# The role of CYP3A7 in the disposition and toxicity of HIV inhibitors in the developing infant

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $399,924

## Abstract

ABSTRACT
 Each year sick and premature infants infected with HIV are treated with a variety of drugs, despite the
fact that these drugs have never been tested for safety and efficacy in this vulnerable population. A primary
determinant for the pharmacokinetic (PK) and hepatotoxicity profile of many of these drugs is cytochrome P450
metabolism. CYP3A7 is the predominant P450 enzyme in the in the developing infant (≤6 mos. Post-
Gestational Age). Recently published reports and our own preliminary results have demonstrated that CYP3A7
can produce a metabolic profile significantly different than that of adult CYP3A4. These differences in
metabolism can alter the PK parameters and safety profiles of many HIV drugs used in pediatric patients,
leading to reduced efficacy or increased toxicity. Therefore, there exists a critical need to determine the PK and
metabolic profiles of clinically relevant CYP3A7 HIV drug substrates to the improve safety and efficacy of these
drugs in infants. The objective of this proposal is to determine the functional consequences and mechanistic
basis of the differences in HIV drug metabolism between CYP3A7 and adult CYP3A4. Our specific hypothesis
is that the differences in HIV drug metabolism are due to changes in enzyme structure which lead to
substantial alterations in drug clearance, drug-drug interactions, and production of reactive metabolites. Our
first aim is to develop a physiologically based PK (PBPK) model for the disposition of four commonly
prescribed HIV inhibitors: ritonavir, lopinavir, nevirapine, and efavirenz. To achieve this, we will monitor drug
metabolism and identify metabolites in vitro with both recombinant CYP3A7 and CYP3A4 enzymes and human
liver microsomes (HLMs) from the adult and the infant at different stages of development. We will utilize the
results from these studies to produce predictive PK models for the developing infant. Our second aim is to
identify the CYP3A7 inhibitory capacity, potential drug-drug interactions, and reactive metabolites for each of
these inhibitors. Finally, our third aim is to define the structural basis of the differences in HIV drug metabolism
observed between CYP3A7 and CYP3A4. To do this, we propose to obtain an X-ray crystal structure for
CYP3A7 with the substrates ritonavir and nevirapine, and perform Saturation Transfer Difference NMR to
identify amino acid residues and ligand functional groups that are important for enzyme-ligand interaction. We
expect that these studies will allow us to determine how structural differences contribute to the observed
metabolic differences. The proposed research is innovative because it seeks to change the current conceptual
framework by producing improved infant PBPK models for HIV drug disposition using HLMs, and novel crystal
structures for this important enzyme. This research will improve health outcomes by improving our ability to
accurately predict pharmacokinetics and drug-drug interactions of some important HIV drugs ...

## Key facts

- **NIH application ID:** 10408010
- **Project number:** 5R01AI150494-06
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jed Noah Lampe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $399,924
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10408010

## Citation

> US National Institutes of Health, RePORTER application 10408010, The role of CYP3A7 in the disposition and toxicity of HIV inhibitors in the developing infant (5R01AI150494-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10408010. Licensed CC0.

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