Alpelisib in pediatric PIK3CA- and TIE-2–mutant vascular anomalies: a case series on safety, efficacy, and drug exposure
Bibliographic record
Abstract
Alpelisib was recently approved by the FDA for the management of pediatric patients with PIK3CA-related overgrowth spectrum. However, this medication was approved in the absence of pediatric pharmacokinetic data, as a fixed 50 mg dose, with no consideration of weight, the primary pharmacokinetically relevant covariate. This raises concerns regarding potential under and over-exposure. Given this gap in information, we aimed to assess the effect of alpelisib in relation to drug exposure (clinical response and drug safety). Alpelisib plasma concentrations were obtained from eight patients under treatment for vascular malformations. Drug exposure determined with area under the curve (AUC) was correlated to drug effect determined by a decrease in the size of lesions and grade of adverse events. Analysis was performed retrospectively. Eight patients received oral alpelisib through the compassionate use program of Novartis. AUC revealed substantial variability (3036 to 16620 ug*h/L) and inversely correlated to weight. Alpelisib resulted in marked clinical improvement, reducing pain, resolving coagulopathy, and improving mobility. Volumetric MRI indicated a 17.4% decrease in targeted vascular anomaly volume after 6 months of alpelisib therapy (p < 0.05), although volume decrease did not correlate with AUC. Adverse events including insulin resistance (n = 8/8) and growth restriction (n = 1/8) were documented, with severity directly correlating to drug exposure. We observed significant weight-related variability in alpelisib plasma concentrations, suggesting that the FDA-approved fixed-dose regimen of alpelisib is not optimal for pediatric patients. Weight-based dosing and therapeutic drug monitoring should be considered to enhance alpelisib safety.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".