Population pharmacokinetic model of carvedilol considering differences correlated to genotype
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
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.
IdentifiersURN: urn:nbn:se:uu:diva-202747OAI: oai:DiVA.org:uu-202747DiVA: diva2:633244
Subject / course
Nielsen, Elisabet, Researcher
Hammarlund-Udenaes, Margareta, Professor