A Comparison of the Pharmacokinetics of Raltegravir during Pregnancy and Postpartum

• BACKGROUND: During pregnancy physiological changes take place which can influence the pharmacokinetics (PK) of antiretroviral agents and lead to decreased drug exposure. Effective plasma concentrations are important to prevent treatment failure, development of resistance and mother-to-child transmission. According to perinatal guidelines raltegravir (RAL) can be used in pregnant HIV infected women in special circumstances, because safety and PK information is limited. The use of RAL in late pregnancy for women who have a high viral load (VL) has been suggested because of its ability to rapidly suppress VL. More data on the PK behaviour and safety of RAL during pregnancy are needed to be able to recommend its use in this setting. • METHODOLOGY: An open-label, multi-centre phase IV study in HIV infected pregnant women recruited in HIV treatment centers in Europe (PANNA Network). Patients treated with RAL 400 mg BID during pregnancy had intensive steady-state12-hour PK profiles in the 3 rd trimester and at least 2 weeks postpartum. Where possible a cord blood (CB) and matching maternal blood samples were taken at delivery to asses placental transfer. Safety and virological efficacy were evaluated. • RESULTS: Fourteen patients (8 Black, 6 Caucasian) were included in the analysis of which 5 patients were treatment naive at conception. Paired PK curves (3 rd trimester and postpartum) were available for 12 and 3 rd trimester only for two patients. Treatment with RAL was started during pregnancy in 11/14 women, of which 5 were in the 3 rd trimester. RAL was combined with a PI-based regimen in 9/14 patients. Median (range) gestational age at delivery was 38 weeks (3641); birth weight was 3115 (2300-3730) gm. Approaching delivery 10/14 patients had a VL <50 cps/mL, all were <1,000 cps/mL. No SAEs were reported. None of the children were HIV infected and no birth defects were reported. Geometric mean ratios (90% CI) of RAL PK parameters 3 rd trimester/postpartum were: 0.77 (0.59-1.00) for AUC 0-12h ; 0.83 (0.55-1.25) for C max ; 0.54 (0.281.05) for C 12h . Geometric mean (95% CI) for AUC 0-12h , C max and C 12h in the 3 rd trimester were: 4.95 (3.01-8.13) mg*h/L, 1.40 (0.74-2.65) mg/L and 0.054 mg/L (0.032-0.091) mg/L respectively. One patient in the 3 rd trimester (and none postpartum) had a C 12h level below the suggested threshold of 0.020 mg/L which was associated with failure to achieve an undetectable VL in QDMRK. The median (range) ratio of CB/maternal RAL concentrations (n=8), was 1.24 (0.13