Population Pharmacokinetics of Antiretroviral Drugs in HIV-Infected Indian Cohorts: Impact of Genetic Polymorphisms on CYP3A4 Metabolism

Abstract

Background: Antiretroviral therapy (ART) is essential for controlling HIV infection, yet significant inter-individual differences in drug pharmacokinetics (PK) can compromise treatment efficacy, especially in genetically diverse populations such as India. Cytochrome P450 3A4 (CYP3A4) is the primary enzyme metabolizing protease inhibitors (PIs) like lopinavir and atazanavir. Polymorphisms in CYP3A4 and associated genes can alter drug exposure, but specific data for Indian cohorts remain underrepresented.

Objective: To construct a population PK model for lopinavir and atazanavir in HIV-infected Indian patients and assess the influence of CYP3A4 polymorphisms on metabolism.

Methods: A prospective cohort study enrolled 150 HIV-positive adults from Western India receiving ritonavir-boosted lopinavir or atazanavir. Plasma concentrations were measured at various post-dose intervals. Genotyping targeted CYP3A41B, CYP3A422, and CYP3A5*3 using PCR-RFLP. NONMEM software facilitated population PK modeling, incorporating covariates including demographics and genotypes.

Results: Median lopinavir clearance was 5.8 L/h (IQR: 4.2-7.5 L/h). Homozygous CYP3A422 carriers displayed 45% reduced clearance versus wild-type (P=0.018), yielding 120% elevated trough levels. The CYP3A53/3 genotype, prevalent at 62%, correlated with 32% lower atazanavir clearance (P=0.032). CYP3A41B showed no notable effect. Model predictability was strong (R²=0.82).

Conclusion: CYP3A4 polymorphisms markedly modulate PI pharmacokinetics in Indian HIV patients, underscoring the value of genotype-informed dosing for enhanced efficacy and reduced toxicity.