Physiologically based pharmacokinetic (PBPK) modeling of pitavastatin in relation to SLCO1B1 genetic polymorphism

초록

Pitavastatin, a potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is indicated for the treatment of hypercholesterolemiaand mixed dyslipidemia. Hepatic uptake of pitavastatin is predominantly occupied by the organic anion transportingpolypeptide 1B1 (OATP1B1) and solute carrier organic anion transporter family member 1B1 ( SLCO1B1 ) gene, which isa polymorphic gene that encodes OATP1B1. SLCO1B1 genetic polymorphism signifi cantly alters the pharmacokinetics ofpitavastatin. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict pitavastatinpharmacokinetics according to SLCO1B1 genetic polymorphism. PK-Sim ® version 10.0 was used to establish the wholebodyPBPK model of pitavastatin. Our pharmacogenomic data and a total of 27 clinical pharmacokinetic data with diff erentdose administration and demographic properties were used to develop and validate the model, respectively. Physicochemicalproperties and disposition characteristics of pitavastatin were acquired from previously reported data or optimized to capturethe plasma concentration–time profi les in diff erent SLCO1B1 diplotypes. Model evaluation was performed by comparing thepredicted pharmacokinetic parameters and profi les to the observed data. Predicted plasma concentration–time profi les werevisually similar to the observed profi les in the non-genotyped populations and diff erent SLCO1B1 diplotypes. All fold errorvalues for AUC and C max were included in the two fold range of observed values. Thus, the PBPK model of pitavastatin indiff erent SLCO1B1 diplotypes was properly established. The present study can be useful to individualize the dose administrationstrategy of pitavastatin in individuals with various ages, races, and SLCO1B1 diplotypes.

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