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0091270009341960v1
49/11/1309    most recent
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PHARMACOKINETICS

Quantitative Population Pharmacokinetic Analysis of Pravastatin Using an Enterohepatic Circulation Model Combined With Pharmacogenomic Information on SLCO1B1 and ABCC2 Polymorphisms

Takafumi Ide, MS, Tomohiro Sasaki, MS, Kazuya Maeda, PhD, Shun Higuchi, PhD, Yuichi Sugiyama, PhD and Ichiro Ieiri, PhD

From the Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (Mr Ide, Mr Sasaki, Dr Higuchi, Dr Ieiri) and Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Dr Maeda, Dr Sugiyama).

The aims of this study were to develop a population pharmacokinetic (PPK) model for pravastatin pharmacokinetics with regard to enterohepatic circulation (EHC) and to evaluate effects of polymorphisms in SLCO1B1 and ABCC2 on the pharmacokinetic (PK) profile of pravastatin quantitatively. A total of 636 blood samples from 57 healthy male volunteers were used. The PPK analysis was carried out using nonlinear mixed effect modeling (NONMEM) and validated by a bootstrap analysis. The PK profile of pravastatin was best described by a model of EHC with Erlang's distribution. A covariate analysis revealed that SLCO1B1*15 significantly influenced relative bioavailability (Frel); Frel was increased 1.50- and 1.95-fold in participants heterozygous and homozygous, respectively, for the *15 allele in comparison with participants without the allele. No ABCC2 polymorphism was identified as a potential covariate for pravastatin. The bootstrap analysis indicated that the PK profile of pravastatin was adequately described by the proposed PPK model. SLCO1B1*15 has a significant effect on Frel, indicating that OATP1B1 is one of the determinants of systemic exposure to pravastatin.

Key Words: pravastatin • NONMEM • enterohepatic circulation model • SLCO1B1 • ABCC2

Address for reprints: Ichiro Ieiri, PhD, Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; e-mail: ieiri-ttr{at}umin.ac.jp.


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