ROLE OF PHARMACOGENOMICS IN OPTIMIZING DRUG THERAPY FOR CHRONIC DISEASES

Abstract

Pharmacogenomics is an approach that has a perspective of personalizing drug therapy using genetic variation; however, there is little evidence prospectively on polypharmacy patients with numerous morbidities. The clinical utility, predictive performance, and cost-effectiveness of preemptive multi-gene pharmacogenomic profiling were compared to conventional care and reactive single-gene testing in this paper. This is a mixed-method study, comprising 1,200 patients (retrospective cohort) and 600 patients (prospective randomized trial) (mean age 64.3 years, 52% female, mean 7.4 medications). A 50-gene genotyping was conducted, and nine nested predictive models were developed to incorporate clinical covariates, polypharmacy indices, drug-gene interactions, environmental factors, epigenetic scores, and polygenic risk scores. Incidence of adverse drug reactions, therapeutic failure, pharmacokinetic parameters, and incremental cost-effectiveness ratios at 60 months and above were the outcome measures. The whole pharmacogenomic model with polygenic risk scores was better (AUC-ROC 0.944, Matthews correlation coefficient 0.791, integrated calibration index 0.011) and reduced the risk of therapeutic failure by 49.6% (HR 0.504, p<0.001). Preemptive testing decreased the incidence of cumulative adverse drug reactions in six months from 28.7 to 4.2 (85.4% relative risk reduction). The greatest drug-drug-gene interaction (DPYD variant in combination with fluorouracil and metronidazole) resulted in an HR of 3.876. The whole model was probably economical at the 50,000/QALY mark with an incremental net financial worth of 523 per patient. Overall, 96.8% of patients have at least one actionable genotype, so polygenic risk score integration with preemptive multi-gene pharmacogenomic profiling is both cost-effective and greatly improves the clinical outcomes of multimorbid polypharmacy patients. These results form an excellent evidence base to support the use of preemptive genotyping as a standard of care by health systems.