# Pharmacoenhancers for antiretroviral therapy: safety and future development

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $382,103

## Abstract

ABSTRACT
The objectives of this application are to determine the mechanisms of hepatotoxicity of the current
available pharmacoenhancers and to provide a mechanism-based guidance for development of the next
generation of pharmacoenhancers with less hepatotoxicity. Ritonavir (RTV) and cobicistat (COBI) are the
first and second generations of pharmacoenhancers. RTV has been known as a hepatotoxin but its
mechanism remains elusive. In a recent series of clinical trials, the hepatotoxicity of RTV was
significantly potentiated in subjects who were pretreated with rifampicin (RIF) or efavirenz (EFV). Both
RIF and EFV are potent ligands of human pregnane X receptor (PXR), a ligand-dependent transcription
factor that upregulates Cytochrome P450 3A4 (CYP3A4) in drug metabolism. Because of the inter-
species differences in ligand-dependent PXR activation, we generated a double transgenic mouse model
expressing human PXR and CYP3A4 (TgCYP3A4/hPXR). By using the TgCYP3A4/hPXR mice, we
recapitulated RTV hepatotoxicity that occurred in clinical trials. In addition, we found that COBI can
cause similar liver damage as RTV. Furthermore, our metabolomic analysis revealed that RTV and COBI
undergo the same bioactivation pathways to generate toxic metabolites, which are produced by CYP3A4.
Based on these preliminary data, we hypothesize that human PXR modulates RTV/COBI hepatotoxicity
through CYP3A4-mediated RTV/COBI bioactivation. We also hypothesize that structural modification to
bypass the bioactivation pathways of RTV and COBI will mitigate their hepatotoxicity. To test our
hypothesis, we propose the following three specific aims: (1) to determine the role of human PXR in
RTV/COBI hepatotoxicity; (2) to determine the role of human CYP3A4 in RTV/COBI hepatotoxicity; and
(3) to explore drug design for the next generation of pharmacoenhancers with less hepatotoxicity.
Accomplishment of this project will have a significant impact on the field of pharmacoenhancers,
especially for their safety and future development.

## Key facts

- **NIH application ID:** 10170229
- **Project number:** 5R01AI131983-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Xiaochao Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,103
- **Award type:** 5
- **Project period:** 2017-06-26 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170229

## Citation

> US National Institutes of Health, RePORTER application 10170229, Pharmacoenhancers for antiretroviral therapy: safety and future development (5R01AI131983-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10170229. Licensed CC0.

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