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Impaired Drug Metabolism Caused by Compound Heterozygous Loss-of-Function Variants in CYP3A4: A Case Report.

Han Byul Kang^1,2, Iris Cohn^1,3, Sanjay Mahant^3,4,5,6

¹Division of Clinical Pharmacology and Toxicology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

Clinical Pharmacology and Therapeutics

|April 29, 2025

Summary

Routine pharmacogenetic testing may miss critical CYP3A4 variants. A child with extremely high sirolimus levels was found to have rare CYP3A4 variants (*8/*20), not detected by standard panels.

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Area of Science:

Pharmacogenomics
Clinical Pharmacology
Drug Metabolism

Background:

Current pharmacogenetic testing guidelines recommend CYP3A4*22 as the sole variant for panels.
This recommendation is based on functional data and allele frequency.
However, this approach may not capture all clinically significant CYP3A4 genetic variations.

Purpose of the Study:

To report a case of severe sirolimus toxicity due to previously unrecognized rare CYP3A4 variants.
To highlight the limitations of current pharmacogenetic testing panels for CYP3A4.
To emphasize the need for broader genetic screening in specific clinical scenarios.

Main Methods:

Clinical case presentation of a pediatric patient with unexplained sirolimus toxicity.
Measurement of sirolimus blood concentration and elimination half-life.
Clinical sequencing of the CYP3A4 gene to identify genetic variants.

Main Results:

The patient exhibited extremely high sirolimus blood concentrations (88.4 μg/L) and a prolonged half-life (121 hours).
Genetic analysis revealed compound heterozygosity for rare loss-of-function CYP3A4 variants (*8/*20).
These variants were not included in the standard pharmacogenetic test panel.

Conclusions:

A pharmacogenetic panel limited to CYP3A4*22 is insufficient for individuals suspected of having impaired CYP3A4 metabolism.
Rare loss-of-function variants like CYP3A4*8 and *20 can lead to severe drug toxicity.
Clinical sequencing should be considered for patients with high pre-test probability of altered CYP3A4 activity.