Prescribed Doses of CYP2D6-Metabolized Drugs and Hemodynamic Responses in Relation to CYP2D6 Genotype Among Older Patients Exposed to Polypharmacy

Drugs Aging. 2020 Jun;37(6):425-433. doi: 10.1007/s40266-020-00763-0.

Abstract

Background: Many drugs with dose-dependent effects on hemodynamic variables are metabolized by cytochrome P450 2D6 (CYP2D6). The aim of this study was to compare prescribed dosages and hemodynamic responses of such drugs in relation to pharmacogenetic variability in CYP2D6 metabolism among patients aged ≥ 70 years exposed to polypharmacy.

Materials and methods: We included 173 patients with detailed information about drug use. The patients were retrospectively subjected to CYP2D6 genotyping, which comprised the most common variant alleles encoding reduced, absent, or increased CYP2D6 metabolism. In order to compare dosages across different CYP2D6-metabolized drugs, all prescribed daily doses were harmonized to the 'percent of a daily defined dose' (DDD). The mean harmonized DDD was compared between genotype-predicted normal metabolizers (NMs) and patients with reduced or absent CYP2D6 enzyme activity, defined as intermediate or poor metabolizers (IMs/PMs). Blood pressure, pulse, and patient proportions with orthostatism and bradycardia were also compared between genotype subgroups.

Results: The genotype-predicted phenotype subgroups comprised 79 NMs (45.7%), 75 IMs (43.4%), and 16 PMs (9.2%). There were no differences in dosing of CYP2D6 substrates between NMs and IMs/PMs (p = 0.76). A higher proportion of CYP2D6 IMs/PMs experienced orthostatism (p = 0.03), while there were no significant subgroup differences for the other hemodynamic variables.

Conclusion: In this real-life clinical setting of patients aged ≥ 70 years, dosing of CYP2D6 substrates were not adjusted according to genotype-predicted CYP2D6 metabolism. The increased occurrence of orthostatism in patients with reduced/absent CYP2D6 metabolism may indicate that individualized dosing based on genotype has the potential to prevent adverse effects in these vulnerable patients.