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Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline

Flarakos, Jimmy and Du, Yancy and Gu, Helen and Wang, Lai and Einolf, Heidi and Chun, Dung Yu and Zhu, Bing and Alexander, Natalya and Natrillo, Adrienne and Hanna, Imad and Ting, Lillian and Zhou, Wei and Dole, Kiran and Sun, Haiying and Kovacs, Steven and Stein, Daniel and Tanaka, Ken and Mangold, James (2017) Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline. Xenobiotica, 47 (8). pp. 682-696. ISSN 1366-5928

Abstract

1. Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects. 2. Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. Omadacycline was a substrate of P-glycoprotein, but not of the other transporters. 3. Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300 mg oral dose of [14C]-omadacycline (36.6 μCi). Absorption was rapid with peak radioactivity (∼610 ngEq/mL) between 1–4 h in plasma or blood. The AUClast of plasma radioactivity (only quantifiable to 8 h due to low radioactivity) was 3096 ngEq h/mL and apparent terminal half-life was 11.1 h. Unchanged omadacycline reached peak plasma concentrations (∼563 ng/mL) between 1–4 h. Apparent plasma half-life was 17.6 h with biphasic elimination. Plasma exposure (AUCinf) averaged 9418 ng h/mL, with high clearance (CL/F, 32.8 L/h) and volume of distribution (Vz/F 828 L). No plasma metabolites were observed. 4. Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.

Item Type: Article
Additional Information: Unmapped bibliographic data: LA - Eng [Field not mapped to EPrints] ET - 2016/08/09 [Field not mapped to EPrints] ST - Clinical disposition, metabolism and in vitro drug-drug interaction properties of omadacycline [Field not mapped to EPrints] AU - Flarakos, J. [Field not mapped to EPrints] AU - Du, Y. [Field not mapped to EPrints] AU - Gu, H. [Field not mapped to EPrints] AU - Wang, L. [Field not mapped to EPrints] AU - Einolf, H. J. [Field not mapped to EPrints] AU - Chun, D. Y. [Field not mapped to EPrints] AU - Zhu, B. [Field not mapped to EPrints] AU - Alexander, N. [Field not mapped to EPrints] AU - Natrillo, A. [Field not mapped to EPrints] AU - Hanna, I. [Field not mapped to EPrints] AU - Ting, L. [Field not mapped to EPrints] AU - Zhou, W. [Field not mapped to EPrints] AU - Dole, K. [Field not mapped to EPrints] AU - Sun, H. [Field not mapped to EPrints] AU - Kovacs, S. J. [Field not mapped to EPrints] AU - Stein, D. S. [Field not mapped to EPrints] AU - Tanaka, S. K. [Field not mapped to EPrints] AU - Villano, S. [Field not mapped to EPrints] AU - Mangold, J. B. [Field not mapped to EPrints] AD - a Drug Metabolism and Pharmacokinetics and. [Field not mapped to EPrints] DP - NLM [Field not mapped to EPrints] AN - 27499331 [Field not mapped to EPrints]
Keywords: Aminomethylcycline cytochrome P450 human transporters
Date Deposited: 10 Mar 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/29122

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