The oral direct thrombin inhibitor (oral DTI) ximelagatran (Exanta™, AstraZeneca) is currently undergoing clinical evaluation for the prevention and treatment of thromboembolic disorders. It is important to understand the pharmacokinetics of ximelagatran in patients who may require long-term anticoagulant therapy, such as for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).

The aim of the study was to characterize the pharmacokinetics of melagatran, the active form of ximelagatran, when ximelagatran is administered to NVAF patients treated for the prevention of stroke and systemic thromboembolism.

This population analysis utilised pharmacokinetic data from 3 studies: A) SPORTIF II, a multicentre, randomized, parallel group, dose-guiding safety and tolerability study of oral ximelagatran (20, 40 or 60 mg bid, given double-blind) versus oral warfarin (at a dose to maintain an International Normalized Ratio [INR] of 2.0-3.0) in NVAF patients at medium-to-high risk of stroke. After 3 months, 3 plasma samples were collected within 2 to 10 h postdosing from each of 153 of the 187 patients receiving ximelagatran. B) SPORTIF IV, an open-label follow-up of SPORTIF II, in which eligible patients continued to receive ximelagatran 36 mg bid or warfarin (INR 2.0-3.0) for a further 21 months During the study, after ~14 months on ximelagatran, a 12 h pharmacokinetic evaluation was performed. Twelve plasma samples per patient were collected during the dosage interval from 49 patients receiving ximelagatran. C) SPORTIF VI, an open-label, nonrandomized, parallel group study in 12 NVAF patients at low-risk of stroke. On the last day of 5-days' treatment with ximelagatran 36 mg bid, 12 plasma samples per patient were collected over 12 h. Pooled melagatran plasma concentration data from the 3 studies were analysed by population mixed-effects modelling using NONMEM version V.

During the study, after ~14 months on ximelagatran, a 12 h pharmacokinetic evaluation was performed. Twelve plasma samples per patient were collected during the dosage interval from 49 patients receiving ximelagatran. C) SPORTIF VI, an open-label, nonrandomized, parallel group study in 12 NVAF patients at low-risk of stroke. On the last day of 5-days' treatment with ximelagatran 36 mg bid, 12 plasma samples per patient were collected over 12 h. Pooled melagatran plasma concentration data from the 3 studies were analysed by population mixed-effects modelling using NONMEM version V.

The analysis was based on 1177 observations of melagatran plasma concentrations. The pharmacokinetics of melagatran conformed to a one-compartment model and was not influenced by dose or treatment time. The absorption rate constant was 1.2 h^-1. The mean elimination half-life of melagatran was 5.1 h. Melagatran clearance (21 L/h) was positively and linearly correlated with renal function (calculated creatinine clearance), the fractional change in clearance per unit change in calculated creatinine clearance was 1.3%. The volume of distribution of melagatran (156 L) was positively and linearly correlated with body weight, the fractional change in volume of distribution was 1.2% per kg of body weight. The residual variability, expressed as the coefficient of variation, in these 2 parameters was ~ 15% between patients and ~ 23% between occasions.

The pharmacokinetic properties of melagatran were stable with low variability, in NVAF patients receiving long-term treatment with the oral DTI ximelagatran.