1. Ther Drug Monit. 2009 Dec;31(6):734-42.

Time of drug administration, CYP3A5 and ABCB1 genotypes, and analytical method
influence tacrolimus pharmacokinetics: a population pharmacokinetic study.

Musuamba FT, Mourad M, Haufroid V, Delattre IK, Verbeeck RK, Wallemacq P.

Universite catholique de Louvain, Louvain Centre for Toxicology and applied
Pharmacology, Brussels, Belgium.

Tacrolimus (TAC) pharmacokinetics are characterized by a very high variability
that complicates its therapeutic use. The aims of this study were: 1) to identify
and model the effect of demographic, clinical, and genetic factors and time of
drug administration on TAC pharmacokinetic variability; and 2) to assess the
influence of the analytical method by modeling the TAC blood concentrations
measured simultaneously by microparticle enzyme immune assay (MEIA) and liquid
chromatography-tandem mass spectroscopy. Data from 19 renal transplant candidates
were analyzed. A total of 266 blood samples were analyzed for TAC by both
techniques. Linear regression and Bland and Altman analyses were performed to
compare TAC blood concentrations obtained with MEIA and liquid
chromatography-tandem mass spectroscopy. A population pharmacokinetic analysis
was performed. As expected, blood concentrations obtained by MEIA were higher
than those obtained by liquid chromatography-tandem mass spectroscopy. A
two-compartment model with first-order absorption and elimination best fit TAC
blood concentrations. An exponential model was used to describe the
interindividual and interoccasion variability and a mixed model was retained for 
the residual variability. A supplementary proportional term was necessary for the
residual error in case of TAC blood concentrations determined by MEIA. The
following covariates were retained in the final model: time of drug
administration on the absorption rate constant and CYP3A5 and ABCB1 genotypes on 
the TAC apparent clearance. All parameter estimates had reliable values. The
final model was found to be stable and generated parameters with good precision. 
The validation of the final model by bootstrapping (2000 bootstraps), case
deletion diagnostics, crossvalidation, and visual predictive check (1000
simulated subjects) gave satisfactory results. This is the first population
pharmacokinetic study confirming the chronopharmacokinetics of TAC and showing an
effect of ABCB1 genotype and analytical method on TAC pharmacokinetics. These
results may be helpful for TAC dose individualization.

PMID: 19855314 [PubMed - in process]