LONDON, Ontario— Strikingly wide variation among patients in plasma levels of atorvastatin and rosuvastatin (Crestor, AstraZeneca), even with consistent dosing, is likely related to gene variants that affect the drugs’ uptake by the liver in some patients, suggests a prospective study. The researchers propose that selective screening of some statin candidates for the presence of the specific polymorphisms could help individualize atorvastatin and rosuvastatin dosing with the goal of lowering the risk of statin side effects, especially myopathy.
In the study of 399 patients taking either statin, senior author Dr Richard B Kim (University of Western Ontario, London) toldheartwire ,”We were surprised at the extent of interpatient [plasma-level] variability at the same dose. Tremendous variation–45-fold. That is to say, there were some people with very low blood levels and an excellent response to statins, and people with unexpectedly high levels and a reasonable response to statins.” It’s the latter group that appears to be at increased risk, given that statins affect lipoproteins in the liver, but the side-effect risk goes up with plasma levels.
“We also were surprised by the role of age. It really did look like, in our patients older than aged 75 with the wrong genetic makeup, the higher doses were particularly bad in terms of risk.”
The study was published online July 22, 2013 in Circulation: Cardiovascular Genetics with first author Dr Marianne K DeGorter (University of Western Ontario).
The group devised a potential management algorithm that includes genotyping and is aimed at avoiding adversely high statin plasma levels, acknowledging that whether it would prevent side effects has yet to be demonstrated. But Kim said it could add to efforts to avoid significant muscle enzyme elevations or actual rhabdomyolysis.
It really did look like, in our patients older than aged 75 with the wrong genetic makeup, the higher doses were particularly bad in terms of risk.
“It’s really an additional decision support tool that incorporates clinical and pharmacogenetic variables that I think gives the prescribing physician a point of reference regarding when to switch [treatments], how to switch, and dose considerations, with a mechanistic point of view in terms of drug level,” Kim said. The current study “does say that if you’re thinking high-dose in an older person, the [algorithm] might be particularly useful.”
In the 165 patients taking rosuvastatin, nearly all the explainable variability in blood concentrations could be attributed to two reduced-function polymorphisms, one in the uptake transporter gene SLCO1B1 (p<0.001) and the other in the efflux transporter gene ABCG2 (p<0.01), the group writes. In the 134 patients on atorvastatin, explainable blood-level variability was split between two polymorphisms in SLCO1B1 (p<0.01 and p<0.05, respectively) and the activity of cytochrome P3A (CYP3A). The analyses were adjusted for gender, age, body-mass index, ethnicity, statin dose, and time from last dose, and echo a 2008 study which concluded that two SLCO1B1variants were associated with simvastatin-related myopathy, as reported by heartwire . The screening concept is currently being applied to simvastatin therapy at least at one major center.
The group retrospectively tested their ideas, looking at the relationships between genotypic and clinical variables and statin dose, in a validation cohort of 579 patients taking either drug in a primary care setting in the US and at a referral clinic in Canada.
The group found that the transporter genotypes that raise statin concentrations were homogeneously distributed among patients taking a range of atorvastatin and rosuvastatin dosages. That is, the prescribing physicians, armed primarily with their clinical judgment to decide dosage levels, failed to achieve optimal dosing with respect to serum drug levels. But it seemed to be only patients receiving the highest dosages who showed higher-than-safe serum levels according to genotype- and age-based criteria.
“Although we didn’t quite get to the sample size we needed, it did seem like people with the wrong genetic makeup are more likely to stop a statin or switch to [another dyslipidemia drug],” Kim said, at least among patients on the highest statin dosages.
The group’s proposed management algorithm recommends a maximum statin dosage that will result in plasma concentrations below the 90th percentile (reflecting an assumption that 10% of patients will have statin-related muscle issues) based on patient age and transporter-related genotype.
The algorithm is based on data predominantly from whites; the group cautions that some other ethnicities, “particularly Asians,” have increased sensitivity to statins.
The research was supported by grants from the Canadian Institutes of Health Research, Drug Safety and Effectiveness Network, Academic Medical Organization of Southwestern Ontario Alternate Funding Plan Innovation Fund, and US National Institutes of Health. Neither Kim nor DeGorter had any disclosures; disclosures for the coauthors are listed in the paper.
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