Pharmacokinetics of nevirapine in HIV positive children receiving Thai fixed dose combination
Polly Clayden, HIV I-Base
Due to cost restraints and lack of available paediatric formulations, it is common practice in Thailand and other resource limited countries to use cut up adult fixed dose combinations (FDCs) for treating HIV positive children. Although dividing tablets is considered by most, to be a transitional option in paediatric scale up, dosing in children is notoriously variable, and pharmacokinetic data are lacking to support the implementation of this strategy.
A study from Chokephaibukit and co-workers published in the September 23rd edition of AIDS evaluated the steady state PK of nevirapine in HIV-positive children receiving GPO-VIR S30 (30mg d4T, 150mg 3TC, 200mg nevirapine) which is the Thai Government Pharmaceutical Organisation (GPO) produced generic FDC. GPO-VIR is the first line regimen provided by the Ministry of Public Health in Thailand.
This cross-sectional study enrolled 34 children (18 girls, 16 boys) with a median age of 8.4 years (range 3-15 years), a median CD4 count of 576 cells/mm3 (range 35-1443 cells/mm3) and a median CD4 percentage of 20.2% (range 1.7-30.2%), who had received GPO-VIR for at least 8 weeks.
The dose was based on a nevirapine dose of 120-200mg/m2 every 12 hours and tablets were divided where necessary to 1/4, 1/2, 3/4 or 1 tablet. Blood samples were taken at three time points, pre-dose and at 2 and 6 hours post dose.
CD4 was measured at baseline and then every 6 months; viral load was measured in children receiving GPO-VIR as their first line treatment.
One child was excluded for non-adherence. The nevirapine dose averaged 164+/- 27mmg/m2 every 12 hours. Twenty-four children (71%) received broken tablets as part of their dose; 32 children swallowed tablets without crushing. Four children also received indinavir boosted with ritonavir with GPO-VIR as salvage regimens.
The median pharmacokinetics parameters were area under the curve (AUC) at 12 hours, 78.4 h ug/ml; minimum plasma drug concentration, 5.98 ug/ml; plasma half-life, 25.5 h; apparent oral clearance, 0.079 l/kg/h; and volume of distribution, 2.95 l/kg.
Only one child (receiving 190mg/m2 every 12 hours) had less than the target drug concentration of 3.4 ug/ml (2.57 ug/ml) however, at 2 and 6 hours after nevirapine drug intake the drug levels were 4.93 and 4.64 ug/ml, respectively, and a good virological, immunological and clinical response was observed.
Nevirapine plasma levels were similar in the four children who also received indinavir boosted with ritonavir, except for one child who had a very high minimum nevirapine concentration of 24.37 ug/ml.
Of the 13 children who received GPO-VIR as their first-line treatment, 12 had plasma HIV-1 RNA < 400 copies/mL at 6-18 months, with a median CD4 increase of 216 and 433 cells/mm3 at 6 and 12 months of treatment, respectively.
The authors write: The pharmacokinetics parameters in our study were in the ranges reported in studies performed in adults. The therapeutic adequacy of nevirapine could be considered by using a minimum concentration of > 3.4 ug/ml or by comparison of AUC values; however, there is no clear defined AUC threshold that correlates with virological response for nevirapine. In our study, all the children apart from one had trough concentrations > 3.4 ug/ml despite a higher clearance than adults. Pill cutting may alter drug absorption and cause inaccuracy of drug dosing, but in this study we demonstrated that this practice gave satisfactory plasma concentrations of nevirapine.
They note that the study was limited as the nevirapine concentrations were only obtained at three time points in each child; therefore, some of the pharmacokinetics parameter estimates, particularly volume of distribution and half-life, have limited accuracy.
They conclude: It is reassuring that dividing the adult fixed-dose combination tablet GPO-VIR does not adversely affect nevirapine bioavailability and can be used to generate paediatric doses between 120 and 200 mg/m2 to achieve therapeutic levels of exposure. This study encourages the use of adult fixed-dose combination as a transitional measure to support scaling-up antiretroviral therapy in children where the paediatric formulations are not available.
Chokephaibulkit K, Plipat, N, Cressey T et al. Pharmacokinetics of nevirapine in HIV-infected children receiving an adult fixed-dose combination of stavudine, lamivudine and nevirapine. AIDS: Vol 19(14) 23 September p1495-1499.