Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects.

Abstract

To investigate the influence of nonvalvular atrial fibrillation (NVAF) on the pharmacokinetic (PK) properties of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran. In an open study, 12 patients with persistent NVAF and 12 age- and gender-matched, healthy control subjects received a 10-min intravenous (i.v.) infusion of 2.66 mg melagatran followed by oral ximelagatran, 36 mg twice daily, for the subsequent five study days. Plasma and urine samples for PK analyses were collected after i.v. and single and repeated oral dosing. The oral absorption of ximelagatran was rapid, and maximum plasma concentrations of ximelagatran (Cmax) were achieved at about 1 h post-dosing. There were no differences between NVAF patients and controls for the area under the plasma concentration versus time curve, Cmax, half-life (t1/2), or bioavailability (F) of melagatran after oral dosing with ximelagatran. The Cmax of melagatran, formed by the rapid bioconversion of ximelagatran, occurred approximately 3 h post-dosing. The geometric means of the t1/2 for melagatran were 4.0 h and 4.2 h for the first and last doses, respectively, in patients, and 3.5 h and 3.7 h, respectively, in controls. Geometric means of F of melagatran following oral administration of ximelagatran were 22% and 24% for the first and last doses, respectively, in patients and 21% and 23%, respectively, in controls. Approximately 80% of the i.v. dose of melagatran was excreted in urine in patients and in controls. The PK properties of oral ximelagatran and i.v. melagatran in elderly patients with NVAF are consistent with those in matched, healthy controls.