Nevirapine pharmacokinetics with infant prophylaxis

In infants whose mothers receive no antiretroviral treatment or mother to child transmission (MTCT) prophylaxis during pregnancy, the optimal composition and duration of postnatal antiretroviral prophylaxis to prevent transmission is unknown.

A poster from Mark Mirochnick, and coworkers from the NICHD HPTN 040/PACTG 1043 (which compares the efficacy of three different post natal MTCT regimens), describes nevirapine (NVP) pharmacokinetics during the second week of life in infants receiving this regimen a nevirapine regimen.

The investigators devised a regimen with the goal of maintaining NVP plasma concentration >100 mg/mL (10 times the in vitro IC50) for the first two weeks of infant life using a minimal number of NVP doses.

NICHD HPTN 040/PACTG 1043 is a 3-arm efficacy study comparing 6 weeks of AZT alone vs 6 weeks of AZT + nelfinavir/3TC for 2 weeks vs 6 weeks of AZT + NVP x 3 doses. Infants in the NVP arm received 12-mg NVP doses at 0 to 2, 2 to 4, and 6 to 8 days of life (if birth weight was low, <2000gm, the dose was 8 mg). Plasma samples for NVP concentration were obtained before the third dose, and 4 hours, 24 hours, 3 to 5 days, and 7 days after the third dose. NVP concentrations were measured by HPLC with a lower limit of detection of 25 ng/mL.

Samples were obtained from 14 infants in Brazil and Pueuto Rico, mean birth weight 3001 (+/-232) gm and mean gestational age 38.6 (+/-1.5) weeks whose mothers had a mean age 26.4 (+/-5.4) years, a mean delivery HIV RNA of 34,992 (+/-37,449) copies/mL) and received no antiretrovirals during pregnancy.

The investigators reported the median NVP concentration before the third dose on day 6 to 8 of life was 362 ng/mL (range 165 -1728), and was 1719 ng/mL (range 1016 – 3811) 24 hours after, 459 ng/mL (range 73 -1747) 3 to 5 days after and 76 ng/mL (below detection level to 652) 7 days after the third dose.

Median NVP pharmacokinetic parameters were T max, 4 hours (4 to 25); C max, 2286 ng/mL (1241 to 3811) and T1/2, 30.2 hours (17.8 to 50.3). All infants had NVP concentrations above 70 ng/mL at 9 to 12 days of life, and all but one had NVP concentrations above 30 ng/mL at 13 to 15 days.

The authors wrote: NVP T1/2 during the second week of life is decreased compared to t12 reported during the first week of life in previous studies (median T1/2 = 44 hours). The 3-dose regimen studied here maintained NVP concentration >70 ng/mL through day 9 to 12 in all infants and >30 ng/mL through the end of the second week of life in nearly all infants. Although the magnitude and duration of NVP exposure needed to prevent HIV MTCT is not known, this 3-dose NVP regimen provides sufficient NVP exposure to make it a suitable candidate for study.

Mirochnick M, Nielsen K, Pilotto J et al. Nevirapine pharmacokinetics with an extended prophylactic regimen during the first 2 weeks of life. 13th CROI, Denver, 2006. Abstract 686.