Raltegravir Pharmacokinetics During Pregnancy

Abstract

Objective We evaluated the pharmacokinetics (pk) of raltegravir in HIV-infected women during pregnancy and postpartum. Methods IMPAACT 1026s is an on-going prospective study of antiretroviral pk during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady state 12-hour pk profiles performed during pregnancy and at 6–12 weeks postpartum. Targets were trough concentration above 0.035 µg/mL, the estimated tenth percentile in non-pregnant historical controls. Results Median raltegravir AUC was 6.6 µg*hr/mL for second trimester (n= 16), 5.4 µg*hr/mL for third trimester (n=41), and 11.6 µg*hr/mL postpartum (n= 38) (p=0.03 pp vs 2nd trimester, p=0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester and postpartum subjects respectively, with wide variability (<0.010–0.917 µg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were < 400 copies/mL in 92% of women at delivery. Adverse events included elevated liver transaminases in one woman and vomiting in one. All infants with known status are HIV-uninfected. Conclusions Median raltegravir AUC was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.

Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy

“…A recent study documented that cART, which includes an INSTI backbone, induces a more rapid reduction in HIV-1 RNA viral load than other regimens during pregnancy, which may be important if HIV-1-infected pregnant women present late to prenatal care or have failed to initiate an appropriately selected ARV regimen (29). Given our findings and previous data (7,29,30), consideration should be given to the use of the newer-generation INSTIs as part of a first-line preferred regimen during pregnancy.…”

“…Low concentration ratios for EVG and DTG were noted between cord plasma and placenta, cord plasma and maternal plasma, and cord PBMCs and maternal PBMCs. There are limited PK data on placental transfer of EVG (4)(5)(6)(7)(8). Distributions of all five drug concentrations for all the matrices were analyzed and are plotted in Fig.…”

“…Protease inhibitors, such as atazanavir (22,23) and lopinavir (20,24) actively cross the placenta; however, undetectable concentrations in cord blood have been reported for nelfinavir, indinavir, and saquinavir (25,26). Fusion/entry inhibitors cross poorly into cord blood (7,11). The human placenta plays a major role in maternal-to-fetal and fetal-to-maternal transfer of nutrients and oxygen and of waste products, respectively.…”

“…tions detected in maternal and cord blood plasma from mothers receiving RTG-based therapy during pregnancy (7,(11)(12)(13). Dolutegravir has also been shown to readily cross the blood-placenta barrier (8).…”

An HIV-infected Pregnant Woman Treated with the Long-term Administration of Antiretroviral Therapy Including Raltegravir

“…The duration of RAL use also varied from just 14 hours to the entire maternal period. Confirmed adverse events caused by RAL were definitive in the case of one mother with elevated liver enzymes (9, 10) and were suspected in two other cases with elevated liver enzymes and vomiting, respectively (11). In the infants, no adverse events and two HIV infections (1.4%) were documented.…”