Single-Dose Longitudinal Pharmacokinetic Evaluation of Doravirine in Pregnant Women Living With HIV: Protocol for a Phase 1 Study.

Background: Women are largely underrepresented in clinical trials of antiretroviral therapy, constituting approximately 20% of participants. Trials often exclude pregnant women from participation to minimize fetal risk, and women enrolled in clinical trials who have a positive pregnancy test may be discontinued from the study. This results in an average 7-year lag between the time of drug approval and when dosing information for pregnancy is available. However, there may be low-risk opportunities to obtain dosing information earlier for pregnant women who need treatment with newer medications. We demonstrate this with a clinical trial of doravirine, a Food and Drug Administration (FDA)-approved nonnucleoside reverse transcriptase inhibitor, designed to assess the pharmacokinetics and dosing strategy for doravirine during pregnancy while maintaining safety for participants. Objective: The primary objective of this study is to quantify single-dose total and protein-unbound pharmacokinetics of doravirine in blood plasma from women living with HIV during their second trimester, third trimester, and postpartum periods. The secondary objective is to evaluate the safety and tolerability of single doses of doravirine in pregnant participants living with HIV. Methods: The proposed study is a single-site phase 1 evaluation of single doses of doravirine across the gestational period in pregnant female participants (n=10) living with HIV currently controlled with antiretroviral therapy. Single doses were administered in the second and third trimesters and postpartum. Pharmacokinetic sampling occurred over a 72-hour dosing interval, and total and protein-unbound drug concentrations were assessed across the 3 dosing phases using LC-MS/MS methods validated according to FDA criteria. Pharmacokinetic parameters of peak drug concentration, concentration at 12 hours into the dosing interval, concentration at the end of the dosing interval, time to reach maximum concentration, and area under the curve were estimated using noncompartmental linear up-log down methods (version 8.6; Phoenix WinNonlin). Comparisons across the 3 sampling visits were made using the Friedman test and post hoc Wilcoxon signed-rank tests with Bonferroni adjustment (version 13.0; SigmaPlot). Results: The proposed study was funded in 2020 and approved by the University of North Carolina-Chapel Hill institutional review board on March 9, 2021. Participant recruitment began the same day, and the first participant was enrolled on June 9, 2022. The last participant was enrolled on October 3, 2024, and all participants were off the study on April 8, 2025. In total, 7 participants were enrolled in the study, and 5 were evaluable. Conclusions: The data collected with this novel single-dose pharmacokinetic study design will provide important insights into the clinical management of patients on doravirine during pregnancy and provide an effective model for obtaining early pharmacokinetic and dosing information for new drugs that can be used in pregnant women.