Impaired Drug Metabolism Caused by Compound Heterozygous Loss‐of‐Function Variants in <i>CYP3A4</i>: A Case Report
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.003 | 0.002 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.003 | 0.001 |
| Science and technology studies | 0.002 | 0.003 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.006 | 0.005 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".