Minimal impact of pregnancy on rilpivirine pharmacokinetics: A POPPK approach

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Minimal impact of pregnancy on rilpivirine pharmacokinetics: A POPPK approach

Minh Lê¹, Benjamin Kably¹, Roland Tubiana², Jade Ghosn³, Quentin Le Hingrat⁴, Marc Wirden⁵, Zeliea Julia³, Naima Hamani², Laurent Mandelbrot⁶ and Gilles Peytavin¹

¹AP-HP, Hôpital Bichat, Pharmacology; ²AP-HP, Hôpital Pitié Salpétrière, Infectious Diseases; ³AP-HP, Hôpital Bichat, Infectious Diseases; ⁴AP-HP, Hôpital Bichat, Virology; ⁵AP-HP, Hôpital Pitié Salpétrière, Virology; ⁶AP-HP, Hôpital Louis Mourier, Obstetrics

Background: Rilpivirine is the most popular non-nucleoside transcriptase inhibitor (NNRTI) recommended to prevent the risk of mother-to-child transmission of HIV. However, a decrease of rilpivirine plasma exposure in the second trimester could be expected due to an increased metabolism and/or elimination in pregnant women. The latter could compromise the efficacy of the ARV strategy. The objectives were to assess maternal rilpivirine plasma concentrations during pregnancy and postpartum.

Material and methods: A multicentre, cross-sectional cohort was conducted from 2020 to 2023. Pregnant women living with HIV receiving rilpivirine 25 mg once-daily containing regimen were enrolled. Plasma concentrations of rilpivirine were determined by UPLC-MS/MS (Waters Acquity) during the three trimesters (Tn) of pregnancy and postpartum. The gestational age was recorded for each sample. A population pharmacokinetic approach was performed using Monolix 2023R1 suite to analyse the plasma concentrations. Rilpivirine trough plasma concentrations (C24h) were estimated using individual parameters. Rilpivirine C24h were interpreted using an efficacy threshold of 50 ng/mL. The results are presented as median (IQR).

Results: Seventy-two (97% sub-Saharan African) pregnant women were enrolled: age 34 years old (28–38). All were receiving FTC/TFV (as TDF or TAF) associated NRTIs with no boosted PI/r or reported CYP3A4 inhibitor. For these women, 222 plasma concentrations were determined corresponding to 20 at T1, 85 at T2, 92 at T3 and 25 postpartum. Population pharmacokinetic parameters (RSE%) were ka 1 h-1 (fixed), V/F 727 L (10.7%), CL/F 6.4 L/h (9.1%). Inter-individual variabilities were 39% (22.7%) and 53% (14.5%) for V/F and CL/F, respectively. Between-occasion variabilities were 73% (8.2%) and 24% (14.1%) for V/F and CL/F, respectively. Additive and proportional errors were 3.7 ng/mL (46.5%) and 0.08 (36.1%), respectively. There was no effect of gestational age or trimester on ka, V/F or CL/F parameters to improve the between-occasion variabilities. Rilpivirine estimated C24h were 90 ng/mL (50–103). Among the 72 patients, 14% of patients presented C24h below the 50 ng/mL. All women presented undetectable viral load during their pregnancy.

Conclusions: In this population of mostly sub-Saharan African pregnant women living with HIV, no significant effect of pregnancy (trimester or gestational age) on rilpivirine pharmacokinetic parameters was reported. Surprisingly, no decrease in rilpivirine plasma exposure was reported during pregnancy, and all patients maintained an undetectable viral load during pregnancy. These results suggest that no systematic dose adjustment should be recommended in this setting. Nevertheless, a close therapeutic drug monitoring should still be performed considering the low genetic barrier to resistance of rilpivirine.