Research Article
Pharmacokinetics, Pharmacodynamics and Drug Transport and Metabolism
Rosuvastatin Pharmacokinetics in Asian and White Subjects Wild Type for Both OATP1B1 and BCRP Under Control and Inhibited Conditions

https://doi.org/10.1016/j.xphs.2017.03.027Get rights and content

Abstract

The Food and Drug Administration recommends rosuvastatin dosage reductions in Asian patients because pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects compared with Caucasian controls. Yet, no explanation for this ethnic difference has been confirmed. Here we show that rosuvastatin exposure in Asians and Whites does not differ significantly when all subjects are wild-type carriers for both solute carrier organic anion transporter 1B1 *1a and ATP-binding cassette subfamily G member 2 c.421 transporters in a 2-arm, randomized, cross-over rosuvastatin pharmacokinetics study in healthy white and Asian volunteers. For single rosuvastatin doses, AUC0-48 were 92.5 (±36.2) and 83.5 (±32.2) ng/mL × h and Cmax were 10.0 (±4.1) and 7.6 (±3.0) ng/mL for Asians and Whites, respectively. When transporters were inhibited by intravenous rifampin, rosuvastatin AUC0-48 and Cmax also showed no ethnic differences. Our study suggests that both SLCO1B1 and ABCG2 polymorphisms are better predictors of rosuvastatin exposure than ethnicity alone and could be considered in precision medicine dosing of rosuvastatin.

Introduction

Statins have been used worldwide in millions of patients to prevent cardiovascular disease and treat lipid disorders. A number of large clinical trials and post-marketing surveys have demonstrated the substantial health benefit to statin use.1, 2, 3 Although adherence to statin therapy is a key factor associated with improved treatment outcomes, it is concerning that as many as 50% of patients stop treatment within 1 year of statin initiation.4 About 62% of former statin users state the reason they stopped their statin was due to side effects, including myopathy and potentially lethal rhabdomyolysis.5 Onset of side effects has been associated with elevated statin blood levels.6, 7 Statin-induced myalgias were reported in 10-20% of statin-treated patients and led to treatment discontinuation in 30% of the symptomatic patients.8 To reduce side effects and achieve an optimal dosing regimen for better adherence to statins in each individual, a holistic understanding of the underlying mechanism is warranted.

Food and Drug Administration (FDA) recommends that Asian patients initiate therapy at half of the normal dose for non-Asians because the rosuvastatin drug label states that “Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared to Caucasian controls.” The molecular mechanism that leads to differential drug exposure between Asians and whites remains unknown.

Previous studies have ruled out extrinsic factors including the environment, diet, and variations in body weight as causing the interethnic rosuvastatin exposure differences.9, 10 Rather intrinsic factors of drug absorption, distribution, metabolism, and elimination are suggested to play the major roles, with hepatic clearance of unchanged drug into the bile believed to be the major route of elimination. Because rosuvastatin is poorly metabolized and mainly excreted as unchanged drug, rather than metabolism, the transporting of rosuvastatin into and out of hepatocytes by drug transporters could be playing important roles in the observed interethnic differences.

Our understanding of drug pharmacokinetics has been advanced greatly since the 1990s by recognizing the roles of drug transporters in drug disposition. Drug transporters are expressed throughout the body in different organs and facilitate uptake or efflux of drugs into or out of the body. Rosuvastatin is a hydrophilic molecule, which strongly depends on drug transporters to cross cell membranes and reach its site of action.11 The effects of hepatic uptake and efflux transporters on the pharmacokinetics and pharmacodynamics of rosuvastatin have been well characterized in the literature.12, 13 Uptake transporters, including organic anion–transporting polypeptides (OATP) 1B1 and 1B3, as well as Na+-taurocholate cotransporting polypeptide, facilitate rosuvastatin uptake into hepatocytes, where the drug inhibits HMG-CoA reductase, whereas efflux transporters, such as breast cancer resistance protein (BCRP), eliminate rosuvastatin into the bile. OATP1B1 is the major hepatic uptake transporter, whereas BCRP is the major efflux transporter, expressed on the canalicular side of the liver and at the apical border of enterocytes.14, 15

Genetic polymorphisms leading to reduced function in OATP1B1 and BCRP transporters have been shown to affect rosuvastatin pharmacokinetics and its subsequent pharmacologic effects.16 Due to their abundance and important roles, SLCO1B1 (gene encoding OATP1B1)17, 18 and ABCG2 (gene encoding BCRP)19, 20 reduced functional polymorphisms and their minor allele frequency have previously been proposed as the cause of interethnic variations in rosuvastatin pharmacokinetics and drug-drug interactions. The reduced function SNP frequency for both SLCO1B1 *15 (defined by c.388A > G and c.521T > C) and ABCG2 c.421C > A are more prevalent in Eastern Asians (14% and 35%, respectively) compared with whites (2.7% and 14.0%).21, 22 Another 2 studies show that at least 2-fold higher rosuvastatin exposure was still observed in Asians compared with whites residing in the same environment after controlling only for the SLCO1B1 wild type.9, 10 Tomita et al.22 suggested that SLCO1B1 and ABCG2 c.421 polymorphisms could not explain the observed plasma concentration variations between Asians and Caucasians. Tomita et al. further proposed that in addition to genetic variants, protein expression could be another contributing factor. However, a recent study showed that OATP1B1 protein expression was similar between Asians and whites.23

None of the previous clinical studies have prospectively evaluated both wild-type OATP1B1 and BCRP transporters to explain interethnic differences in rosuvastatin systemic exposure. Thus, here we prospectively investigate if interethnic differences in rosuvastatin drug exposure could be mitigated by controlling for both SLCO1B1 *1a/*1a or *1a/*1b together with ABCG2 c.421 wild type. Our results could improve treatment adherence by providing a more sound basis for determining the appropriate dosage of rosuvastatin when taken alone or combined with other medications.

Section snippets

Study Design

We conducted an investigator-initiated, prospective, 2-arm, crossover, randomized, controlled trial to evaluate the pharmacogenomic effect of drug transporters on rosuvastatin pharmacokinetics in Asian and white healthy volunteers. Recruitment was from the general public in the San Francisco/Bay area from November 2014 to July 2015. Each participant provided written informed consent.

Subjects were block randomly assigned to receive either an oral 20 mg rosuvastatin tablet (Crestor®; AstraZeneca,

Participant Demographics

During recruitment, 39 Asians and 21 whites were screened. We found 8 eligible healthy volunteers in each ethnic group, who underwent randomization and completed the study. Asian volunteers were mainly Han-Chinese descendants (87.5%), with only one being Japanese (12.5%). All the white volunteers were self-reported to be of European decent. The study population averaged 33.8 years old for Asians and 43.1 years old for whites. Average weights were 63.4 kg for Asians and 68.1 kg for whites. BMIs

Discussion

This prospective study demonstrates that the consistently observed 2-fold average difference in rosuvastatin drug exposure between Asian and white was mitigated after controlling for 2 drug transporters, SLCO1B1 *1a and ABCG2 c.421 wild type. In our cohort, both Asian and white volunteers exhibited similar rosuvastatin AUC and Cmax, which implicates similar pharmacologic effects. In addition, our study result aligns with the previous literature finding of no significant difference in

Conclusions

The most recent ACC/AHA Blood Cholesterol Guideline recommends rosuvastatin as one of the 2 most potent statins to reduce the risk of cardiovascular events in moderate and high-risk patients. And the Food and Drug Administration recommends beginning at a lower starting dose in patients of Asian descent. Yet, our study suggests that about one third of Asian patients (39%) exhibit wild-type genotype of the important transporters for rosuvastatin disposition. Treating these patients with lower

Acknowledgments

This study was supported in part by National Institutes of Health(NIH) grant GM61390. It was carried out in part in the Clinical Research Center, Moffitt Hospital, University of California, San Francisco, which is supported by NIH/National Center for Research Resources UCSF-CTSI grant UL1RR024131. H.-F.W. was supported in part by a GEMS-CTSI Clinical Research Student Award. The authors thank the nurses and staff at the Clinical Research Center, Moffitt Hospital, University of California, San

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    Conflicts of interest: The authors declare no conflict of interest.

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