The treatment of cardiovascular diseases often involves polypharmacy. Due to the patient’s genetic predisposition, the efficacy and tolerability of the prescribed medications can be affected, making dosage determination more difficult. For drugs such as clopidogrel, statins, and beta-blockers, genetic polymorphisms are known that may lead to delayed or accelerated metabolism, potentially resulting in intolerance and therapy resistance. For mavacamten, genotyping is required by the manufacturer before the start of treatment. Determining the patient's metabolizer type based on the enzymes responsible for breaking down the respective active substances can optimize therapy planning.
In this section:
See also: PGx Mavacamten
Clopidogrel therapy
The active substance clopidogrel is a prodrug that is only converted into an active metabolite in the body. Various cytochrome P450 enzymes are involved in this reaction. The conversion of clopidogrel to 2-oxo-clopidogrel occurs primarily via CYP1A2, CYP2C19, and CYP2B6. The further conversion to the active metabolite is mainly mediated by CYP3A4, CYP2C19, CYP2B6, and CYP2C9.
Variants in the genes of the involved enzymes that lead to reduced enzymatic activity can cause clopidogrel resistance. Compared to individuals with normal metabolizing capacity, carriers of inactivating CYP2C19 gene variants, in particular, show reduced inhibition of platelet aggregation and a higher risk of cardiovascular events (e.g., stent thrombosis, stroke, or heart attack) when treated with clopidogrel. For affected patients, dose adjustment or an alternative medication (e.g., prasugrel, acetylsalicylic acid) may be considered. Due to the involvement of CYP2C19 in both conversion steps, variants in this gene are of particular importance for treatment efficacy. If needed, the other enzymes can also be analyzed. The correlation between the CYP2C19 genotype and clopidogrel resistance has already been included in the prescribing information. Further information and dosage recommendations can also be found in the DPWG and CPIC guidelines for clopidogrel and CYP2C19.
References
Lee et al., CPIC Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update Clin Pharmacol Ther. 2022;112(5):959-967
Statin therapy
The tolerability of HMG-CoA reductase inhibitors (statins) is influenced, among other factors, by variants in the SLCO1B1 gene, which encodes the organic anion transporter OATP1B1. OATP1B1 is predominantly expressed on the sinusoidal membrane of human hepatocytes and is involved in the uptake of various substances from sinusoidal blood into the liver. In addition to endogenous compounds, statins are also substrates of OATP1B1. Some variants in the SLCO1B1 gene are associated with altered transport capacities of the OATP1B1 protein. The C allele of the polymorphism c.521T>C leads to a reduced transport rate of the protein, thereby lowering hepatic substrate uptake and potentially increasing the plasma concentration of statins and other medications.
Several studies have shown that carriers of the C allele exhibit significantly elevated plasma concentrations of simvastatin, pravastatin, pitavastatin, atorvastatin, and rosuvastatin. In this patient group, the risk of myopathy under high-dose therapy (e.g., 80 mg/day of simvastatin) was also significantly increased (OR 4.7). No elevated plasma levels were found for fluvastatin. The frequency of the C allele is approximately 15% in the European population. Other OATP1B1 substrates include the antidiabetic drug repaglinide, the antihistamine fexofenadine, and the active ingredient atrasentan.
Information and dosage recommendations for simvastatin can also be found in the CPIC guideline for simvastatin and SLCO1B1.
References
Prescribing information ZOCOR® (simvastatin)
Xiang et al. 2018, Pharmacogenomics J. (Epub ahead of print) / Ramsey et al. 2014, Clin Pharmacol Ther 96:423
ß-blocker therapy
Beta-receptor blockers such as metoprolol are medications used to lower blood pressure and heart rate. They are prescribed for conditions such as hypertension, coronary artery disease, and chronic heart failure. The enzyme CYP2D6 plays a key role in the metabolism of these drugs. Various variants in the CYP2D6 gene result in accelerated, reduced, or absent enzyme activity, leading to the phenotypic classifications of “ultrarapid,” “intermediate,” or “poor metabolizer.” Impaired or absent enzyme activity can lead to signs of overdose, as the breakdown of beta-blockers is delayed. If suspected, testing for the “poor metabolizer” phenotype can be conducted.
In cases of increased enzyme activity, the drug is metabolized too quickly, resulting in insufficient therapeutic effect. To clarify this, testing for the “ultrarapid metabolizer” phenotype may be appropriate.
References
Prescribing information Metoprolol
DPWG Guideline for metoprolol and CYP2D6
