Alpelisib in pediatric PIK3CA- and TIE-2–mutant vascular anomalies: a case series on safety, efficacy, and drug exposure

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 (<i>p</i> < 0.05), although volume decrease did not correlate with AUC. Adverse events including insulin resistance (<i>n</i> = 8/8) and growth restriction (<i>n</i> = 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.