Pharmacokinetics of nevirapine, d4T, and 3TC in Zambian children treated with Pedimune (Triomune)
4 May 2007. Related: Conference reports, Paediatric care, CROI 14 (Retrovirus) 2007.
Polly Clayden, HIV I-Base
The Indian generic company Cipla Pharmaceuticals has developed two scored, dispersible fixed-dose combination (FDC) tablets to treat HIV-positive children, Pedimune (Triomune) Baby and Junior.
The dose ratios for the Baby dose tablets are 50mg nevirapine (NVP) plus 6mg d4T plus 30 mg 3TC. The Junior dose is double the Baby dose. The NVP: NRTI ratios are higher than in adult FDCs because children metabolise NVP more quickly than adults. WHO recommendations for paediatric doses are NVP 320 to 400mg/m2 up to a maximum dose of 400mg; d4T 2mg/kg for children weighing less than 30kg; 3TC 8mg/kg up to a maximum dose of 300mg. [1]
A poster from Desirée Kabamba and coworkers reported findings from a study from the CHAPAS trial to determine the pharmacokinetics of NVP, d4T and 3TC in a group of Zambian children receiving Pedimune (Triomune). [2]
The investigators dosed 64 children: aged <3 (n=16), 3 to 6 (n=19), 7 to 10 (n=17), and 11 to14 years (n=12).
Children were dosed 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 in morning, 1.5 Junior in evening
20 to <25 kg 1.5 Junior twice daily
25 to <30 kg 2 Junior twice daily.
At least 4 weeks after initiating treatment with Pedimune (Triomune), a 12-hour post dose pharmacokinetic curve was recorded after observed intake.
The investigators excluded 5 children because of poor prior adherence. Of the remaining 59 children 21 (36%) were female, the median age was 6.9 (IQR 0.5 to 13.6) years. Most were malnourished: median weight for age, height for age and BMI for age z-scores were -3.4 (IQR -9.5 to -0.9), -3.2 (IQR -6.5 to – 0.7) and -1.2 (IQR -2.2 to -0.4) respectively. Both d4T and 3TC analyses failed for one child. Table 1 compares the resulting pharmacokinetic parameters with adult data from the literature (NVP, d4T, 3TC investigators brochures).
Table 1: Pharmacokinetic parameters
| CHAPAS trial | Adult literature data | |||
|---|---|---|---|---|
| Mean | (range) | [SD] | Mean | |
| NVP (n=59) | ||||
| Cmin (mg/L) | 6.0 | (1.4, 16.9) | [2.9] | 3.7 |
| Cmax (mg/L | 9.9 | (3.8, 22.5) | [3.6] | 5.7 |
| AUC 12h (mg/L.h) | 94.2 | (32.1, 232 | [37.7] | 54.5 |
| d4T (n=58) | ||||
| Cmin (mg/L) | <0.015 | (<0.015, 0.03) | [-] | 0.009 |
| Cmax (mg/L | 0.44 | (0.09, 0.89) | [0.16] | 0.54 |
| AUC 12h (mg/L.h) | 1.02 | (0.35, 2.16 | [0.39] | 1.28 |
| 3TC (n=58) | ||||
| Cmin (mg/L) | 0.09 | (<0.05, 0.20) | [-] | 0.09 |
| Cmax (mg/L | 1.32 | (0.20, 3.42) | [0.68] | 1.2 |
| AUC 12h (mg/L.h) | 5.36 | (1.59, 11.45 | [2.27] | 4.7 |
SD=standard deviation
They found four (7%) children had subtherapeutic NVP levels at 12 hours post dose, defined as nevirapine Cmin less than 3.0mg/L; one child in each weight group 3-<6, 10 to <15, 20 to <25, 25 to <30kg). They found no evidence of a difference in NVP AUC12h across the six weight groups or the four age groups.
There were few adverse events reported in the children: 3 had grade 2 NVP rash (all resolved after 9 to 11 days following temporary discontinuation of the NVP; 3 had grade 3 raised liver enzymes (all returned to normal on continued NVP); 1 had grade 1 NVP rash (resolved after 7 days) followed by grade 3 raised liver enzymes (reduced to grade 1; NVP continued throughout) and 1 excluded child had grade 3 raised liver enzymes (returned to normal on continued NVP).
Overall the investigators found that NVP concentrations were higher than previously reported in adults and that pharmacokinetic parameters of d4T and 3TC were comparable to those previously reported in adults.
They concluded that the Pedimune (Triomune) Baby and Junior antiretroviral ratio appears to be appropriate over the entire range of weights. They also noted further analysis to investigate the effect of malnutrition is important, as we have previously demonstrated lower NVP levels in stunted children and higher levels in wasted children for the same dose/m2. [3]
References:
Unless stated otherwise, all references are to the Programme and Abstracts of the 14th Conference on Retroviruses and Opportunistic Infections, 25-28 February 2007, Los Angeles.
- WHO. Antiretroviral therapy of HIV infection in infants and children in resource-limited settings, towards universal access: recommendations for a public health approach (2006 revision). February 2006. Geneva: World Health Organisation.
- Kabamba D, Lhomme R, Ewings F et al. Pharmacokinetics of nevirapine, stavudine, and lamivudine in HIV-infected children in Zambia treated with pediatric fixed-dose combination tablets. Abstract 580.
- Ellis J, Lhomme R, Ewings F et al. Nevirapine concentrations in HIV-infected children treated with divided fixed-dose combination antiretroviral tablets in Malawi and Zambia. Antiviral Therapy 2007; 12: 253-260