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

Recent consensus guidelines recommend including *22 as the only CYP3A4 variant in pharmacogenetic test panels, given the presence of sufficient functional data as well as a relatively high minor allele frequency. We here describe the clinical presentation of a child with an extremely high sirolimus blood concentration (88.4 μg/L; therapeutic range at trough: 5-15 μg/L) and prolonged elimination half-life of 121 hours (mean 14 hours in the pediatric population) following only eight standard-dose administrations. Due to the clinical suspicion of impaired CYP3A4 metabolism, in the absence of drug-drug or drug-food interactions, clinical sequencing of CYP3A4 was performed. This revealed that the patient is compound heterozygous for two rare loss-of-function variants in CYP3A4 (*8/*20). This clinical case highlights that a routine pharmacogenetic test panel that includes *22 as the only CYP3A4 variant is not a suitable diagnostic test for individuals with an increased pre-test probability of altered CYP3A4 metabolism.