Maternal-fetal pharmacokinetics and dynamics of a single intrapartum dose of maraviroc in rhesus macaques.
Single-dose nevirapine (NVP) is effective in reducing mother-to-child transmission (MTCT) of HIV; however, the subsequent development of drug resistance is problematic. The pharmacokinetic profile of the HIV entry inhibitor maraviroc after a single intrapartum dose in rhesus macaques was studied to determine whether maraviroc could serve as an alternative to NVP in a single-dose strategy. Four pregnant macaques received an oral dose of maraviroc 2 h before delivery, and both infant and maternal plasma maraviroc concentrations and CCR5 receptor occupancy on CD4(+) lymphocytes were measured over time. Maximum plasma maraviroc concentrations were found at delivery (2-h-postintrapartum dose) in both the mothers and infants, with median concentrations of 974 ng/ml (range, 86 to 2,830 ng/ml) and 22 ng/ml (range, 4 to 99 ng/ml), respectively. Maraviroc was detected in the plasma of mothers up to 48 h after dosing but only as long as 3.5 h in the infants. The median fetal-maternal area under the concentration-time curve (AUC) ratio was 0.009 (range, 0.000 to 0.015). Maraviroc receptor occupancy data showed evidence of unprotected CCR5 receptors on CD4(+) cells in the mothers 24 to 48 h after dosing. Extremely low CCR5 expression on CD4(+) cells of newborn macaques prevented determination of receptor occupancy in the infants. In rhesus macaques, maraviroc was poorly transferred across the placenta and was quickly cleared from the infants' blood. The low concentrations of fetal maraviroc and short pharmacokinetic profile in infants suggest that a single maternal intrapartum dose of maraviroc would not be effective in reducing the risk of MTCT of HIV.
Winters
Mark A
MA
AIDS Research Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA. mark.winters@stanford.edu
Van Rompay
Koen K A
KK
Kashuba
Angela D M
AD
Shulman
Nancy S
NS
Holodniy
Mark
M
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003510:Cyclohexanes / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control; D008253:Macaca mulatta; D000077592:Maraviroc; D011247:Pregnancy; D019713:Receptors, CCR5 / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc