# CYP2D6 Pharmacogenetics in Nigerian Sickle Cell Disease: Phase 1 of Implementing Pharmacogenomics Testing for Effective Care and Treatment in Africa (iPROTECTA) program

## TL;DR

This study shows that pre-emptive genetic testing for CYP2D6 can help guide safer and more effective opioid use in Nigerian sickle cell disease patients.

## Contribution

The study demonstrates the feasibility of implementing pharmacogenomic testing for CYP2D6 in a resource-limited African setting.

## Key findings

- 36.6% of participants had actionable CYP2D6 variants affecting opioid metabolism.
- 54.1% were normal metabolizers, while 8.8% were ultrarapid metabolizers and 1.8% poor metabolizers.
- Medication safety cards were successfully generated to guide opioid prescriptions.

## Abstract

Sickle Cell Disease (SCD) is highly prevalent in Nigeria, with severe pain crises being a primary cause of morbidity. Codeine and tramadol are frequently used opioids, but their effectiveness and safety are significantly influenced by
CYP2D6 genetic variations. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines exist for opioid therapy based on CYP2D6 phenotypes. There’s a critical need for pre-emptive pharmacogenomic (PGx) testing in African SCD patients to guide opioid selection. This study aimed to determine
CYP2D6 allele, phenotype frequencies and evaluate the feasibility of implementing pre-emptive pharmacogenomic (PGx) testing to guide opioid therapy for SCD patients in Nigeria.

This prospective, multicenter implementation study recruited 503 consenting SCD patients (HbSS or HbSC) aged ≥15 years from five Nigerian sites. Blood samples were collected for DNA extraction.
CYP2D6 single-nucleotide polymorphisms and copy number variations were determined using Taqman assays based open array, GenoPharm. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines using the Genomics Information Management System (GIMS). and patient-specific medication safety cards were generated.

We successfully genotyped 503 SCD patients with a mean age of 25.1 years, while 61.4% were female, and hydroxyurea use was less than 9.4%. Actionable
CYP2D6 variants were found in 36.6% of participants. The predicted phenotype distribution was 8.8% Ultrarapid Metabolizers (UM), 54.1% Normal Metabolizers (NM), 26.0% Intermediate Metabolizers (IM), and 1.8% Poor Metabolizers (PM), with 9.3% undetermined. Patient medication safety cards were provided to guide prescriptions.

This study successfully established a genotyped cohort of 503 Nigerian SCD patients, demonstrating the feasibility of pre-emptive pharmacogenetic testing through a Pan-African collaborative model in a resource-limited setting. The identification of PM and UM provides direct clinical guidance, as CPIC guidelines recommend avoiding codeine and tramadol in these groups due to the high risk of diminished efficacy or serious toxicity, respectively. The high prevalence of actionable CYP2D6 variants indicates a substantial proportion of Nigerian SCD patients may experience altered opioid responses, underscoring the need for tailored prescribing to optimise pain control and minimise adverse drug reactions.