Pharmacokinetic and safety of raltegravir in pregnancy

Abstract

Dear Sirs:The aim of anti-HIV treatment in pregnancy is the suppression of the HIV-1 RNA viral load in the plasma before delivery [1] to prevent mother-to-child transmission of the infection. The achievement of this outcome may be complicated in pregnant women who have been treated with multiple drugs by the lack of active drugs available. Although there are limited data on the use of the integrase inhibitor raltegravir in pregnancy, the availability of this drug is important in the management of multidrug-resistant virus in pregnant women.We describe a case of a 22-year-old woman who acquired the infection via vertical transmission and who has been followed up at our Centre since March 2009. Past antiretroviral treatments include numerous drugs; the historical genotypic resistance test showed mutations in the regions of reverse transcriptase (41L, 74V, 101Q, 103N, 103S, 108I, 115F, 179I, 184V, 215D, 215N, 215S, 215Y) and protease (36I, 63P). These mutations confer resistance or poor efficacy to all the nucleoside/nucleotide reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors except etravirine.Since April 2009 the patient has received treatment with tenofovir/emtricitabine (fixed dose combination) plus darunavir/ritonavir (600/100 mg twice daily) plus raltegravir (400 mg twice daily). At the time of conception she presented HIV-RNA <20 cp/mL. Despite safety and pharmacokinetics data of raltegravir in pregnancy being insufficient to recommend its use during pregnancy, it was decided to continue the treatment with tenofovir/emtricitabine (fixed dose combination) plus raltegravir (400 mg twice daily); only darunavir/ ritonavir had been discontinued since the 4th week of pregnancy and substituted with lopinavir/ritonavir (400/100 mg twice daily), the gold standard for protease inhibitors in pregnant women [2]. Therapeutic drug monitoring was performed by a validated HPLC-UV method [3] in the third trimester, which demonstrated good adherence; at that time lopinavir, ritonavir and raltegravir plasma levels were 9.59 μg/mL (minimum target trough concentration 1 μg/mL) [3], 0.81 μg/mL and 0.21 μg/mL (median trough concentration from clinical trials 0.029-0.118 μg/mL) [2].At 39 weeks' gestation a 2.4-kg neonate was delivered by elective caesarean section without complications; at the time of delivery the HIV-RNA viral load in plasma was <20 cp/mL. Despite the low birth weight the infant was healthy; the Apgar scores were 9 and 10 at 1 and 5 min respectively. The mother received zidovudine intravenous prophylaxis during labour and the newborn received 4 weeks of oral zidovudine; the HIV-RNA was undetectable at birth and at 1 and 3 months of age. At delivery the raltegravir level in cord and in maternal plasma was the same (0.19 μg/mL) with a cord/maternal plasma ratio of 1. The lopinavir levels were 1.3 μg/mL and 8.05 μg/mL and the ritonavir levels were 0.26 μg/mL and 0.94 μg/mL, corresponding to a ratio of 0.16 and 0.28 respectively.The low plasma cord concentration of lopinavir can be ex...

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

“…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.…”

“…A few studies have measured the PK of INSTIs during pregnancy (6). RTG has been shown to cross the placenta well, with drug concentrations detected in cord blood plasma from mothers receiving this ARV during pregnancy (11,14). DTG has also been shown to readily cross the blood-placenta barrier (8).…”

“…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).…”

Raltegravir Pharmacokinetics During Pregnancy

“…Croci et al reported a trough level of raltegravir of 0.21 µg/mL in the third trimester in one patient, compared to median trough concentrations in a trial of non-pregnant adults of 0.029–0.118 µg/mL. 7 Maternal plasma raltegravir at delivery was 0.19 µg/mL with cord:maternal ratio of 1.0. 7 In another case report, the maternal trough level was 0.162 µg/mL, cord blood was 0.173 µg/mL and a cord:maternal ratio of 1.06.…”

“…7 Maternal plasma raltegravir at delivery was 0.19 µg/mL with cord:maternal ratio of 1.0. 7 In another case report, the maternal trough level was 0.162 µg/mL, cord blood was 0.173 µg/mL and a cord:maternal ratio of 1.06. 6 In a case series from London, maternal levels near delivery ranged from 0.022–0.493 µg/mL five to 13 hours after maternal dosing, and levels in infant blood one to three hours after delivery ranged from seven to nine times higher than concomitant maternal levels.…”