Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

Abstract

Aim(s): Ethnicity has a modulating role in atorvastatin pharmacokinetics, with Asian subjects reported to have higher exposure compared to Caucasians. Therefore, it is difficult to safely extrapolate atorvastatin pharmacokinetic data and models across ethnic groups. This work aims to develop a population pharmacokinetic model for atorvastatin and its pharmacologically active metabolites specifically for the Japanese population. Subsequently it is aimed to identify genetic polymorphisms affecting atorvastatin pharmacokinetics in this population. Methods:Atorvastatin acid and o-OH-atorvastatin acid plasma concentrations, clinical/ demographic characteristics and genotypes for 18 genetic polymorphisms (3, 3, 1, 1, 7, 2 and 1 in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes respectively) were collected from 27 Japanese individuals (taking 10mg atorvastatin once daily) and analysed using a population pharmacokinetics modelling approach. Results:The developed population pharmacokinetic model (one-compartment for atorvastatin acid linked through metabolite formation to an additional compartment describing the disposition of o-OH-atorvastatin acid) accurately described the observed data and the associated population variability. Our analysis suggested that subjects carrying one variant allele for the rs2622604 polymorphism (ABCG2) exhibit a 55% (95%CI: 16%-131%) increase in atorvastatin oral bioavailability relatively to the value in individuals without the variant allele. Conclusion:The current work reports the identification in the Japanese population of a BCRP polymorphism, not previously associated with the pharmacokinetics of any statin, that substantially increases atorvastatin acid and o-OH-atorvastatin acid exposure. The developed model may be of clinical importance in order to guide dosing recommendations tailored specifically for the Japanese.

Atorvastatin population pharmacokinetics in a real‐life setting: Influence of genetic polymorphisms and association with clinical response

“…[40][41][42][43][44] Some population PK (PopPK) studies have been published but with strict, rich sampling and/or in a limited number of (healthy) individuals without considering genetic polymorphisms and, thus, are not likely to reflect the constraints of real-life clinical settings. 29,[45][46][47][48] In this context, with the support of rich datasets from former studies, 49,50 our study aimed at constructing a PopPK model with data prospectively collected in a cohort of ambulatory patients sparsely sampled and including relevant pharmacogenetic information. Next, we derived the apparent clearance (CL/F) of the drug in each individual and related it with indicators of statin-related muscle toxicity and cholesterol-lowering response.…”

Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review

“…The Keskitalo group ( 39 ) found that carriers of the c. 421AA genotype had a 72 % larger mean atorvastatin AUC than those with the c. 421CC genotype. Another study ( 91 ) in a Japanese population revealed that patients carrying the rs2622604 ABCG2 allele variant had a 55 % increase in oral atorvastatin bioavailability vs non-carriers.…”

Influence of Drug–Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho-OH-Atorvastatin in Aging People Living with HIV

“…The present study also identified large between-subject variability in atorvastatin clearance and central volume of distribution. Although non-compartmental analyses showed an effect of age on atorvastatin disposition [ 10 , 11 ], the majority of previously published population PK analyses did not report any significant influence [ 13 , 14 , 16 ], while one of the studies found an effect in men only [ 12 ]. In our study, this association did not reach statistical significance, although visual inspection of the plots evaluating the effect of age on atorvastatin clearance suggested a slight decrease in clearance for PLWH older than 60 years of age.…”

“…One non-compartmental PK study showed an effect of sex (11% decrease in area under the curve [AUC] in women) on atorvastatin disposition [11]. Moreover, population PK studies indicate a body weight-related decrease in atorvastatin clearance [13], an influence of liver enzymes (aspartate aminotransferase [AST] and lactate dehydrogenase) on atorvastatin disposition [14,15], and an effect of polymorphisms in the intestinal breast cancer resistance protein (BCRP) on atorvastatin bioavailability [16]. However, to our knowledge, no study investigated the effect of ARVs on atorvastatin disposition in a real-life setting.…”