A pharmacokinetic study has found that the fixed-dose combinations (FDCs) of nevirapine, stavudine and lamivudine specifically formulated for children (Triomune Baby and Triomune Junior generally appear to provide appropriate antiretroviral doses for children weighing 6 kg and over, mostly overcoming the deficiencies in nevirapine dosing previously seen with paediatric FDCs. Data were insufficient to draw conclusions for children under 6 kg. The results were reported in AIDS.
Background
Fixed-dose combinations developed for adults do not allow easy dose adjustment for children, and do not allow for adjustments of the dosing ratios between their constituent drugs. In particular, children have been shown to metabolise nevirapine more quickly than adults. This has resulted in inadequate nevirapine plasma levels when using "scaled-down" doses of the adult FDC, Triomune.
Two paediatric versions of Triomune - Triomune Baby and Triomune Junior - have been formulated with increased relative dosages of nevirapine. These formulations have shown preliminary indications of overcoming this dosing problem; the current paper reports the first full pharmacokinetic data from the use of Triomune Baby and Triomune Junior in Zambian children.
The study
Triomune Baby combines 50 mg nevirapine, 6 mg stavudine, and 30 mg lamivudine in one tablet; Triomune Junior is double the baby dose. An open, randomised controlled phase I/II trial, CHAPAS1, is currently assessing these two formulations; the current paper reports on a pharmacokinetic (PK) substudy of the ongoing CHAPAS1 trial.
Seventy-one children, enrolled in CHAPAS1 through the University Teaching Hospital, Lusaka, Zambia, were originally enrolled in the PK trial; six were excluded due to poor adherence, leaving 65 in the analysis. All were antiretroviral-naïve (including any ART received for prevention of mother-to-child transmission), and had no severe laboratory abnormalities, active opportunistic infections, or known contraindications to nevirapine, stavudine or lamivudine.
Sixteen children were under the age of three, eighteen were aged three to six, sixteen aged seven to ten, and fifteen were aged eleven to fourteen. Most were of low weight for their age, and moderately to severely immunodeficient (88% at WHO stage 3; 11% at stage 4; median CD4 cell percentage of 13%).
Doses were given according to weight, as follows:
| Weight (kg) | Formulation | Daily dose (am / pm) | Resultant NVP dose, mg (mg/m2) | Resultant d4T dose, mg (mg/kg) | Resultant 3TC dose, mg (mg/kg) |
| 3 to | Baby | 2 tablets (1 / 1) | 100 (294-476) | 12 (2.0-4.0) | 60 (10.0-20.0) |
| 6 to | Baby | 3 tablets (1.5 / 1.5) | 150 (306-441) | 18 (1.8-3.0) | 90 (9.0-15.0) |
| 10 to | Junior | 2 tablets (1 / 1) | 200 (308-408) | 24 (1.6-2.4) | 120 (8.0-12.0) |
| 15 to | Junior | 2.5 tablets (1 / 1.5) | 250 (316-385) | 30 (1.5-2.0) | 150 (7.5-10.0) |
| 20 to | Junior | 3 tablets (1.5 / 1.5) | 300 (326-380) | 36 (1.4-1.8) | 180 (7.2-9.0) |
| 25 to | Junior | 4 tablets (2 / 2) | 400 (364-435) | 48 (1.6-1.9) | 240 (8.0-9.6) |
(Most recent WHO daily dose recommendations are: 300-400 mg/m2 nevirapine, 2 mg/kg stavudine (d4T), and 8 mg/kg lamivudine (3TC).) Thirty-one were randomised to receive full-dose nevirapine from the first day, and thirty-four to fourteen-day nevirapine dose escalation.
A full twelve-hour PK curve (0, 1, 2, 4, 6, 8 and 12 hr) was obtained from all the children, between 26 and 56 days (median 27 days) after starting the medication. All but breastfeeding infants fasted for at least three hours before the first sample, immediately preceding the dose, and standardised meals were given at 1-2, 4-6, and 8-12 hours after dosing.
Results
Overall, the observed PK parameters for d4T and 3TC were comparable to those typically seen in adults, while nevirapine concentrations were higher and more variable. (No paediatric reference drug concentrations are currently available.) Detailed PK results for all three agents are presented in the paper; here we summarise only the mean characteristics for nevirapine:
| Weight in kg | C12h (mg/l) | Cmax (mg/l) | AUC12h (mg/l.h) |
| 3 to (n=2) | 5.7 | 8.5 | 76.1 |
| 6 to (n=13) | 6.4 | 10.7 | 102 |
| 10 to (n=9) | 5.0 | 9.1 | 80.8 |
| 15 to (n=19) | 5.6 | 9.6 | 90.6 |
| 20 to (n=12) | 5.6 | 9.0 | 85.9 |
| 25 to (n=10) | 7.9 | 12.0 | 118 |
| Overall (n=65) | 6.0 | 10.0 | 94.4 |
| Adult data | 3.7 | 5.7 | 54.5 |
(C12h = concentration 12 hours post-dose; Cmax = maximum concentration; AUC12h = area under the concentration curve for 12-hr period.)
Subtherapeutic (12h variability was also high, with a 95% confidence interval [CI] of 1.4-16.9 mg/l. In spite of higher average exposure, nevirapine-related adverse reactions were "transient", with only temporary treatment interruptions, and PK characteristics were not notably different between children with and without adverse reactions.
The researchers concluded that "the paediatric FDCs Triomune Baby and Triomune Junior [contain antiretroviral dosages] appropriate for children weighing 6 kg and over." As there were only two children in the lowest weight band, data are insufficient to draw conclusions for children weighing less than 6 kg. A further substudy is currently enrolling to study pharmacokinetics in this critical group.
Reference:
L'homme, RFA, et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS 2008;22:557-565.