Our study is the first to describe nelfinavir and lamivudine pharmacokinetics in infants during the first 2 weeks of life treated with weight band dosing regimens. Weight band dosing was chosen to facilitate study implementation across sites, to simplify drug administration to enrolled infants, and to make the results more easily transferable to a variety of settings once the optimum regimen was determined. Weight or age band dosing of antiretrovirals is currently recommended by the WHO for use in low resource settings.3
Nelfinavir was chosen as the protease inhibitor used in the study because at the time of initiation of the protocol it was the only protease inhibitor available in a formulation suitable for use in neonates. While liquid formulation lopinavir/ritonavir is now available, there are no lopinavir pharmacokinetic data from infants in the first 2 weeks of life.4
In addition, recent reports of life threatening toxicities in premature infants receiving lopinavir/ritonavir have led to a warning against its use in term infants younger than 2 weeks postnatal age and in premature infants younger than 42 weeks postmenstrual age.5
Previous studies of nelfinavir pharmacokinetics in neonates have shown significant differences compared with older infants, children and adults. Nelfinavir apparent oral clearance has been shown to be highly variable and to decrease with age, with nelfinavir clearance 2–3 times higher in children aged 2–13 years than in adults and further increased in children below age 2 years.6–9
The current recommended dose of nelfinavir in children aged 2–13 years is 45–55 mg/kg twice a day; there is no approved dose for children under age 2. Previous studies in neonates have shown high variability and inadequate nelfinavir concentrations with doses up to 40–45 mg/kg twice a day.1–2
In the present study we used a weight based nelfinavir dosing regimen that provided a median nelfinavir dose of 58.8 mg/kg twice a day. The per kg nelfinavir doses ranged from 18% below the median dose to 34% above and are presented graphically in . While the median AUC and Cmin in our subjects exceeded the pharmacokinetic targets, interpatient variability was very large, with AUC varying from 1.7 to 183.5 μg*hr/mL. Nearly half (46%) of individual subjects failed to meet the AUC or Cmin target. suggests that AUC did not vary with per kg dose administered and that although the per kg doses were greater than those used in previous studies, interpatient variability increased as well, resulting in larger maximum exposures while a significant proportion of subjects remained below the pharmacokinetic target. A recent population analysis of nelfinavir pharmacokinetics in a large group of infants and children suggested that in those less than 2 months nelfinavir doses of 40 mg/kg twice a day were not adequate and that 50 to 60 mg/kg three times a day should be studied.10
The large amount of interpatient variability in nelfinavir exposure observed in our subjects suggests that a further increase in nelfinavir dosing might result in high and potentially toxic nelfinavir concentrations in some infants along with suboptimal concentrations in others. If nelfinavir is to be used to treat HIV infected neonates during the first weeks of life, however, therapeutic drug monitoring should be encouraged to ensure adequate but not excessive nelfinavir exposure.
Figure 1 Scatter plots of nelfinavir AUC versus dose size (normalized to 12 hour dosing) from PACTG 0531 (open triangles) and current study (open squares). Dashed line represents AUC target of 15 μg*hr/mL.
Lamivudine elimination was prolonged in these neonates studied during the first week of life compared to older infants and children, consistent with previous studies.11–12
. Lamivudine is primarily renally eliminated, and its elimination increases during the first weeks and months of life in parallel with postnatal maturation of renal function.12–13
Current dosing recommendations for lamivudine are 2 mg/kg twice a day during the first 4 weeks of life and 4 mg/kg twice a day after age 4 weeks. The weight band dosing regimen used in the current study resulted in a median dose of 2 mg/kg, with a range of 1.5 to 3.2 mg/kg. While there is no target lamivudine concentration for prevention of HIV infection, lamivudine AUC values were in the same range as those previously observed in prior studies of neonatal and pediatric patients and trough lamivudine concentrations in nearly all subjects exceeded the range of lamivudine IC50 in wild type HIV (0.0006-.021 μg/ml).14
Mother to child HIV transmission can be reduced to less than 1% with the use of maternal combination antiretroviral therapy during pregnancy and infant formula feeding. The results of the parent protocol of this study demonstrated that when HIV infected pregnant women do not receive combination antiretroviral therapy prior to delivery, treating infants with six weeks of ZDV plus either daily lamivudine/nelfinavir for two weeks or three doses of nevirapine during the first week of life will reduce intrapartum HIV transmission by roughly 50%.15
We have previously reported that nevirapine concentrations with the three dose weight band regimen remain above our prophylactic target of 100 ng/mL through the first 10 days of life but well below the 3000 ng/mL trough concentration target used in HIV infected patients receiving nevirapine as part of combination treatment regimens.16
As we report here, the weight band nelfinavir regimen resulted in trough nelfinavir concentrations below 0.8 μg/mL, the standard nelfinavir trough concentration target for treating HIV infection in nearly half of our subjects, although nearly all had nelfinavir trough concentration above 0.05 μg/ml (10 times the upper limit of nelfinavir IC50 for wild type HIV). While there are no data establishing definitive target concentrations for antiretrovirals used for prevention of HIV infection, the equivalent efficacy of these regimens in reducing intrapartum HIV transmission when used in combination with zidovudine suggests that HIV infection can be prevented with antiretroviral concentrations lower than those used in treatment of HIV infected individuals.