Supichaya Narongchartsopon (1), Tiago Antunes Paz (2), Alessandro Di Deo (1), Salvatore D’Agate (1), Geraldo Duarte (3), Vera Lucia Lanchote (2), Oscar Della Pasqua (1)
(1) Clinical Pharmacology and Therapeutics Group, School of Pharmacy, University College London, London, United Kingdom, (2) Department of Clinical, Toxicological and Bromatological Anlayses, University of Sao Paulo, Ribeirao Preto, Brazil (3) Department of Gynecology and Obstetrics, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Objectives: While integrase inhibitors have become first line antiretroviral therapy for non-pregnant adults [1], there have been few studies supporting the dose rationale of raltegravir (RAL) during pregnancy. Even though, the current label of RAL indicates that 1200 mg is not recommended for pregnant women, a large amount of data following 400 mg twice daily during the first trimester of pregnancy has shown no malformative toxicity. Moreover, limited attention has been given to the effects of pregnancy on the pharmacokinetics of RAL and its metabolite, raltegravir glucuronide (RGLU), which reflects the primary elimination pathway of the parent drug [1,2]. To date, it has been shown that there is large interindividual variability in systemic levels of RAL during pregnancy [3], but no assessment has been made of the potential implications of such variability for the overall treatment efficacy, namely, the prevention of vertical transmission.
This study aimed to describe the pregnancy-related changes in pharmacokinetics of RAL and RGLU, taking into account the known effect of pregnancy on gastrointestinal motility, fluid absorption, expanded extracellular volume, and maternal fat increase, which can affect bioavailability and drug distribution, in particular during the third trimester of pregnancy.
Methods: Using a previously published population pharmacokinetic model for RAL in pregnant and post-partum women, we have analysed the pharmacokinetics of parent and metabolite data obtained in pregnant women in the third trimester of pregnancy (mean: 35 weeks gestational age) and in the postpartum period (mean: 5 weeks after delivery), who were receiving the standard combination anti-retroviral therapy (cART), with 400 mg RAL twice daily in combination with tenofovir/lamivudine (300 mg/300 mg once daily). The study was approved by the Research Ethics Committee of the local hospital. Blood samples for pharmacokinetics were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 12 hours after the administration of RAL. Using a Bayesian approach, parameter estimates from a model developed by Bukkems et al [4] were used as priors for the characterization of the pharmacokinetics in the current study population. In addition to re-assessing covariate factors, lag-time and different transit compartments were tested. Goodness-of-fit and model performance were evaluated using standard graphical and statistical criteria. The final model was selected based on predictive performance, precision of parameter estimates, and biological plausibility.
Results: In total fifteen pregnant women were enrolled in the study. However, only 8 patients completed the second visit for evaluation during the postpartum period. Large interindividual (IIV) and inter-occasion (IOV) variability was observed in the rate and extent of absorption, which could be assigned primarily to changes in bioavailability (F). Whereas maximum RAL concentrations were significantly lower during pregnancy, no changes were observed in RGLU, suggesting primary differences in distributional processes. The pharmacokinetics of RAL was best described by a 2-compartment model with 3 transit compartments and RGLU by a 2-compartment model. Main parameter estimates were Ka = 0.9 h-1, CLT = 40.2 L h-1, V2 = 66.0 L, Q = 10.0 L h-1, V3 = 100.0 L, V4 = 0.338 L, fraction metabolised = 0.01, CLM – 0.788 L h-1, V5 = 0.447 L, QM = 5.25 L h-1. The observed differences between pregnant versus post-partum were explained partly by a change of approximately 18 % in relative oral bioavailability. Metabolite formation rate and systemic exposure to RGLU appear to remain unaltered during pregnancy.
Conclusions: The observed high interindividual variability in the concentration vs time profile of RAL during pregnancy may be clinically relevant. The 40% decrease in systemic exposure compared to data in non-pregnant women deserves further investigation. In fact, a dose increase to 600 mg b.i.d. should be considered along with an integrated assessment of the pharmacokinetic changes of all agents in the cART regimen.
References:
[1] Temesgen Z, Siraj DS. Raltegravir: mirst in class HIV integrase inhibitor. Ther Clin Risk Manag. 2008;4(2):493-500.
[2] European Medicines Agency. (2022). Isentress | European Medicines Agency. European Medicines Agency. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/isentress (Accessed: 12 March 2024).
[3] Moreira, FL et al. Total, unbound, renal, and hepatic clearances of raltegravir and the formation and elimination clearances of raltegravir glucuronide in pregnant women. J Clin Pharmacol. 2023; 63 (9):1053–1060.
[4] Bukkems, VE et al. A population pharmacokinetics analysis assessing the exposure of raltegravir once-daily 1200 mg in pregnant women living with HIV. CPT Pharmacometrics Syst Pharmacol. 2021;10(2):161-172.
Reference: PAGE 32 (2024) Abstr 11150 [www.page-meeting.org/?abstract=11150]
Poster: Drug/Disease Modelling - Other Topics