Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide

Abstract

Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters’ genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, β = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, β = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics.

Exploring CYP2D6 polymorphisms and angiotensin receptor blocker response in the Bai hypertensive population

“…Notably, its association with portal hypertension in liver cirrhosis patients has been elucidated [ 31 ]. In addition, research by Soria-Chacartegui suggested a potential involvement of CYP2D6 in the metabolism of valsartan [ 9 ]. These developments suggest a more complex and nuanced role for CYP2D6 in drug metabolism, particularly concerning ARBs.…”

“…This unique domain structure enables the enzyme to oxidize a wide range of pharmaceutical compounds. Responsible for metabolizing nearly a quarter of all clinically used drugs, including adrenergic antagonists [ 7 , 8 ] and ARBs [ 9 ], CYP2D6 exhibits considerable polymorphic diversity. To date, over 172 CYP2D6 gene variants have been identified ( https://www.pharmvar.org/ , last accessed: 11 December 2023), with many of which are linked to reduced enzymatic function, potentially affecting drug efficacy [ 10 , 11 ].…”