Mechanistic Modeling of the Drug-Drug Interaction Between Efavirenz and Dolutegravir: Is This Interaction Clinically Relevant When Switching From Efavirenz to Dolutegravir During Pregnancy?

Authors

André Dallmann, Pharmacometrics/Modeling & Simulation, Research & Development, Pharmaceuticals, Bayer AG, Germany.
John van den Anker, Division of Clinical Pharmacology, Children's National Hospital, Washington, District of Columbia, USA.
Homa K. Ahmadzia, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Natella Rakhmanina, Division of Pediatric Infectious Diseases, Children's National Hospital, Washington, District of Columbia, USA.

Document Type

Journal Article

Publication Date

6-1-2023

Journal

Journal of clinical pharmacology

Volume

63 Suppl 1

DOI

10.1002/jcph.2225

Keywords

HIV/AIDS; PBPK; drug-drug interactions; modeling and simulation; pregnancy

Abstract

Following the 2021 World Health Organization's updated recommendations on the management of HIV infection, millions of people living with HIV are currently switched from efavirenz-based antiretroviral therapy to dolutegravir-based antiretroviral therapy. Pregnant individuals transitioning from efavirenz to dolutegravir might be at increased risk of insufficient viral suppression in the immediate postswitch period because both efavirenz- and pregnancy-related increases in hormone levels induce enzymes involved in dolutegravir metabolism, namely, cytochrome P450 3A4 and uridine 5'-diphospho-glucuronosyltransferase 1A1. This study aimed at developing physiologically based pharmacokinetic models to simulate the switch from efavirenz to dolutegravir in the late second and third trimester. To this end, the drug-drug interaction between efavirenz and the uridine 5'-diphospho-glucuronosyltransferase 1A1 substrates dolutegravir and raltegravir was first simulated in nonpregnant subjects. After successful validation, the physiologically based pharmacokinetic models were translated to pregnancy and dolutegravir pharmacokinetics following efavirenz discontinuation were predicted. Modeling results indicated that, at the end of the second trimester, both efavirenz concentrations and dolutegravir trough concentrations fell below respective pharmacokinetic target thresholds (defined as reported thresholds producing 90%-95% of the maximum effect) during the time interval from 9.75 to 11 days after dolutegravir initiation. At the end of the third trimester, this time interval spanned from 10.3 days to >4 weeks after dolutegravir initiation. These findings suggest that dolutegravir exposure in the immediate post-efavirenz switch period during pregnancy may be suboptimal, leading to HIV viremia and, potentially, resistance. The clinical implications of these findings remain to be substantiated by future studies.

APA Citation

Dallmann, André; van den Anker, John; Ahmadzia, Homa K.; and Rakhmanina, Natella, "Mechanistic Modeling of the Drug-Drug Interaction Between Efavirenz and Dolutegravir: Is This Interaction Clinically Relevant When Switching From Efavirenz to Dolutegravir During Pregnancy?" (2023). GW Authored Works. Paper 2781.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/2781

Department

Pediatrics