Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV-infected Ugandans

Pharmacokinetic variability of the nonnucleoside reverse transcriptase inhibitor efavirenz has been documented, and high variation in trough concentrations or clearance has been found to be a risk for virological failure. Africans population exhibits greater variability in efavirenz concentrations than other ethnic groups, and so a better understanding of the pharmacokinetics of the drug is needed in this population. This study characterized efavirenz pharmacokinetics in HIV-infected Ugandans.

Efavirenz plasma concentrations were obtained for 66 HIV-infected Ugandans initiating efavirenz- based regimens, with blood samples collected at eight time-points over 24 h on day 1 of treatment, and at a further eight time-points on day 14. Noncompartmental analysis was used to describe the pharmacokinetics of efavirenz.

The mean steady-state minimum plasma concentration (C(min) ) of efavirenz was 2.9 µg/mL, the mean area under the curve (AUC) was 278.5 h µg/mL, and mean efavirenz clearance was 7.4 L/h. Although overall mean clearance did not change over the 2 weeks, 41.9% of participants showed an average 95.8% increase in clearance. On day 14, the maximum concentration (C(max) ) of efavirenz was >4 µg/mL in 96.6% of participants, while C(min) was <1 µg/mL in only 4.5%. Overall, 69% of participants experienced adverse central nervous system (CNS) symptoms attributable to efavirenz during the 2-week period, and 95% of these participants were found to have efavirenz plasma concentrations >4 µg/mL, although only half maintained a high concentration until at least 8 h after dosing.

The findings of this study show that HIV-infected patients on efavirenz may exhibit autoinduction to various extents, and this needs to be taken into consideration in the clinical management of individual patients. Efavirenz CNS toxicity during the initial phase of treatment may be related to C(max) , regardless of the sampling time.