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Session 128 Poster Abstracts
Treatment in Pregnant Women and Children: Pharmacokinetics
Wednesday, 1:30 - 3:30 pm
Poster Hall


933    
Population Pharmacokinetics of Low-dose Nevirapine for Prevention of Breast Milk HIV Transmission in Infants from Birth through 6 Months of Age
M Mirochnick*1, E Capparelli2, Suzette Blanchard3, A K Shetty4, H M Coovadia5, J Wells6, A Dilraj7, P Mateta6, L Mofenson8, S Adeniyi Jones9, and HPTN 023 Protocol Team
1Boston Univ. Sch. of Med., MA, USA; 2Univ. of California, San Diego, Sch. of Med., USA; 3Statistical and Data Analysis Ctr. (SDAC), Harvard Sch. of Publ. Hlth., Boston, MA, USA; 4Stanford Univ. Sch. of Med., Palo Alto, CA, USA; 5Univ. of Natal, Durban, South Africa; 6Zimbabwe AIDS Prevention Project and Univ. of Zimbabwe, Harare; 7Med. Res. Council South Africa, Durban, South Africa; 8NICHD, NIH, DHHS, Bethesda, MD, USA; and 9NIAID, NIH, DHHS, Bethesda, MD, USA

Background: Breast milk HIV transmission is a major problem in areas of the world where safe alternatives to breast feeding are not available to HIV infected mothers. A low dose infant NVP regimen may be useful in preventing mother to infant breast milk HIV transmission. We examined the population pk of 3 infant NVP regimens.

Methods: Infants born to HIV infected women in Durban, South Africa, and Harare, Zimbabwe, were randomized to receive one of 3 NVP dosing regimens:  weekly  (4 mg/kg from birth to 14 days and 8 mg/kg from 15 days to 24 weeks); twice weekly (4 mg/kg from birth to 14 days and 8 mg/kg from 15 days to 24 weeks), and daily (2 mg/kg from birth to 14 days and 4 mg/kg from 15 days to 24 weeks). All mothers were offered a single oral NVP dose during labor; 55 mothers (93%) were dosed.  Plasma for NVP assay was obtained from cord blood, just before doses at 2, 8, 16, 20, and 24 weeks, and post-dose at 2, 8, and 20 weeks.  NVP concentrations were determined by HPLC. Population pharmacokinetic parameters were determined by maximum likelihood using NONMEM V software.

Results:  From 59 infants, 486 evaluable concentrations were obtained. The data best fit was a one-compartment model with scaling of oral clearance (Cl/F) and volume of distribution (Vd/F) for weight. The influence of the covariates age, gender, dosing cohort and study site on Cl/F and Vd/F were evaluated with graphical and statistical analysis. Average Vd/F was 3.01 L/kg with interindividual variability of 27%. NVP Cl/F increased progressively, ranging from 0.015 L/h/kg at birth to 0.045 L/h/kg from first dose to age 6 weeks, and 0.062 L/h/kg above age 6 weeks, with inter-individual variability of 11%. Typical half-life fell from 139 hrs immediately after birth to 46 hours between first dose and 6 weeks and 34 hours from 6 weeks to 6 months. No other covariates significantly improved model fit. The daily regimen maintained trough NVP plasma concentrations above 100 ng/mL (10 times the in vitro IC50 of NVP against HIV) in all patients at all ages.

Conclusions:  NVP Cl/F is low immediately after birth, but rapidly increases over the first 6 months of life. This increase is likely due to both maturation and autoinduction.  Despite the increase in NVP Cl/F, the daily regimen maintained trough NVP concentrations above the therapeutic target in all patients over the first 6 months of life and is most appropriate for future investigations of infant NVP therapy to prevent HIV acquisition from breast feeding.

Keywords: nevirapine; pharmacokinetics; infants