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The Clinical Pharmacogenomics Implementation Consortium: CPIC Guideline for SLCO1B1 and Simvastatin-Induced Myopathy

Clin Pharmacol Ther. 2012 July; 92(1): 112–117.

Published online 2012 May 23. doi:  10.1038/clpt.2012.57

PMCID: PMC3384438

The Clinical Pharmacogenomics Implementation Consortium: CPIC Guideline for SLCO1B1 and Simvastatin-Induced Myopathy

RA Wilke,^1,2 LB Ramsey,³ SG Johnson,^4,5 WD Maxwell,⁶ HL McLeod,⁷ D Voora,⁸ RM Krauss,⁹ DM Roden,^1,2 Q Feng,^1,2 RM Cooper-DeHoff,¹⁰ L Gong,¹¹ TE Klein,^11,12 M Wadelius,¹³ and M Niemi¹⁴

¹Oates Institute for Experimental Therapeutics, Vanderbilt University Medical Center, Nashville, Tennessee, USA;

²Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA;

³Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA;

⁴Department of Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, Colorado, USA;

⁵Clinical Pharmacy Services, Kaiser Permanente Colorado, Denver, Colorado, USA;

⁶Department of Clinical Pharmacy and Outcomes Sciences, South Carolina College of Pharmacy, Columbia, South Carolina, USA;

⁷Department of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, North Carolina, USA;

⁸Department of Medicine, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA;

⁹Department of Medicine, Atherosclerosis Research, Children’s Hospital Oakland Research Institute, Oakland, California, USA;

¹⁰Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida, USA;

¹¹Department of Genetics, Stanford University, Palo Alto, California, USA;

¹²PharmGKB (Pharmacogenetics and Pharmacogenomics Knowledge Base), Stanford University, Palo Alto, California, USA;

¹³Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden;

¹⁴Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland

Correspondence: RA Wilke (Email: russell.a.wilke@vanderbilt.edu )

Author information ► Article notes ► Copyright and License information ►

Received February 9, 2012; Revised May 23, 2012; Accepted March 28, 2012.

Copyright © 2012 American Society for Clinical Pharmacology and Therapeutics

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Abstract

Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A non-synonymous coding single-nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.

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BACKGROUND

The purpose of this study was to provide interpretive guidance when SLCO1B1 genotype is already available in the clinical environment. We do not argue directly in this guideline that SLCO1B1 genotyping is absolutely necessary. However, it seems that the implementation of a gene-based dosing approach is inevitable. We therefore provide guidance for clinicians treating patients with simvastatin in the event that SLCO1B1 genotype is available during routine care.

This guideline is written for providers attempting to manage myopathy risk. Because the strength of the evidence is highest for simvastatin, we limit our recommendations accordingly. We do not present guidelines for all statins. Furthermore, our primary goal is to reduce muscle toxicity and optimize patient adherence. Although efficacy studies are under way, we do not yet see a clear basis for making recommendations on the role of SLCO1B1 genotype in lipid-lowering efficacy.

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FOCUSED LITERATURE REVIEW

A systematic literature review was conducted that focused on SLCO1B1 gene polymorphisms and statin-related end points in humans. Emphasis was placed on the SLCO1B1 variant rs4149056 and two primary end points: (i) statin pharmacokinetics (including parent drugs, lactones, acids, and derivatives related to phase I oxidation and/or phase II conjugation) and (ii) relevant studies of clinical outcome. Because rs4149056 acts via its damaging effect on OATP1B1 protein function, it is assumed that other damaging SLCO1B1 gene variants may have similar clinical impact. However, we limit our recommendations to rs4149056 because the vast majority of pharmacokinetic and clinical outcome data have been published for this variant only.

At present, our recommended approach does not include other pharmacokinetic genes. The quality of evidence linking other pharmacokinetic candidates to myopathy is low to moderate, and additional study is needed. The evidence linking pharmacodynamic candidates to statin-induced myopathy is sparse. The mechanism underlying this adverse drug reaction (ADR) is only partly understood. Although some data show promise in terms of identifying pharmacodynamic variants, the clinical utility of typing these variants remains unclear.