Background:  Approximately a quarter of HIV-infected Thai children are co-infected with TB. In Thailand the current first line ART is a nevirapine (NVP) -based HARRT regimen, primarily administered using adult fixed-drug combinations. Rifampin is a key component of TB treatment but is a potent inducer of the hepatic cytochrome P450 enzymes responsible for the metabolism of NVP. Concomitant NVP-rifampin treatment can lead to subtherapeutic NVP plasma levels in adults. We report the pharmacokinetics of NVP in HIV/TB-co-infected children receiving NVP-based HAART and rifampin.

Methods:  This is a cross-sectional, open-label, single-arm pharmacokinetic study. Thai children with HIV/TB co-infection receiving NVP (either as a fixed-drug combinations of zidovudine [AZT] + lamivudine [3TC] + NVP (250/150/200-mg tablet, called GPOvir-Z250), fixed-drug combinations of stavudine [d4T] + 3TC+NVP (30/150/200-mg tablet called GPOvir-S30) or individual liquid formulations) for at least 4 weeks and rifampin-based anti-TB therapy for at least 2 weeks were enrolled. NVP fixed-drug combinations dosing was based upon the NVP dose of 150 to 220 mg/m², twice daily. Adherence to ART and anti-TB drugs was assessed during the 3 days prior to pharmacokinetic blood sampling. Blood samples were taken at predose and 2, 4, and 6 hours after NVP drug administration. Plasma concentrations of NVP were measured by high-performance liquid chromatography and pharmacokinetic data were analyzed using a one-compartment model with empiric Bayesian individual subject parameter estimates generated by the program NONMEM.

Results:  As of October 2008, 8 children have completed the pharmacokinetic sampling:  5 children were using GPOvir-S30, 2 children using GPOvir-Z250, and 1 child using the liquid formulations. At the time of pharmacokinetic sampling, median age (range) was 9.7 (4.4 to 11.0) years, weight was 17.0 kg. (14.5 to 23.2), CD4 percentage was 17.4 (7.8 to 29.8), and 4 of 7 children had an HIV RNA viral load <40 copies/mL. Average NVP and rifampin doses were 194.9 mg/m² (149.3 to 262.7) and 11.4 mg/kg (8.3 to 14.5) respectively. Median (range) NVP clearance was 0.081 L/h/kg (0.058 to 0.157). Median NVP AUC and predose levels were 85.22 µg*h/mL (40.41 to 172.14) and 6.34 µg/mL (3.01 to 13.78), respectively. All children achieved a pre-dose NVP concentration above the recommended therapeutic target of 3.0 µg/mL. No drug adverse events occurred during the study.

Conclusions:  These preliminary results show that co-administration of rifampin with NVP, using fixed-drug dose combinations at the higher end of the NVP dose range, resulted in appropriate NVP exposure in Thai children.