Effects of Genetic Variation at the CYP2C19/CYP2C9 Locus on Pharmacokinetics of Chlorcycloguanil in Adult Gambians

Abstract

Aims: Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria. Materials & methods: Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated. Results: All CYP2C19/CYP2C9 alleles obeyed Hardy–Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus curve at 24 h (AUC_0–24) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher C_max (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071). Conclusion:CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.

KEYWORDS::

• chlorcycloguanil
• CYP2C19
• CYP2C9
• drug metabolism
• pharmacokinetics
• polymorphisms

Acknowledgements

We are grateful to anonymous referees for helpful comments on the manuscript. We are grateful to the study participants and to the staff of the MRC Unit in The Gambia and to GlaxoSmithKline for making the pharmacokinetic data available.

Financial & competing interests disclosure

We thank the Medical Research Council (MRC) and the European and Developing Countries Clinical Trials Partnership (EDCTP) for funding this study through a PhD fellowship awarded to Ms Ramatoulie Janha. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

We thank the Medical Research Council (MRC) and the European and Developing Countries Clinical Trials Partnership (EDCTP) for funding this study through a PhD fellowship awarded to Ms Ramatoulie Janha. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.