Pharmacogenetic Variability in Drug Response

Abstract

Pharmacogenetic variability -- the contribution of inherited genetic variants to inter-individual differences in drug pharmacokinetics and pharmacodynamics -- accounts for 20-95% of observed drug response variability depending on the drug class, with consequential clinical implications spanning therapeutic failure (poor metaboliser exposure insufficiency), adverse drug reactions (ultrarapid metaboliser accumulation; narrow therapeutic index drugs), and idiosyncratic toxicity (HLA-associated hypersensitivity). Clinically actionable pharmacogenes include CYP2D6 (codeine, tamoxifen, tricyclic antidepressants), CYP2C19 (clopidogrel, proton pump inhibitors, SSRIs), CYP2C9 + VKORC1 (warfarin), SLCO1B1 (statins), DPYD (fluoropyrimidines), TPMT/NUDT15 (thiopurines), and HLA-B*57:01 (abacavir). This study evaluated 284 patients prospectively genotyped for a 12-gene pharmacogenetic panel (Italy n = 148; Sweden n = 136; 2020-2023) across five drug classes, developing a Pharmacogenetic Variability Quality Index (PVQI) integrating genotype actionability, phenotype prediction confidence, drug-gene interaction severity, clinical outcome impact, and implementation guideline availability to predict clinically significant drug response deviation (dose adjustment required or drug contraindicated per CPIC guidelines). PVQI predicted clinically significant response deviation with AUC = 0.883 and Pearson r = +0.84 (p < 0.001), identifying CYP2D6 and DPYD drug-gene interactions as the highest-impact actionable pharmacogene-drug pairs across the 284-patient cohort.