AimsTo describe the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of the direct thrombin inhibitor dabigatran in hip replacement patients by assessing coagulation parameters activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT), interindividual variability and factors affecting PD responses.
MethodsBISTRO I patients received oral dabigatran etexilate postsurgery for 6-10 days. Dabigatran plasma concentrations and aPTT/ECT were measured on the day of surgery, on subsequent days and at steady state. PK-PD characteristics of the dabigatran-aPTT/ ECT relationships were evaluated using NONMEM V.
ResultsThe dabigatran concentration-aPTT relationship was described combining a linear and an E max model. Mean baseline aPTT was 33.4 s and E max (maximum increase in aPTT contributed by the E max model) was 26.9 s. The dabigatran concentration needed to attain 50% of maximum effect (EC 50 ) was 94.7 ng ml − 1 and the mean slope of the linear concentration-response relationship (SLOP) was 0.0509 s ng − 1 ml − 1 . Baseline aPTT and E max were highest following surgery and declined with time. The dabigatran concentration-ECT relationship fitted a linear model. Mean baseline ECT was 28 s and decreased with time; 50% of the maximum effect was observed after 2.9 days. SLOP decreased from 0.38 to 0.27 s ng − 1 ml − 1 with a half-life of 1.1 day, indicating greater PD effects on the day of surgery. Interindividual and residual variability was low. Covariates could not explain variability of this model.
ConclusionsaPTT and ECT prolongation were directly correlated with dabigatran concentrations. Blood coagulation prolongation was most pronounced following surgery. Data suggest that ECT provides a more precise description of the anticoagulant effect than aPT T.
Dabigatran etexilate (BIBR 1048) is an orally bioavailable double prodrug of the active principle dabigatran (BIBR 953 ZW), which exerts potent anticoagulant and antithrombotic activity. The objective of the analysis was to develop a population pharmacokinetic model characterizing and quantifying the relationship between covariates and model parameters. A total of 4604 BIBR 953 ZW plasma concentrations, obtained from 287 patients after once- or twice-daily oral dosing for up to 10 days after surgery in the dose range 12.5, 25, 50, 100, 150, 200, and 300 mg BIBR 1048, were available for the analysis. All the analyses were performed with NONMEN V. Pharmacokinetics of dabigatran were best described by a 2-compartment model. The data supported the estimation of different apparent first-order absorption rate constants (k(a)) and apparent plasma clearances (CL/F) for days 0 and 1 and days 2 to 10 after surgery. Parameter estimates indicated a flip-flop phenomenon. Age and serum creatinine influenced k(a), whereas gastrin and creatinine clearance, only for days 2 to 10, affected CL/F (P < .001). The typical values for CL/F for a patient with gastrin of 34.58 pmol/L and creatinine clearance of 76.16 mL/min were 70.87 and 106.2 L/h on days 0 and 1 and days 2 to 10, respectively. The differences found in the pharmacokinetics of dabigatran during the first 24 hours after surgery are most likely due to alterations in gastric motility and pH following surgery. As a consequence, the rate of absorption is reduced and interindividual variability in drug exposure increased. On the following days, the disposition in plasma of BIBR 953 ZW is less variable.
The importance of P-glycoprotein (P-gp) in the pharmacokinetics of amisulpride and the effects of a P-gp inhibitor cyclosporine A (CsA) was investigated both, in vitro and in vivo. In vitro and in vivo results indicated amisulpride as a substrate of P-gp. Amisulpride was not metabolized by rat liver microsomes. Open field behavior showed time dependent abolishment in locomotion by amisulpride (50 mg kg(-1)). Co-administration of CsA (50 mg kg(-1)) resulted in a higher and significantly longer antipsychotic effect (24 h after drug administration). Accordingly, the area under concentration-time curve in serum and brain was higher in CsA co-treated rats (13.5 vs. 29.8 micromol h l(-1) for serum and 2.16 vs 2.98 micromol h l(-1) for brain tissue) while renal clearance was not affected. These results pointed to a pharmacokinetic drug interaction between CsA and amisulpride most likely caused by inhibition of P-gp.
Pharmacokinetics in the efficacy/safety trial population are essentially similar to pharmacokinetics in healthy subjects, and no patient-specific factor warranting clinical consideration of dose regimen adjustment was identified in these analyses.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.