BackgroundPharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.MethodsIn total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.ResultsEFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.ConclusionResults of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.

Background Suboptimal anti-TB drugs exposure may cause multidrug-resistant TB. The role of African predominant SLCO1B1 variant alleles on rifampicin pharmacokinetics and the subsequent effect on the occurrence of Mycobacterium tuberculosis–rifampicin sensitivity needs to be defined. We describe the rifampicin population pharmacokinetics profile and investigate the relevance of SLCO1B1 genotypes to rifampicin pharmacokinetics and rifampicin-TB sensitivity status. Methods Fifty patients with TB (n=25 with rifampicin-resistant TB and n=25 with rifampicin-susceptible TB) were genotyped for SLOC1B1 rs4149032 (g.38664C&gt;T), SLOC1B1*1B (c.388A&gt;G) and SLOC1B1*5 (c.521 T&gt;C). Steady state plasma rifampicin levels were determined among patients infected with rifampicin-sensitive TB. Data were analysed using NONMEM to estimate population rifampicin pharmacokinetics as well as the effect of SLOC1B1 genotypes on rifampicin pharmacokinetics and on rifampicin-TB sensitivity status. Results Overall allele frequencies of SLOC1B1 rs4149032, *1B and *5 were 0.66, 0.90 and 0.01, respectively. Median (IQR) Cmax and Tmax were 10.2 (8.1–12.5) mg/L and 1.7 (1.125–2.218) h, respectively. Twenty-four percent of patients exhibited Cmax below the recommended 8–24 mg/L range. SLOC1B1 genotypes, gender and age did not influence rifampicin pharmacokinetics or TB-rifampicin sensitivity. Conclusions Although SLOC1B1 genotype, age and gender do not influence either rifampicin pharmacokinetics or rifampicin-TB sensitivity status, one in every four Ugandan TB patients achieve subtherapeutic plasma rifampicin concentrations.

Plasma efavirenz exposure is mainly influenced by CYP2B6 genotype, but not by rifampicin cotreatment. Therefore, no efavirenz dosage adjustment during rifampicin cotreatment is required in Ugandans.