Population pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, in atrial fibrillation patients receiving long-term anticoagulation therapy.
BACKGROUND
Ximelagatran is an oral direct thrombin inhibitor for the prevention of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran.


OBJECTIVE
To characterise the pharmacokinetics of melagatran in patients with nonvalvular atrial fibrillation (NVAF) receiving long-term treatment for prevention of stroke and systemic embolic events.


METHODS
A population pharmacokinetic model was developed based on data from three phase II studies (1177 plasma concentration observations in 167 patients, treated for up to 18 months) and confirmed by including data from two phase III studies (8702 plasma concentration observations in 3188 patients, treated for up to 24 months). The impact of individualised dosing on pharmacokinetic variability was evaluated by simulations of melagatran concentrations based on the pharmacokinetic model.


RESULTS
Melagatran pharmacokinetics were consistent across the studied doses and duration of treatment, and were described by a one-compartment model with first-order absorption and elimination. Clearance of melagatran was correlated to creatinine clearance, which was the most important predictor of melagatran exposure (explained 54% of interpatient variance in clearance). Total variability (coefficient of variation) in exposure was 45%; intraindividual variability in exposure was 23%. Concomitant medication with the most common long-term used drugs in the study population had no relevant influence on melagatran pharmacokinetics. Simulations suggested that dose adjustment based on renal function or trough plasma concentration had a minor effect on overall pharmacokinetic variability and the number of patients with high melagatran exposure.


CONCLUSIONS
The pharmacokinetics of melagatran in NVAF patients were predictable, and consistent with results from previously studied patient populations. Dose individualisation was predicted to have a low impact on pharmacokinetic variability, supporting the use of a fixed-dose regimen of ximelagatran for long-term anticoagulant therapy in the majority of NVAF patients.
Bååthe
Sofie
S
AstraZeneca R&D Mölndal, Mölndal, Sweden. sofie.baathe@astrazeneca.com
Hamrén
Bengt
B
Karlsson
Mats O
MO
Wollbratt
Maria
M
Grind
Margaretha
M
Eriksson
Ulf G
UG
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001596:Benzylamines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D011355:Prodrugs; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin