Drug Metabolism Letters

Zhiyang Zhao
Amgen
Cambridge, MA
USA

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Disposition and Mass Balance of [14C]Vernakalant After Single Intravenous and Oral Doses in Healthy Volunteers

Author(s): Z. L. Mao, A. Alak, J. J. Wheeler, J. Keirns.

Abstract:

Vernakalant hydrochloride is a novel antiarrhythmic drug for the rapid conversion of atrial fibrillation to sinus rhythm and prevention of relapse. In this open-label, parallel design study, 8 healthy men received single 240-mg doses of [14C]vernakalant hydrochloride, given as a 10-minute intravenous (IV) infusion on day 1, and as an oral gel capsule on day 22. Plasma, urine, and fecal samples were collected for 7 days after dosing to measure vernakalant and its metabolites and to estimate mass balance of total [14C] recovery. The disposition and metabolic profile of vernakalant after both IV and oral administration, depended on cytochrome P450 (CYP)2D6 genotype. Vernakalant underwent rapid and extensive distribution during infusion, which resulted in similar maximum plasma concentrations in extensive metabolizers (EMs) and poor metabolizers (PMs) for IV but not oral administration. Vernakalant was metabolized rapidly and extensively to a 4-O-demethylated metabolite with glucuronidation in EMs; direct glucuronidation predominated in PMs. Slower clearance in PMs contributed to 3- and 6-fold higher drug exposure (AUC0-∞; IV and oral dosing, respectively). Urinary recovery of unchanged vernakalant was higher in PMs as well. Total [14C] was recovered predominantly in urine, while lower levels were recovered in feces. Mass balance was achieved, with a mean recovery of 99.7% of the IV dose and 98.7% of the oral dose, in EMs, and 89.2% and 88.2% of the IV and oral doses, respectively, in PMs. Vernakalant was well tolerated. The pharmacokinetics and metabolism of vernakalant depend on CYP2D6 genotype with more pronounced effects on exposure following oral administration; however, the differences between EMs and PMs are unlikely to be clinically significant following short-term IV infusion.

Keywords: Vernakalant hydrochloride, RSD1235, antiarrhythmic drug, pharmacokinetics, metabolism, mass balance, CYP2D6 genotype, glucuronidation, 3-O-demethylated vernakalant (RSD1390), Electrocardiogram (ECG)

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Article Details

VOLUME: 5
ISSUE: 2
Year: 2011
Page: [114 - 125]
Pages: 12
DOI: 10.2174/187231211795305249
Price: $58