November 20, 2014 – Recent research has addressed the clinically strikingly wide variation among patients in plasma levels of Atorvastatin (Lipitor) and Rosuvastatin (Crestor), even with consistent dosing. This research proposes that the phenomenon is likely related to gene variants that affect the drugs’ uptake by the liver in some patients.
The researchers propose that selective genetic sscreening of patients for the presence of the specific genetic polymorphisms could help to 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, the researchers found a huge interpatient variability (45 fold) in the blood plasma
levels of the respective statin given to each patient at the same dose. Apparently, in the study, there were some people with very low blood plasma levels and an excellent response to statins, and people with unexpectedly high blood plasma levels and a reasonable response to statins. The latter group appeared to be at increased risk for adverse effects. This is interesting in that statins affect lipoproteins in the liver, but the adverse effect risk seemingly correlates and goes up with blood plasma levels. Presumably, in the study, age was an important factor also because in patients older than aged 75 with the wrong genetic makeup, the higher doses were particularly bad in terms of increased risk for adverse effects.
This is now where theragenomic medicine might come into play to the benefit of the patient. Theragenomic medicine uses genomic methods to tailor therapy according to the genetic outfit of the patient. In the case discussed here with statins ,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 researcher found. 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 P4503A4 (CYP3A4).
The analyses were adjusted for gender, age, body-mass index, ethnicity, statin dose, and time from last dose. The researcher 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 researchers 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.
Eventually, the researchers 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. Nevertheless, the researchers 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 caucasianss; the researchers cautions that some other ethnicities, in particular patients with asian decent have increased sensitivity to statins.
For the scientifically interested patient expert, the study was published online July 22, 2013 in Circulation: Cardiovascular Genetics with first author Dr Marianne K DeGorter (University of Western Ontario) and can be found here.