Background
Efavirenz (EFV) remains a recommended component of alternative first-line antiretroviral regimens. Its pharmacokinetics (PK) is strongly influenced by single nucleotide polymorphisms (SNPs) in CYP2B6. However, data on the impact of these variants in Nigerians living with HIV are limited. This study aimed to estimate the population apparent oral clearance (CL/F) of EFV and evaluate the influence of CYP2B6 SNPs on EFV CL/F in this population using population PK modelling.
Methods
Dried blood spots (DBS) were collected from HIV-positive adults receiving 600mg EFV once daily (N=93, 70.3% female). EFV was quantified in DBS using Liquid Chromatography-Mass Spectrometry (LC-MS/MS) while CYP2B6 genotyping was carried out using TaqMan SNP genotyping assays. Plasma EFV concentrations were then calculated using a previously validated equation [DBS[EFV]/(1-hematocrit)*protein binding]. Plasma concentrations were used to develop an EFV population PK model using nonlinear mixed-effects modeling (NONMEM v. 7.4.1). Ethical approval for this study was obtained from joint UI/UCH ethical review board, University of Ibadan, Nigeria.
Results
EFV concentrations (446.8–15,592.3 ng/mL; sampled 8–16 h post-dose) were well described by a one-compartment model. EFV CL/F in the base model was 8.96L/hr with relative standard error (RSE) of 4.7%. Significant differences were observed across CYP2B6 516 G>T (P < 0.001) and CYP2B6 983T>C (P = 0.011) genotypes. Approximately three-fold reduction in apparent clearance was seen for slow metabolizers compared to extensive metabolizers (Table 1).
Conclusion
CYP2B6 variants significantly influenced EFV apparent oral clearance in Nigerians living with HIV. Although based on the 600 mg dose, these findings remain relevant for current practice as genetic effects persist even at lower doses, supporting the role of pharmacogenetic profiling in optimizing therapy among Africans with large genetic diversity.
KEY WORDS: Pharmacogenetics; Efavirenz; DBS, HIV; Population pharmacokinetic modeling
References
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Table 1: Population Oral Clearance based on Composite CYP2B6 genotype
| Composite genotype (516G>T plus 983T>C) | No of variant allele | Average Cl/F (L/h) |
| Extensive metabolizer (516GG plus 983TT) | 0 | 13.10 |
| Intermediate metabolizer (516GT plus 983TT or 516GG plus 983CT) | 1 | 11.03 |
| Slow metabolizer (516TT plus 983TT or 516GT plus 983CT or 516GG plus 983CC) | 2 | 4.53 |
