Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof‐of‐concept study

Abstract

Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease‐related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross‐sectional, proof‐of‐concept association study to replicate the well‐established association between metoprolol concentrations and CYP2D6 genotype‐inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α‐hydroxymetoprolol (α‐OH‐metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6‐inferred phenotype was significantly associated with both metoprolol and α‐OH‐metoprolol in unadjusted and adjusted models (all p < 10 −14 ). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.

Females present higher dose‐adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males

“…All participants reported metoprolol or allopurinol as part of their daily pharmacotherapy regimen at the time of enrollment in the MHI Hospital Cohort at which moment plasma was collected. Exclusion criteria were limited to solid organ transplantation as previously reported 15,16 . Participants self‐identified as male or female at the baseline visit of the MHI Hospital Cohort.…”

“…The genotyping of selected samples was completed at the Université de Montréal Beaulieu‐Saucier Pharmacogenomics Centre (PGx Center) as previously described 15 . Briefly, the genotyping was performed using a combination of Agena iPLEX Gold Chemistry (Agena Bioscience) and the MassARRAY® Analyzer Compact system.…”

“…The objective of this study was to compare drug dosing and drug/metabolite concentrations between females and males for two widely used drugs, the β 1 ‐adrenergic receptor antagonist metoprolol and the uric acid‐lowering agent allopurinol, and to identify potential clinical, anthropometric, genetic, and socioeconomic factors that could explain PK differences between males and females. Metoprolol and allopurinol were selected because they had been investigated as part of two cross‐sectional studies conducted at the Montreal Heart Institute (MHI) 15,16 …”

An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites

“…Samples (DNA and plasma) and clinical data used as part of this study were collected as previously described. 18 , 19 , 20 , 21 , 22 In the current analysis, for 24 patients, plasma was collected during follow‐up, at which time a complete pharmacological and medical history was again completed and used as part of these analyses. All information was collected directly from participants, their medical records, and MHI electronic databases, with the exception of allopurinol, oxypurinol, and allopurinol d‐ribose concentrations, which were measured from plasma as detailed below.…”

“…These data provide information on the medical, genealogical, psychological, biological, pharmacological, and genetic profile of the participants. Samples (DNA and plasma) and clinical data used as part of this study were collected as previously described 18–22 . In the current analysis, for 24 patients, plasma was collected during follow‐up, at which time a complete pharmacological and medical history was again completed and used as part of these analyses.…”