabolized by and/or inhibit the cytochrome P450 (CYP) 3A4 metabolic pathway. These types of medicines are commonly coprescribed to treat comorbidities in patients with type 2 diabetes mellitus (T2DM) and the potential for drug-drug interactions of these medicines with new medicines for T2DM must be carefully evaluated.Objective: To investigate the effects of CYP3A4 substrates or inhibitors, simvastatin (substrate), diltiazem (moderate inhibitor), and ketoconazole (strong inhibitor) on the pharmacokinetics and safety of saxagliptin, a CYP3A4/5 substrate; and the effects of saxagliptin on these agents in three separate studies.Methods: Healthy subjects were administered saxagliptin 10 mg or 100 mg. Simvastatin, diltiazem extended-release, and ketoconazole doses of 40 mg once daily, 360 mg once daily, and 200 mg twice daily, respectively, were used to determine two-way pharmacokinetic interactions.Results: Coadministration of simvastatin, diltiazem extended-release, or ketoconazole increased mean area under the concentration-time curve values (AUC) of saxagliptin by 12%, 109%, and 145%, respectively, versus saxagliptin alone. Mean exposure (AUC) of the CYP3A4-generated active metabolite of saxagliptin, 5-hydroxy saxagliptin, decreased with coadministration of simvastatin, diltiazem, and ketoconazole by 2%, 34%, and 88%, respectively. All adverse events were considered mild or moderate in all three studies; there were no serious adverse events or deaths.Conclusion: Saxagliptin, when coadministered with simvastatin, diltiazem extended-release, or ketoconazole, was safe and generally well tolerated in healthy subjects. Clinically meaningful interactions of saxagliptin with simvastatin and diltiazem extended-release are not expected. The dose of saxagliptin does not need to be adjusted when coadministered with a substrate or moderate inhibitor of CYP3A4. A limitation to the lowest clinical dose of saxagliptin (2.5 mg) is proposed when it is coadministered with a potent CYP3A4 inhibitor such as ketoconazole.Keywords: cytochrome P450 3A4/5, diltiazem extended-release, ketoconazole, pharmacokinetics, simvastatin, type 2 diabetes mellitusPatel CLi LGirgis SKornhauser DFrevert EBoulton DDove Medical PressarticleTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol 2011, Iss default, Pp 13-25 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 Patel C Li L Girgis S Kornhauser D Frevert E Boulton D Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole
description	Chirag G Patel, Li Li, Suzette Girgis, David M Kornhauser, Ernest U Frevert, David W BoultonBristol-Myers Squibb, Princeton, NJ, USABackground: Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin), antihypertensives (eg, diltiazem, nifedipine, verapamil), and antifungals (eg, ketoconazole) are metabolized by and/or inhibit the cytochrome P450 (CYP) 3A4 metabolic pathway. These types of medicines are commonly coprescribed to treat comorbidities in patients with type 2 diabetes mellitus (T2DM) and the potential for drug-drug interactions of these medicines with new medicines for T2DM must be carefully evaluated.Objective: To investigate the effects of CYP3A4 substrates or inhibitors, simvastatin (substrate), diltiazem (moderate inhibitor), and ketoconazole (strong inhibitor) on the pharmacokinetics and safety of saxagliptin, a CYP3A4/5 substrate; and the effects of saxagliptin on these agents in three separate studies.Methods: Healthy subjects were administered saxagliptin 10 mg or 100 mg. Simvastatin, diltiazem extended-release, and ketoconazole doses of 40 mg once daily, 360 mg once daily, and 200 mg twice daily, respectively, were used to determine two-way pharmacokinetic interactions.Results: Coadministration of simvastatin, diltiazem extended-release, or ketoconazole increased mean area under the concentration-time curve values (AUC) of saxagliptin by 12%, 109%, and 145%, respectively, versus saxagliptin alone. Mean exposure (AUC) of the CYP3A4-generated active metabolite of saxagliptin, 5-hydroxy saxagliptin, decreased with coadministration of simvastatin, diltiazem, and ketoconazole by 2%, 34%, and 88%, respectively. All adverse events were considered mild or moderate in all three studies; there were no serious adverse events or deaths.Conclusion: Saxagliptin, when coadministered with simvastatin, diltiazem extended-release, or ketoconazole, was safe and generally well tolerated in healthy subjects. Clinically meaningful interactions of saxagliptin with simvastatin and diltiazem extended-release are not expected. The dose of saxagliptin does not need to be adjusted when coadministered with a substrate or moderate inhibitor of CYP3A4. A limitation to the lowest clinical dose of saxagliptin (2.5 mg) is proposed when it is coadministered with a potent CYP3A4 inhibitor such as ketoconazole.Keywords: cytochrome P450 3A4/5, diltiazem extended-release, ketoconazole, pharmacokinetics, simvastatin, type 2 diabetes mellitus
format	article
author	Patel C Li L Girgis S Kornhauser D Frevert E Boulton D
author_facet	Patel C Li L Girgis S Kornhauser D Frevert E Boulton D
author_sort	Patel C
title	Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole
title_short	Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole
title_full	Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole
title_fullStr	Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole
title_full_unstemmed	Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole
title_sort	two-way pharmacokinetic interaction studies between saxagliptin and cytochrome p450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole
publisher	Dove Medical Press
publishDate	2011
url	https://doaj.org/article/245b79bc6e874bf6a7d03ee071325afe
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Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole

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