Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: Preliminary pharmacokinetics and pharmacodynamic data.

Extensive venous malformations involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. But patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Available pharmacological treatments (e.g., sirolimus) are not universally effective. Novel therapies are urgently needed for patients with treatment-resistant venous malformations. We report three patients with TIE-2 receptor mutations treated with alpelisib for 6 months (daily dosing: 50 mg for children weighing <50 kg and 100 mg for those >50 kg). Pain was controlled, gait improved, size of the abnormal venous network decreased, and coagulopathy dramatically improved. Drug exposure was highly variable, suggesting that alpelisib dosing should be individualized to patient's characteristics and guided by therapeutic drug monitoring.

Is Busulfan Clearance Different in Patients With Sickle Cell Disease? Let's Clear Up That Case With Some Controls.

In busulfan-based conditioning regimen for hematopoietic stem cell transplantation in children, accurate a priori determination of the first dose is important because of its narrow therapeutic window. Sickle cell disease (SCD) influences pharmacokinetics of the commonly used drugs by affecting organs responsible for drug metabolism and elimination. This pharmacokinetics study assesses the influence of SCD on the metabolic pathway of busulfan that is mainly metabolized in the liver. In this retrospective cross-sectional case-control study, 16 patients with SCD were matched to 50 patients without SCD on known busulfan clearance's covariates (glutathione-S-transferase alpha1 polymorphisms, age, weight). Clearance of the first dose of busulfan was not significantly different independently of genetic or anthropometric factors in patients with or without SCD.