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Clinical Trial
. 2024 Oct 16;230(4):878-888.
doi: 10.1093/infdis/jiae298.

Pharmacokinetics and Safety of Remdesivir in Pregnant and Nonpregnant Women With COVID-19: Results From IMPAACT 2032

Kristina M Brooks  1 , Kristin Baltrusaitis  2 , Diana F Clarke  3 , Sharon Nachman  4 , Jennifer Jao  5 , Murli U Purswani  6 , Allison Agwu  7 , Christy Beneri  4 , Jaime G Deville  8 , Kathleen M Powis  9   10 , Alice M Stek  11 , Ahizechukwu C Eke  12   13 , David E Shapiro  2 , Edmund Capparelli  14   15 , Elizabeth Greene  16 , Kathleen George  16 , Dwight E Yin  17 , Patrick Jean-Philippe  17 , Nahida Chakhtoura  18 , Frederic Bone  19 , Kira Bacon  19 , Benjamin Johnston  19 , Christina Reding  19 , Kathryn Kersey  20 , Rita Humeniuk  20 , Brookie M Best  14   15 , Mark Mirochnick  21 , Jeremiah D Momper  14 ; IMPAACT 2032 Study Team
Collaborators, Affiliations
Clinical Trial

Pharmacokinetics and Safety of Remdesivir in Pregnant and Nonpregnant Women With COVID-19: Results From IMPAACT 2032

Kristina M Brooks et al. J Infect Dis. .

Abstract

Background: Pregnant people with coronavirus disease 2019 (COVID-19) experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy.

Methods: IMPAACT 2032 was a phase 4 prospective, open-label, nonrandomized opportunistic study of hospitalized pregnant and nonpregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks after last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and nonpregnant women were calculated.

Results: Fifty-three participants initiated remdesivir (25 pregnant; median gestational age, 27.6 weeks; interquartile range, 24.9-31.0 weeks). Plasma exposures of remdesivir, its 2 major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and nonpregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI, 1.35-3.03) with each additional infusion in nonpregnant versus pregnant participants. Three adverse events in nonpregnant participants were related to treatment (1 grade 3; 2 grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected.

Conclusions: Plasma remdesivir PK parameters were comparable between pregnant and nonpregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.

Clinical trials registration: NCT04582266.

Keywords: SARS-CoV-2; antiviral; pharmacology; pregnancy; remdesivir.

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Conflict of interest statement

Potential conflicts of interest. K. M. B. has received consulting fees from ViiV Healthcare. K. B. has received research support from Gilead Sciences, Inc and ViiV Healthcare paid to her institution. D. S. has received research support from Gilead Sciences, Inc, Merck, and ViiV Healthcare paid to his institution. A. A. serves on scientific advisory boards for Gilead Sciences, Inc and ViiV Healthcare; is a site principal investigator for a multisite and investigator-initiated studies with Gilead Sciences, Inc; and is a consultant for Merck. E. V. C. is serving on a data and safety monitoring board for Melinta Pharmaceuticals. D. E. Y. was previously an unpaid technical advisor for the nonprofit Cover the Globe and Maipelo Trust. M. M. has received research support from Gilead Sciences, Inc, Merck, and ViiV Healthcare paid to his institution. R. H. and K. K. are employees of Gilead Sciences, Inc and hold stock in the company. J. D. M. has received research support from Gilead Sciences, Inc paid to his institution. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Study design. The preinfusion period provided baseline data collection for 48 hours prior to initiating remdesivir. The infusion period included the initiation of RDV (200 mg on day 1 and 100 mg every 24 hours thereafter) for up to 5 or 10 days as clinically indicated. The safety follow-up period was inclusive of the time from discontinuing or completing remdesivir through 4 weeks after the last infusion. Among pregnant women (Arm 1), safety and birth outcomes were collected from the onset of labor or start of the cesarean delivery through 24 hours after delivery. The delivery visit could occur during remdesivir treatment, safety follow-up, or afterward. Except for PK sampling, study procedures and data collections were largely performed by medical chart abstraction or remote contact. Abbreviations: EOI, end of infusion; IV, intravenous; PBMC, peripheral blood mononuclear cell; PK, pharmacokinetics; RDV, remdesivir.
Figure 2.
Figure 2.
Concentration-time profiles for total remdesivir (A), free remdesivir (B) GS-704277 (C), and GS-441524 (D). Data presented as median concentrations for each nominal time point by arm assuming a 1-hour infusion duration. Total remdesivir plot overlaid with half maximal effective concentration (EC50) in human airway epithelial (HAE) cells [15].
Figure 3.
Figure 3.
GS-443902 concentrations in PBMCs. Data presented as geometric mean (geometric SD) by study arm across nominal time points and overall. Gray shaded area shows 25th and 75th percentile concentrations measured in healthy volunteers on days 5 and 10 following administration of a 200-mg dose on day 1 with 100-mg daily thereafter for 5 or 10 days (6.7 and 12.4 µM, respectively). The GMR for GS-443902 in nonpregnant versus pregnant participants increased by 2.04-fold (90% CI, 1.35–3.03) with each additional infusion. Comparisons at each time point reflect GMR (90% CI) for nonpregnant versus pregnant participants from the same generalized linear mixed effects model. Pooled results reflect up to 2 observations per participant but were overlaid to show comparisons by arm. Abbreviations: CI, confidence interval; GMR, geometric mean ratio; PBMC, peripheral blood mononuclear cell.
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