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Population pharmacokinetic model of carvedilol considering differences correlated to genotype
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2013 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Introduction: Carvedilol is a β1, β2 and α1 adrenergic receptor antagonist. It contains of a mixture of both R- and S-enantiomers. Treatment with 25 mg carvedilol during a mean time period of 10,4 months decreases the risk of death by 35% . Carvedilol is metabolized by different pathways, one pathway is through the isoenzyme cytochrome P450 2D6. The enzyme activity varies among people and can have a strong effect on substrates metabolized by the CYP2D6.

Aim: The primary objective was to develop a population PK model of carvedilol based on data from a clinical study. The secondary objective was to investigate how different covariates (including CYP2D6) influence the PK characteristics of carvedilol. A previously developed PKPD model was evaluated based on the developed PK model and available PD data.

Materials and Methods: The clinical data were obtained from 24 healthy volunteers who were given a single 25 mg dose of carvedilol. Plasma concentrations of R- and S-carvedilol, heart rate, systolic and diastolic blood pressure were measured during a time period of 36 hours. One- and two-compartment models were developed using the population modeling software NONMEM.

Results: A 2-compartment model had a significantly better fit to the data than the 1-compartment model. There was a trend in individual post hoc CL parameter values when plotted against enzyme activity and CYP2D6 genotype was identified as a significant covariate on CL for both R- and S-carvedilol.

Conclusions: A 2-compartment model with CYP2D6 genotype as a covariate on CL was developed, that well described the PK profile of both R- and S-carvedilol. 

Place, publisher, year, edition, pages
2013. , 29 p.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-202747OAI: oai:DiVA.org:uu-202747DiVA: diva2:633244
Subject / course
Available from: 2013-06-28 Created: 2013-06-26 Last updated: 2013-06-28Bibliographically approved

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