Joint population pharmacokinetic/pharmacodynamic model for the heart rate effects at rest and at the end of exercise for cilobradine.

PURPOSE: To develop a semi-mechanistic population pharmacokinetic/pharmacodynamic (PKPD) model for the selective bradycardic agent cilobradine describing simultaneously the heart rate (HR) measured at rest and just after the end of exercise sharing the same set of PKPD parameters. METHODS: Healthy subjects received cilobradine orally once daily over 2 weeks at 0.25-5 mg doses or placebo. Plasma drug concentrations and HR were measured at rest and following 3 min of exercise over the entire study period. PK and HR data were analyzed using the population approach with NONMEM VII. RESULTS: Plasma disposition of cilobradine was described with a three compartment model. Cilobradine showed dose proportional and time independent pharmacokinetics. HR response was drug concentration dependent and appeared with a significant delay with respect to PK profiles, a phenomenon modeled using two transit compartments. Perturbation in HR at rest as a consequence of exercise was described assuming that physiological processes controlling cardiac frequency were constantly increased over the period of exercise only. CONCLUSIONS: The selected model provides a useful modeling tool for cases where the PD response measured is the result of a temporal experimental induced perturbation.

Population pharmacokinetics of tamsulosin hydrochloride in paediatric patients with neuropathic and non-neuropathic bladder.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Tamsulosin is available on prescription as a modified release capsule in the US (Flomax), and in most European countries for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). The pharmacokinetics of tamsulosin hydrochloride (HCl) have been extensively studied in adults, but no pharmacokinetic data for paediatrics have been published to date. WHAT THIS STUDY ADDS: A population pharmacokinetic model of tamsulosin HCl was developed in paediatric patients. Covariate analysis revealed that body weight and alpha(1)-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. AIMS: The 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. METHODS: Tamsulosin 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. RESULTS: Beside the priori-implemented body weight, only alpha(1)-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. CONCLUSIONS: A 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.

Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery.

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.