Pharmacogenetics biomarkers predictive of drug pharmacodynamics as an additional tool to therapeutic drug monitoring.

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Abstract

Conventional TDM refers to the individualization of drug dosage by maintaining plasma or blood drug concentrations within a targeted therapeutic range. Accordingly, an individualized dose is proposed to the clinician according to the drug plasma or blood concentration using an a posteriori approach. Pharmacogenetics (PGx) has recently emerged as an additional tool to refine dose selection or, more interestingly to select, a priori, the first dose to administer. To date, the vast majority of genes explored in the context of PGx are those coding for metabolizing enzymes or membrane drug transporters, which mainly influence drug pharmacokinetics (PK) parameters. Indeed, among the 94 PGx-based drug dosing guidelines currently published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) on PharmGKB website, 81 (86%) are associated with the genotype determination of either a metabolizing enzyme or a membrane drug transporter while only 13 (14%) are associated with the genotype determination of a pharmacodynamics (PD)-associated gene. In this article, we describe selected PGx biomarkers that predict/or could predict PD (both in terms of efficacy and toxicity). First, the most relevant clinical applications already subject to validated international guidelines (CPIC and DPWG), and ready to be implemented in routine clinical settings, are discussed to illustrate the clinical potential of PD-associated PGx biomarkers (G6PD, HLA-B*57:01, HLA-B*15:02, VKORC1). Then, to illustrate not only the research potential of such biomarkers, but also the complexity of PGx-PD relationships, the case of immunosuppressive drugs (for which conventional TDM is widely accepted) is extensively described with the potential to include some of these PGx biomarkers in future PGx dosing guidelines.