Population Pharmacokinetics of Carvedilol and its metabolites in Type II Diabetes Mellitus

GHB Nardotto1, EB Coelho2, VL Lanchote1, F Musuamba3, O Della Pasqua3. 1Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil, 2Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil, 3Clinical Pharmacology & Therapeutics, School of Life and Medical Sciences, University College London, London, UK

Carvedilol, a drug widely prescribed in cardiac arrhythmia, heart failure and hypertension, is available as a racemic mixture of R-(+) and S-(-) enantiomers. Two of the main carvedilol metabolites are 4’-hydroxyphenyl-carvedilol and O-desmethyl-carvedilol are also pharmacologically active. Unlike other β-blockers, the use of carvedilol does not affect diabetes control [1]. Yet, little is known about the the effects of disease on the pharmacokinetics of carvedilol and its metabolites to allow rational drug dose titration in the target population [2].

Here we investigate the pharmacokinetics of carvedilol and its metabolites in healthy subjects (n=13) and in type II diabetes Mellitus patients (n=13) with the objective of characterising the influence of disease on drug disposition parameters. Serial blood sampling were collected before and at various time points up to 24 hours after administration of a single oral dose of 25 mg carvedilol. All experimental procedures were performed as defined by the clinical protocol, which was approved by the Ethics Committee of the Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo. Plasma levels of the enantiomers were assessed by chiral liquid chromatography coupled to a tandem triple quadrupole mass spectrometry. Given the role of oral bioavailability, intravenous data from a previous literature publication [3] were used in conjunction with the current study data. Population pharmacokinetic modelling was performed using a non-linear mixed effects approach as implemented in NONMEM. R was used for data manipulation, graphical and statistical summaries.

Our results show that R(+)- and S(-)-carvedilol can be characterised by the same structural model. A two-compartment model was found to best describe the pharmacokinetics of Carvedilol enantiomers, whereas a one-compartment model was used for O-desmethyl-carvedilol and 4’-hydroxyphenyl-carvedilol. Based on a univariate covariate analysis no significant differences were observed in pharmacokinetic parameters between health subjects and diabetes patients. With exception of a modest effect of total body weight, other demographic factors or co-medication were found to have no effect on the pharmacokinetics of carvedilol. As expected, slow metabolizers for CYP2D6 presented lower 4’-hydroxyphenyl-carvedilol formation clearance. The slow metabolizing phenotype had however no impact on the overall profile of the parent compound.

It can be concluded that whilst the treatment of hypertension in patients with co-morbidities remains empirical, a model-based analysis of the pharmacokinetics of carvedilol suggests that no dose adjustment is required in Type II diabetes.

[1] Fonseca V et al. (2007). Diabetic Medicine 24: 759–763

[2] Dostalek M et al. (2012). Clinical pharmacokinetics 51(8): 481-499.

[3] Neugebauer G et al. (1990). Eur J Clin Pharmacol Stereoselective 38: S108-S111.