Background:  Cipla Pharmaceuticals has developed 2 scored, dispersible fixed-dose combination ART tablets for HIV-infected children: Pedimune Baby (50 mg nevirapine [NVP] + 6 mg stavudine [d4T] + 30 mg lamivudine [3TC]) and Junior (double Baby dose). Both have higher NVP to nucleoside reverse transcriptase inhibitor (NRTI) ratios than adult fixed-dose combinations in accordance with pediatric dose recommendations. We determined the pharmacokinetics of NVP, d4T, and 3TC in Zambian children on Pedimune.

Methods:  We dosed 35 children according to body weight (3 to <6 kg, 1 Baby twice daily; 6 to <10 kg, 1.5 Baby twice daily; 10 to <15 kg, 1 Junior twice daily; 15 to <20 kg, 1 Junior twice daily, 0.5 once daily; 20 to <25 kg, 1.5 Junior twice daily; 25 to <30 kg, 2 Junior twice daily). At least 4 weeks after starting Pedimune, a 12-hour pharmacokinetic curve was recorded after observed intake.

Results:  We excluded 4 children because C₀ suggested poor prior adherence. Of the remaining 31 children, 9 (29%) were female, the median age was 8.1 years (IQR 6.1 to 10.5); 3, 9, 13, 6 were aged <3, 3 to 6, 7 to 10, and 11 to 14 years; 9 (29%) weighed <15 kg. Most were malnourished (median weight 18 kg, IQR 13 to 23; weight-for-age z-score –3.1, IQR –3.9 to –1.8). Mean±SD (range) NVP C_min, C_max, and AUC_12h of 6.0±2.7 mg/L (1.4 to 14.4), 9.8±3.6 mg/L (3.8 to 18.8) and 94.0±37.5 mg/L.h (32.1 to 200) were higher than those previously reported in adults (3.7 mg/L, 5.7 mg/L, 54.5 mg/L.h). NVP C_min was below the 3.0 mg/L therapeutic cut-off in 3 (10%) children; 1 child (12 years) had a grade 2 NVP rash and 1 of those excluded (6 years) had temporarily raised liver enzymes; both resolved on NVP. Mean±SD (range) d4T C_min, C_max and AUC_12h of 0.01±0.01 mg/L (0.00 to 0.03), 0.44±0.14 mg/L (0.19 to 0.89) and 1.07±0.38 mg/L.h (0.35 to 2.16) were comparable to adults (0.01 mg/L, 0.54 mg/L, 1.17 mg/L.h) and other children (AUC_12h 1.63 mg/L.h). Mean±SD (range) 3TC C_min, C_max and AUC_12h of 0.09±0.04 mg/L (0.03 to 0.17), 1.29±0.60 mg/L (0.44 to 3.42), and 5.43±1.94 mg/L.h (2.25 to 10.28) were also similar to adults (0.09 mg/L, 1.2 mg/L, 4.7 mg/L.h) and other children (AUC_12h 5.2 mg/L.h). Although numbers are small, there is no evidence of a difference in NVP AUC_12h by age group (mean [SD] 98.9±14.1, 94.2±39.7, 83.4±34.0, 114±47.5 mg/L.h in the 4 groups, respively; p = 0.7).

Conclusions:  NVP concentrations were higher than those previously reported in adults, while pharmacokinetic parameters of d4T and 3TC were comparable to those in adults and children. Because NVP underdosing is of greater concern than overdosing, the Pedimune antiretroviral ratio appears to be appropriate for children.