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PHARMACOKINETICS OF NEVIRAPINE PROPHYLAXIS IN HIV-EXPOSED LOW BIRTH WEIGHT INFANTS
Adrie Bekker1, Avy Violari2, Mae Cababasay3, Jiajia Wang3, Lubbe Wiesner4, Edmund Capparelli5, Mark Cotton1, Firdose Nakwa2, Mark Mirochnick6
1Stellenbosch Univ, Cape Town, South Africa,2Univ of Witwatersrand, Johannesburg, South Africa,3Harvard Univ, Boston, MA, USA,4Univ of Cape Town, Cape Town, South Africa,5Univ of California San Diego, La Jolla, CA, USA,6Boston Med Cntr, Boston, MA, USA
There are limited data on nevirapine (NVP) pharmacokinetics (PK) and safety in low birth weight (LBW) infants (< 2500g).
IMPAACT P1106 is a Phase IV study on PK and safety in LBW infants receiving antiretroviral and tuberculosis medicines as part of their clinical care in two South African sites. Arm 1 focused on NVP for HIV-1 prophylaxis. Infants were stratified by birth weight (<1400 g, 1400 - <1800 g, and 1800 - <2500g). NVP was dosed at 2 mg/kg once daily (birth to 14 days of age), followed by 4 mg/kg once daily. Infant characteristics, PK samples and safety data were collected at study entry (day 7-14 of age) and at 4, 6, 10, 16 and 24 weeks of age. An adverse event (AE) was classified as expected (associated with prematurity) or unexpected. Plasma samples were assayed for NVP by LC-MS with lower limit of detection of 0.02 μg/ml. The NVP trough target was > 0.1 μg/ml.
Forty LBW infants, mean birth weight of 1675 g (range 950-2460 g) and mean gestational age of 33 weeks (range 28-40 weeks) were enrolled. NVP trough concentrations were available for 27 infants (94 observations) with mean weight of 2147 g (range 965 – 6050 g) and mean postmenstrual age of 37 weeks (range 29 – 56 weeks) at time of PK sampling. Mean NVP trough concentration across all visits was 1.87 μg/mL (range < 0.02 - 10.69 μg/mL). NVP trough concentrations were < 0.1 μg/ml in 6/94 (6%) observations. Below target samples were all from later visits (median postmenstrual age 44 weeks; median weight of 3903 grams) on infants already discharged to home and receiving NVP from caregiver. At the initial visit, lower gestational age was associated with higher NVP concentration. Across all visits, NVP trough concentrations were inversely related (p=0.001) to infant postnatal age (see figure). Three infants died; 2 from sudden unexpected death and 1 from confirmed septicemia. Ten infants had Grade 3/4 unexpected AEs, most common being pneumonia (n=4). Nine infants had Grade 3/4 expected AEs, most common being presumed or confirmed sepsis (n=6). All AEs were assessed as unrelated to NVP.
In premature infants, the NVP dosing regimen studied was safe and achieved trough concentrations above the 0.1 μg/mL prophylaxis target. NVP concentration at the initial visit increased with decreasing gestational age and subsequent concentrations decreased with increasing postnatal age. No treatment related adverse events were observed.