Primary Care Prescription Drug Use and Related Actionable Drug-Gene Interactions in the Danish Population

Abstract

Pharmacogenetics (PGx) aims to improve drug therapy using the individual patients' genetic make-up. Little is known about the potential impact of PGx on the population level, possibly hindering implementation of PGx in clinical care. Therefore, we investigated how many patients use actionable PGx drugs, have actionable genotypes or phenotypes and which patients could benefit the most of PGx testing. We included PGx recommendations from two international PGx consortia (Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG)). Using data from publically accessible sales information drawn from the Danish Register of Medicinal Product Statistics (MEDSTAT), we identified the number of users of actionable prescription PGx drugs among the total Danish population in 2017. We estimated actionable genotypes or phenotypes based on reported frequencies from literature. We identified 49 drug-gene interactions related to 41 unique prescription drugs. The estimated median frequency of actionable genotypes or phenotypes among prescription drug users was 25% (interquartile range 7-26%). Six of 41 drugs were used more than twice as much in women. Actionable PGx drugs were most frequently used by 45-79 year old patients (62%), followed by 25-44 year old patients (18%). Almost half of the actionable PGx drugs (19/41) were psychotropics (i.e., antidepressants, antipsychotics, or psychostimulants). PGx testing can have a substantial impact on the population, as one in four prescription drug users has an actionable genotype or phenotype and could thus benefit from PGx testing. We advocate for prospective panel-based PGx testing at the time of the first PGx drug prescription ("as needed"), with PGx results ready prior to start of the first, and all future, therapies.

Figure 1

Overview of actionable drug‐gene interactions (DGIs). Shown is a representation of all 87 actionable DGIs in pharmacogenetics (PGx; 68 unique drugs), including disease area and associated genes. In total, 49 actionable DGIs (41 unique drugs) were included in the actionable PGx drug list in this study. These drugs are shown in bold and marked with an * in the fourth text column (Drug). In addition, these drugs are color‐coded in orange instead of yellow in the third colored waves column (between Drug group and Drug). All CYP genes are colored blue, and non‐CYP genes are green with the intention to improve readability of the figure. The figure has no scale. CVD, cardiovascular disease.

Figure 2

Drug‐gene interactions (DGIs) in the study. Flowchart of DGIs and drugs identified using Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG) guidelines. Some drugs were excluded because there was no information in MEDSTAT for these drugs, possibly due to no market authorization in Denmark, no sale, no data, or no calculation available. The figure was build using CPIC and DPWG guidelines and data from MEDSTAT. ¹² , ¹³ , ¹⁴ , ²⁴ , ²⁹

Figure 3

Actionable genotypes or phenotypes. The figure shows actionable genotypes or phenotypes (metabolizer status, transport activity, sensitivity, or genotype, expresser, or carrier status) of actionable drug‐gene interactions. The figure was build using Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG) guidelines. ¹² , ¹³ , ¹⁴ , ²⁹ Estrogens*: Contraceptives with estrogens (i.e.< progestogens and estrogens). het, heterozygous (yellow); hom, homozygous (red); IM, intermediate metabolizer (yellow); PM, poor metabolizer (red); transp., transporter (yellow); UM, (ultra)rapid metabolizers (blue).

Figure 4

Heat‐map of number of users of actionable drug‐gene interactions (DGIs). The figure shows a list of actionable pharmacogenetics drugs included in this study. Drugs are sorted on anatomic therapeutic chemical (ATC) code and shown per ATC drug class. For each DGI, the (i) total number of drug users, (ii) total estimated number of users with an actionable genotype or phenotype, (iii) the estimated ratio of actionable genotypes or phenotypes, (iv) sex ratio in favor of women, and (v) estimated number of users with an actionable genotype‐ or phenotype per age group are shown. Data originate from the population of Denmark in 2017 (MEDSTAT) ²⁴ and is calculated using Figure  3 and Table  1 and Table  S1 . Age groups are 0–17, 18–24, 25–44, 45–64, 65–79 years, and 80 years or older. Drugs in dark blue are psychotropic drugs. ¹Contraceptives with estrogens (i.e., progestogens and estrogens). A, alimentary tract and metabolism; Act, actionables; B, blood and blood forming organs; C, cardiovascular system; Freq, frequency; G, genito urinary system and sex hormones; J, general anti‐infectives for systemic use; L, antineoplastic and immunomodulating agents; M, musculo‐skeletal system; N, nervous system; ND, not done, cannot divide by 0 users.