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We represent a community with a shared interest in data analysis using the population approach.


2003
   Verona, Italy

Population pharmacokinetics/-dynamics of dabigatran, the active form of the new oral direct thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing hip replacement

Joachim Stangier, Karl-Heinz Liesenfeld, Christiane Tillmann, Inaki Troconiz (#), Hans Guenter Schaefer

Boehringer Ingelheim Pharma GmbH & Co. KG, (#) School of Pharmacy, University of Navarra, Pamplona, Spain

Introduction: The oral direct thrombin inhibitor prodrug dabigatran etexilate is under development for the prevention of thrombosis in patients at risk of thrombotic events. The population pharmacokinetics and pharmacodynamics of dabigatran were assessed in a dose escalation safety study (BISTRO I) involving 289 patients treated with 12.5 to 300 mg dabigatran etexilate. This trial was the first study with dabigatran etexilate in patients. The aim of the population PK/PD analysis was to provide information on pharmacokinetics and dynamics in orthopaedic patients in order to support dose selection and rational planning of further clinical studies with the new oral thrombin inhibitor for prevention of deep vein thrombosis.

Methods: Dabigatran plasma concentrations and the pharmacodynamic parameters activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT) were measured. In total, about 5000 PK and PD data from 287 patients were included in the pharmacokinetic/-dynamic population analysis. Pharmacokinetic and pharmacodynamic models were developed independently. Population PK and PD models were developed using NONMEM (Version 5). The influence of patient characteristics on the pharmacokinetic and -dynamic model parameters were investigated.

Results: Pharmacokinetics of dabigatran were best described by a two- compartmental body model with first order absorption and elimination. The pharmacokinetics of dabigatran are different during the initial 24 hours after surgery. The rate constant of drug absorption KA was significantly lower than KA on days 2-10 of treatment. This is most likely due to alterations in gastric motility after surgery. Dabigatran clearance was significantly correlated with the calculated serum creatinine clearance. This was to be expected because renal excretion of unchanged drug is the principal route of elimination. The higher age and the lower renal function of the patient population accounted for the fact that they had lower plasma clearance than young healthy volunteers. Dabigatran plasma concentrations and the blood coagulation parameters aPTT and ECT displayed a close correlation. The relationship of dabigatran concentration and aPTT was best described by a combination of an Emax and a linear model. ECT was linearily related to dabigatran concentrations in plasma. The magnitude of the PD response was apparently higher early after surgery and decreased with time. This time dependent variations in aPTT and ECT response might be rationalised by surgical effects on haemostasis caused by transfusion of large fluid volumes during operation.

Conclusions: Population pharmacokinetic analysis showed that differences exist in the pharmacokinetics of dabigatran between the initial 24 hours after surgery and days 2 - 10 of treatment. Effects of surgery on drug absorption required further investigations of the absorption of direct thrombin inhibitors administered orally early after orthopaedic surgery. The population pharmacodynamic investigation of the direct thrombin inhibitor dabigatran revealed a close correlation between drug plasma concentrations and prolongation of blood coagulation. The prolongation of aPTT and ECT by dabigatran was apparently more pronounced early after surgery. The population PK and PD models were employed to simulate the dose response relationship of dabigatran in order to support dose selection and planning of further clinical trials with the dabigatran in prevention of deep vein thrombosis after orthopaedic surgery.



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