The influence of personal genetics on a drug against Parkinson’s disease

Rasagiline is part of the therapeutic armamentarium available for the treatment of Parkinson’s disease. A recent study has discovered to what extent the genetics of each person can influence the activity of rasagiline

Specifically, the study has found that some genetic variants in drug transporters alter the pharmacokinetics of rasagiline.

The study authors have found that three genetic polymorphisms located in drug transporters alter the pharmacokinetics of rasagiline in a way that includes drug efficacy and toxicity.

This new knowledge could be harnessed in the future to provide personalized and precise treatments that would avoid toxicity and ensure efficacy.

The study is the work of researchers from the Autonomous University of Madrid (UAM) and the Clinical Pharmacology Service and Health Research Institute of the University Hospital of La Princesa, in Spain.

Artist’s rendering of a nerve cell and DNA segment. (Illustration: Amazings/NCYT)

Pharmacogenetics studies DNA variants that can alter the efficacy and safety of drugs, located in genes that code for metabolizing enzymes, transporters, or targets.

This discipline is widely implemented in routine clinical practice for some drugs. For example, before the prescription of fluoropyrimidines (antineoplastic drugs), it is mandatory to genotype DPYD, the gene that codes for its main metabolizing enzyme (DPD).

There are different variants that cause the reduction or complete loss of function of this enzyme, which is associated with severe toxicity. In patients carrying variants, it is recommended to reduce the dose (in intermediate metabolizers) or fluoropyrimidines are contraindicated (in poor metabolizers).

The published work is an observational study of candidate genes, where 120 variants or polymorphisms in 33 genes were evaluated for their potential relationship with the pharmacokinetic variability and tolerability of rasagiline in 118 healthy volunteers who participated in various bioequivalence clinical trials.

Bioequivalence clinical trials are carried out to demonstrate that a generic drug is equivalent from the pharmacokinetic point of view to the innovator, which allows its commercialization without the need to go through all the phases of clinical research that it went through. The Clinical Trials Unit of the University Hospital of La Princesa (UECHUP) is a national reference in this type of clinical trials.

When these clinical trials are conducted, healthy volunteers are asked for an extra blood sample (and their informed consent) to investigate variations in their DNA related to the pharmacokinetic variability and tolerability of the drug they receive.

For the rasagiline study, the researchers used a ‘QuantStudio 12K Flex Open Array’ instrument, and a ‘custom genotyping array’ containing the 120 variants in the 33 genes analysed. As dependent variable, they used the pharmacokinetic parameters derived from the bioequivalence clinical trial and the incidence of adverse reactions (ADRs).

Depending on the genotype of the volunteers (ABCB1 rs1045642, ABCC2 rs2273697 and SLC22A1 rs34059508), they presented a higher or lower volume of distribution (adjusted for bioavailability), maximum time to reach maximum concentration, and maximum concentration adjusted by dose/weight.

According to the study authors, these variations could have clinical repercussions. For example, patients carrying SLC22A1*5 (or A in rs34059508 G>A) may not achieve therapeutic concentrations of rasagiline, so a dose increase may be considered in these patients.

“Additional studies are required to confirm these associations before proposing interventions in routine clinical practice. To our knowledge, this is the first paper to comprehensively study the pharmacogenetics of rasagiline,” the study authors conclude.

The study is titled “Polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline”. And it has been published in the academic journal Pharmaceutics. (Source: UAM)