Yi Zheng1, Jade Ghosn2, Sihem Benaboud1, Jerome Lechedanec3, Jean-Marc Tréluyer1,Camille Gobeaux4, Gabrielle Lui1, Elisa Arezes3, Sandrine Delmas3, Josiane Warszawski3, Déborah Hirt1 for the ANRS 160 RalFe Study Group
1. Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin, Paris, France 2. Hôpital Hôtel Dieu, AP-HP, Paris, France 3. Service d’Epidemiologie et Santé Publique, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France 4.Service de Diagnostic Biologique Automatisé, AP-HP, Hôpital Cochin, Paris, France
Objectives: Raltegravir can be used for the prevention of mother-to-child HIV transmission, especially when a rapid decline of HIV RNA load is necessary. Physiological changes during pregnancy have an impact on raltegravir elimination. Indeed, exposure of total raltegravir was shown to decrease from 29 to 50% during the third trimester of pregnancy compared to postpartum(1). However albumin level is known to be lowered during pregnancy which could increase the active free fraction of the drug and reduce this effect. The objective of this study was to describe the unbound, total and glucuronide raltegravir pharmacokinetics during pregnancy.
Methods: The RalFe ANRS160 study was a non-randomized, open label, multicenter phase II trial in HIV-infected pregnant women receiving raltegravir 400 mg twice daily. Samples were collected during pregnancy (between 30 and 37 weeks of amenorrhea), at delivery and at postpartum (4 to 6 weeks after delivery). None of these women received an antiretroviral drug which could interact with raltegravir. Free raltegravir, total raltegravir and raltegravir glucuronide concentrations were measured using a validated liquid chromatography-tandem mass spectrometry and ultrafiltration methods. Aspartate transaminase, alanine transaminase, creatinine, biribuline and albumin of each sample were systematically measured. Furthermore, raltegravir has been shown to be primarily metabolized by the UDP-Glucuronosyltransferase (UGT1A1) and to be a substrate of the drug efflux transporter P-glycoprotein(PgP)(2). Two polymorphisms, one in UGT1A1 and another in P-glycoprotein, were also genotyped by sequencing and real time PCR and respectively. A population pharmacokinetic model was developed by using NONMEM software.
Results: A total of 414 samples were collected from 43 women (aged from 23.3 to 45.9 years old) in which free, total and glucuronide raltegravir concentrations were measured. Free raltegravir was described by a one-compartment model with first order absorption and lag time, evolving either to bound raltegravir (by a linear binding to albumin), or to glucuronide raltegravir (through an additional compartment) or to a first order elimination. The influence of body weight, age, aspartate transaminase, alanine transaminase, creatinnie, biribuline and two polymorphisms were evaluated for the raltegravir pharmacokinetics analysis and no effect was found. Pregnancy increased free raltegravir clearances: by 26% for glucuronide formation which could be explained by increased activity of UGT1A1 during pregnancy and 17% for other elimination. During pregnancy, trough concentrations and exposures decreased by 28 and 37% respectively for total raltegravir and by 25 and 22% respectively for free raltegravir. The decrease was negligible for the glucuronide form.
Conclusions: This is the first data reporting free and glucuronide raltegravir pharmacokinetics during pregnancy. Pregnancy effect was moderate on the active raltegravir free fraction, especially when compared to its intersubject variability. Our data suggest that this pregnancy effect could be considered not to be of clinical importance, raltegravir does not need to be modified during pregnancy.
References:
[1] Blonk MI, Colbers APH, Hidalgo-Tenorio C, Kabeya K, Weizsäcker K, Haberl AE, et al. Raltegravir in HIV-1–Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy. Clin Infect Dis. 2015 Sep 1;61(5):809–16.
[2] Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos Biol Fate Chem. 2007 Sep;35(9):1657–63.
Reference: PAGE 27 (2018) Abstr 8645 [www.page-meeting.org/?abstract=8645]
Poster: Drug/Disease Modelling - Infection