A team of pharmacogenetics experts from the Universidad Autónoma de Madrid (UAM) and the Hospital Universitario de La Princesa have questioned the clinical utility of a biomarker that has been assumed to hold promise for personalized drug treatments. The results, published in the journal Clinical Pharmacology and Therapeutics, highlight the importance of rigorous and continuous evaluation of pharmacogenetic biomarkers prior to their implementation in clinical practice.
The implementation of pharmacogenetic biomarkers in clinical practice has revolutionized the personalized treatment of patients. These biomarkers make it possible to identify those patients with a higher risk of suffering adverse drug reactions (ADRs) or lower drug efficacy, which facilitates the adjustment of therapies to prevent undesirable events.
An example with a very common drug is that of slow metabolizers of CYP2C9, a key enzyme in the metabolism of ibuprofen, who present a significantly increased risk of AMR with standard doses and therefore require a dose reduction to ensure efficacy and minimize the risk of AMR.
Recently, the Pharmacogenetics Unit of the Hospital Universitario La Princesa studied a haplotype-physical grouping of genomic variants-associated with the ultrafast metabolism of several CYP2C19 substrates. Specifically, it investigated the impact of the CYP2C:TG haplotype on three variables: the pharmacokinetic variability of several drugs, the protein concentration of different enzymes in human liver tissue, and in vitro enzymatic activity. These investigations were developed with the collaboration of the Children’s Mercy Research Institute, Kansas City, USA, regarding the liver tissue samples for the study.
According to the results, published in the journal Clinical Pharmacology and Therapeutics, the researchers did not observe any significant impact of this haplotype on any of these variables.
However, they did detect an increase in CYP2C18 liver concentration in the presence of the CYP2C19*17 allele, suggesting that CYP2C18 may influence the overall metabolism of certain drugs.
Scientific debate
The findings of this study have generated a scientific debate, and after exchanging correspondence with the authors of a previous work that discovered this haplotype, both groups agree that there is still insufficient evidence to justify the implementation of CYP2C:TG genotyping in current clinical practice.
"The effect of this haplotype appears to be very small or null, and several additional independent studies confirming the association are necessary before considering its clinical relevance," the authors say.
"It is as important to implement in clinical practice those biomarkers with sufficient relevance as it is to control the enthusiasm that some research findings with respect to pharmacogenetic biomarkers may provoke," they stress.
Finally, the researchers highlight the role of organizations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC), of which Pablo Zubiaur is a member, the Pharmacogenetics Working Group of the Royal Dutch College of Pharmacists (DPWG) and the Spanish Society of Pharmacogenetics, of which research professionals form part, among others, because these bodies are "those who play a crucial role in the elaboration of clinical implementation guidelines and in the evaluation of the clinical relevance of pharmacogenetic biomarkers, ensuring the quality and impartiality of their recommendations".
The Pharmacogenetics Unit of the Hospital Universitario La Princesa, associated with the Department of Pharmacology of the Faculty of Medicine of the Universidad Autónoma de Madrid (UAM), has been a pioneer in providing pharmacogenetic assistance for more than fifteen years. Currently, it is a reference institution thanks to its PriME-PGx initiative(La Princesa Multidisciplinary Initiative for the Implementation of Pharmacogenetics).
Bibliographic reference:
Zubiaur, P. et al. (2023). "Impact of CYP2C:TG Haplotype on CYP2C19 Substrates Clearance In Vivo, Protein Content, and In Vitro Activity" . Clin Pharmacol Ther.
