Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis

J Clin Pharm Ther. 2013 Feb;38(1):56-61. doi: 10.1111/jcpt.12016. Epub 2012 Nov 20.

Abstract

What is known and objective: Rifampicin (RIF) shows wide variability in its pharmacokinetics. The purpose of this study was to develop and validate a population pharmacokinetic model to characterize the inter- and intra-individual variability in pharmacokinetic parameters of RIF in Mexican patients.

Methods: Ninety-four patients receiving antituberculosis therapy participated in this prospective study. Plasma concentration-time data were described using a one-compartment model with lag time, absorption and first-order elimination. The potential influence of demographic and clinical characteristics of the patients, and the pharmaceutical formulation (A, B, C and D) on the pharmacokinetics parameters, was evaluated by non-linear mixed-effect modelling (nonmem). Seventy-seven additional patients participated in the validation of the model.

Results and discussion: The final population pharmacokinetic model obtained was as follows: apparent clearance CL/F = 8·17 L/h (1·40 as high for males), apparent distribution volume V(d)/F = 50·1 L (1·29 as high for males), absorption rate constant K(aA) = 0·391/h, K(aB,C,D) = 2·70/h, relative bioavailability F(A) = 0·468, F(B,C,D) = 1, lag time in the absorption phase T(lag) = 0·264 h. The final model improved the precision on the parameter estimates (CL/F, V(d) /F and K(a) by 31·9%, 16·7% and 92·9%, respectively). The residual variability was 27·3%.

What is new and conclusion: Gender was associated with changes in CL/F and V(d) /F whereas the pharmaceutical formulation was associated with changes in F and altered the K(a) . The validation data set showed that the model could be used in clinical practice for Bayesian dose adjustment of RIF in TB patients.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibiotics, Antitubercular / administration & dosage
  • Antibiotics, Antitubercular / pharmacokinetics*
  • Antibiotics, Antitubercular / therapeutic use
  • Biological Availability
  • Female
  • Humans
  • Male
  • Mexico
  • Middle Aged
  • Models, Biological*
  • Nonlinear Dynamics
  • Prospective Studies
  • Rifampin / administration & dosage
  • Rifampin / pharmacokinetics*
  • Rifampin / therapeutic use
  • Sex Factors
  • Tissue Distribution
  • Tuberculosis / drug therapy*
  • Young Adult

Substances

  • Antibiotics, Antitubercular
  • Rifampin