Population pharmacokinetics of rosuvastatin: implications of renal impairment, race, and dyslipidaemia.

OBJECTIVES: To build the structural model of pharmacokinetics for rosuvastatin and evaluate the impact of demographic characteristics including renal function on its pharmacokinetic parameters. METHODS: A population pharmacokinetic analysis of rosuvastatin in healthy volunteers, subjects with dyslipidaemia, and renal failure patients was performed using non-linear mixed-effects modelling and a two-compartment pharmacokinetic model with simultaneous first- and zero-order absorption. Demographic covariates, dyslipidaemic state and renal function were evaluated for their impact on pharmacokinetic parameters by step-wise additions or deletions using the likelihood ratio test. RESULTS: Typical pharmacokinetic parameters were estimated for a healthy white male subject. For example, apparent oral clearance (CL/F) was estimated to be 257 L/h. Age, smoking status, weight, body surface area, and lean body mass had no significant effect on rosuvastatin pharmacokinetics. The model predicted that CL/F for subjects with creatinine clearance (CLCR) of 30 mL/min (moderate renal impairment) and of 50 mL/min (mild renal impairment) was 17% and 9.7% lower, respectively, relative to subjects with CLCR of 94 mL/min, the data set median value. CL/F was reduced by 71.1% and 43.7% in subjects with dyslipidaemia and in Asian subjects, respectively. CONCLUSIONS: Reduction of CL/F of rosuvastatin is not considered clinically significant for patients with mild-to-moderate renal impairment. Rosuvastatin CL/F was reduced in subjects with dyslipidaemia, but it is important to realise that the safety/efficacy profile of rosuvastatin has been well established in this population. However, the potential for increased exposure in Asian subjects should be considered when initiating rosuvastatin treatment or increasing dose in this population.

Characterization of the pharmacokinetics of buprenorphine and norbuprenorphine in rats after intravenous bolus administration of buprenorphine.

The purpose of this project was to characterize the dose-dependent pharmacokinetics of buprenorphine (BN) and norbuprenorphine (NBN), the primary metabolite, after intravenous administration of different doses of BN to rats. Adult male Sprague-Dawley rats were divided into six groups and received a single intravenous bolus dose of 0.1, 0.3, 1, 3, 10 or 30 mg/kg of BN. A separate study was performed where BN and NBN were simultaneously administered intravenously (1 mg/kg+1 mg/kg). Plasma samples were obtained by centrifugation of the blood and analyzed for BN and NBN using a sensitive and selective gas chromatographic-mass spectrometric (GC-MS) bio-analytical method. Noncompartmental and compartmental methods were used to perform pharmacokinetic data analysis. BN declined triexponentially with a dose-dependent increase in its volume of distribution, V(ss) (8.37-18.2 l/kg) and clearance CL (2.70-6.10 l/h per kg). The pharmacokinetics of NBN were linear and biexponential. Coadministration of BN and NBN resulted in a significant increase in the volume of distribution and clearance of BN. The present results suggest that the nonlinear disposition in the clearance and volume of distribution of BN can be attributed, in part, to the increasing concentration of the metabolite.