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.

A population pharmacokinetic model of tamsulosin HCl was developed in paediatric patients. Covariate analysis revealed that body weight and a1-acid glycoprotein influenced both the apparent clearance and the apparent volume of distribution. This study confirms that there is no major difference in the pharmacokinetics of tamsulosin HCl between paediatrics (age range 2-16 years) and adults when the effect of body weight is taken into consideration. AIMSThe main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults. METHODSTamsulosin HCl plasma concentrations in 1082 plasma samples from 189 paediatric patients (age range 2-16 years) were analyzed with NONMEM, applying a one compartment model with first-order absorption. Based on the principles of allometry, body weight was incorporated in the base model, along with fixed allometric exponents. Covariate analysis was performed by means of a stepwise forward inclusion and backward elimination procedure. Simulations based on the final model were used to compare the pharmacokinetics with those in adults. RESULTSBeside the priori-implemented body weight, only a1-acid glycoprotein had an effect on both apparent clearance and apparent volume of distribution. No other investigated covariates, including gender, age, race, patient population and concomitant therapy with anti-cholinergics, significantly affected the pharmacokinetics of tamsulosin HCl (P < 0.001). The results of simulations indicated that the exposure in 12.5 kg paediatric patients was 3.5-4.3 fold higher than that in 70.0 kg adults. After a weight-based dose administration, the exposure in paediatric patients was comparable with that in healthy adults. CONCLUSIONSA population pharmacokinetic model of tamsulosin HCl in paediatric patients was established and it described the data well. There was no major difference in the pharmacokinetics of tamsulosin HCl between paediatric patients (age range 2-16 years) and adults when the effect of body weight was taken into consideration.

The limitations of pre-marketing clinical trials are analyzed and the need for ongoing drug research after approval is emphasized. Rare adverse drug reactions constitute the most important but not the only question. In addition to so-called post-marketing Drug Utilization Observation studies and spontaneous event reporting systems, other pharmacoepidemiologic study approaches like comparative cohort studies and case control studies, and also randomized clinical trials, are necessary to meet the multitude of scientific objectives of post-approval drug research.

The selected model provides a useful modeling tool for cases where the PD response measured is the result of a temporal experimental induced perturbation.