Tamoxifen (TAM) is widely used in the treatment of hormone receptor-positive breast cancer. TAM is metabolized into the active secondary metabolite endoxifen (ENDO), primarily by CYP2D6. We aimed to investigate the effects of an African-specific CYP2D6 variant allele, CYP2D6*17, on the pharmacokinetics (PK) of TAM and its active metabolites in 42 healthy black Zimbabweans. Subjects were grouped based on CYP2D6 genotypes as CYP2D6*1/*1 or *1/*2 or *2/*2 (CYP2D6*1 or *2), CYP2D6*1/*17 or 2*/*17, and CYP2D6*17/*17. PK parameters for TAM and three metabolites were determined. The pharmacokinetics of ENDO showed statistically significant differences among the three groups. The mean ENDO AUC0-∞ in CYP2D6*17/*17 subjects was 452.01 (196.94) h·*ng/mL, and the AUC0-∞ in CYP2D6*1/*17 subjects was 889.74 h·ng/mL, which was 5-fold and 2.8-fold lower than in CYP2D6*1 or *2 subjects, respectively. Individuals who were heterozygous or homozygous for CYP2D6*17 alleles showed a 2- and 5-fold decrease in Cmax, respectively, compared to the CYP2D6*1 or *2 genotype. CYP2D6*17 gene carriers have significantly lower ENDO exposure levels than CYP2D6*1 or *2 gene carriers. Pharmacokinetic parameters of TAM and the two primary metabolites, N-desmethyl tamoxifen (NDT) and 4-hydroxy tamoxifen (4OHT), did not show any significant difference in the three genotype groups. The African-specific CYP2D6*17 variant had effects on ENDO exposure levels that could potentially have clinical implications for patients homozygous for this variant.

Objective Pharmacogenomics (PGx) is a clinically significant factor in the safe and efficacious use of medicines. While PGx knowledge is abundant for other populations, there are scarce PGx data on African populations and is little knowledge on drug-gene interactions for medicines used to treat diseases common in Africa. The aim of this study was to use a customdesigned open array to genotype clinically actionable variants in a Zimbabwean population. This study also identified some of the commonly used drugs in Zimbabwe and the associated genes involved in their metabolism.Methods A custom-designed open array that covers 120 genetic variants was used to genotype 522 black Zimbabwean healthy volunteers using TaqMan-based single nucleotide polymorphism genotyping. Data were also accessed from Essential Drugs' List in Zimbabwe (EDLIZ), and the medicines were grouped into the associated biomarker groups based on their metabolism. We also estimated the national drug procurement levels for medicines that could benefit from PGx-guided use based on the data obtained from the national authorities in Zimbabwe. ResultsThe results demonstrate the applicability of an open-array chip in simultaneously determining multiple genetic variants in an individual, thus significantly reducing cost and time to generate PGx data. There were significantly high frequencies of African-specific variants, such as the CYP2D6*17 and *29 variants and the CYP2B6*18 variant. The data obtained showed that the Zimbabwean population exhibits PGx variations in genes important for the safe and efficacious use of drugs approved by the EDLIZ and are procured at significantly large amounts annually. The study has established a cohort of genotyped healthy volunteers that can be accessed and used in the conduct of clinical pharmacogenetic studies for drugs entering a market of people of predominantly African ancestry. ConclusionOur study demonstrated the potential benefit of integrating PGx in Zimbabwe for the safe and efficacious use of drugs that are commonly used.

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