Drug Use in Denmark for Drugs Having Pharmacogenomics (PGx) Based Dosing Guidelines from CPIC or DPWG for CYP2D6 and CYP2C19 Drug–Gene Pairs: Perspectives for Introducing PGx Test to Polypharmacy Patients

Abstract

Background: The cytochrome P450 drug metabolizing enzymes CYP2D6 and CYP2C19 are the major targets for pharmacogenomics (PGx) testing and determining for drug response. Clinical dosing guidelines for specific drug-gene interactions (DGI) are publicly available through PharmGKB. The aim of this register study was to map the use of drugs in Denmark for drugs having actionable dosing guidelines (AG) i.e., dosing recommendations different from standard dosing for CYP2D6 or CYP2C19 DGI in terms of consumption. Methods: The Danish Register of Medicinal Product Statistics was the source to retrieve consumption in Defined Daily Dose (DDD) i.e., the assumed average maintenance dose per day for a drug used for its main indication in adults and number of users (2017 data). Clinical dosing guidelines were available from the PharmGKB website. Results: Forty-nine drugs have guidelines corresponding to 14.5% of total sales in DDD. Twenty-eight drugs have AG corresponding to 375.2 million DDD. Pantoprazole, lansoprazole, omeprazole, clopidogrel, and metoprolol constituted fifty-eight percent of the consumption in DDD of drugs having AG. The consumption of antidepressant drugs, opioids, and antipsychotic drugs were 157.0 million DDD; with 441,850 users, 48.9 million DDD; with 427,765 users, and 23.7 million DDD; with 128,935 users, respectively. Age distributions of consumption of drugs and drug combinations, e.g., for sertraline redeemed either alone or in combination with metoprolol and tramadol, are presented. Conclusion: This exploratory register study clearly showed that a large fraction of the Danish population, especially the elderly, are exposed to drugs or drug combinations for which there exist AG related to PGx of CYP2D6 or CYP2C19.

Drug Use among Nursing Home Residents in Denmark for Drugs Having Pharmacogenomics Based (PGx) Dosing Guidelines: Potential for Preemptive PGx Testing

“…The most used drugs with AG and N-AG within each drug class (Table 3) very much reflects our previous findings when looking at the total Danish population in general [24]. However, the prevalence of use of the most used drugs in each drug class in this study is significantly higher in comparison to our previous study [24]. For example, the prevalence of use of citalopram (antidepressant), quetiapine (antipsychotic) and tramadol (opioid) in this study are 17.0%, 17.7% and 8.5%, whereas in our previous study the same numbers were 1.8%, 0.1% and 4.6%, respectively.…”

“…This underlines that the use of drugs with AG are not only widespread among nursing home residents, but among the elderly population in general [4,35]. The most used drugs with AG and N-AG within each drug class (Table 3) very much reflects our previous findings when looking at the total Danish population in general [24]. However, the prevalence of use of the most used drugs in each drug class in this study is significantly higher in comparison to our previous study [24].…”

“…In our previous study [24] we showed, for the first time, that a large fraction of the Danish population is exposed to drugs or drug combinations for which there exists PGx-based dosing guidelines and FDA annotations. In spite of this, the use of PGx-based tests have not gained foothold in daily clinical practice probably because the significance has not been recognized, but also because skepticism has been expressed due to question marks about evidence levels [30,31].…”

A Review of the Important Role of CYP2D6 in Pharmacogenomics

“…Epigenetic regulation, drug-drug interactions and some foodstuffs influence CYP2D6 activity. Of note, drugs that inhibit CYP2D6 function can lead to an individual having a less functionally active metaboliser phenotype than would be predicted by their genotype, a process termed 'phenoconversion' [79,80]. Examples of strong CYP2D6 inhibitors that increase the area under the concentration-time curve (AUC) of sensitive CYP2D6 substrates (e.g., dextromethorphan, nortriptyline, eliglustat) by ≥5-fold include fluoxetine, paroxetine and bupropion [81].…”

“…Furthermore, a recent review suggested that a link between CYP2D6 genotype and tamoxifen adherence was uncovered in these large studies [106] and other studies linked a specific CYP2D6 haplotype to outcome in tamoxifen-treated patients [107]. Accordingly, clinical guidance for tamoxifen-CYP2D6 has been developed by CPIC and DPWG as well as other societies, which generally recommends alternative treatment, such as an aromatase inhibitor, in CYP2D6 IMs and PMs [80,108]. Figure 5.…”