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Impact of CYP polymorphisms, ethnicity and sex differences in metabolism on dosing strategies: the case of efavirenz

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Abstract

Purpose

Differences in drug metabolism due to cytochrome P450 (CYP) polymorphisms may be significant enough to warrant different dosing strategies in carriers of specific cytochrome P450 (CYP) polymorphisms, especially for drugs with a narrow therapeutic index. The impact of such polymorphisms on drug plasma concentrations and the resulting dosing strategies are presented in this review, using the example of efavirenz (EFV).

Methods

A structured literature search was performed to extract information pertaining to EFV metabolism and the influence of polymorphisms of CYP2B6, ethnicity, sex and drug interactions on plasma concentrations of EFV. The corresponding dosing strategies developed for carriers of specific CYP2B6 genotypes were also reviewed.

Results

The polymorphic CYP2B6 enzyme, which is the major enzyme in the EFV

metabolic pathway, is a key determinant for the significant inter-individual differences seen in EFV pharmacokinetics and pharmacodynamics (PKPD). Ethnic differences and the associated prevalence of CYP2B6 polymorphisms result in significant differences in the PKPD associated with a standard 600 mg per day dose of EFV, warranting dosage reduction in carriers of specific CYP2B6 polymorphisms. Drug interactions and auto-induction also influence EFV PKPD significantly.

Conclusion

Using EFV as an example of a drug with a narrow therapeutic index and a high inter-patient variability in plasma concentrations corresponding to a standard dose of the drug, this review demonstrates how genotyping of the primary metabolising enzyme can be useful for appropriate dosage adjustments in individuals. However, other variables such as drug interactions and auto-induction may necessitate plasma concentration measurements as well, prior to personalising the dose.

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The authors contributed equally to this work.

Conflict of interest/disclosure

MC is an employee of Simcyp, now part of Certara.

VC is an employee of Novartis South Africa.

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Authors and Affiliations

  1. University of KwaZulu Natal, School of Health Science, Discipline of Pharmaceutical Sciences, Private Bag X54001, Durban, 4001, KZN, South Africa

    Panjasaram Naidoo & Manoranjenni Chetty

  2. Novartis, South Africa

    Vasudevan V. Chetty

  3. Simcyp Ltd (a Certara Company), Blades Enterprise Centre, John St, Sheffield, S24SUUK3, United Kingdom

    Manoranjenni Chetty

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  1. Panjasaram Naidoo
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Naidoo, P., Chetty, V.V. & Chetty, M. Impact of CYP polymorphisms, ethnicity and sex differences in metabolism on dosing strategies: the case of efavirenz. Eur J Clin Pharmacol 70, 379–389 (2014). https://doi.org/10.1007/s00228-013-1634-1

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