Pharmacokinetics/pharmacodynamics, safety, and tolerability of fosaprepitant for the prevention of chemotherapy‐induced nausea and vomiting in pediatric cancer patients

Abstract

Background Current antiemetic regimens are less effective in children than in adults. Fosaprepitant was recently approved for prevention of chemotherapy‐induced nausea and vomiting (CINV) in children aged six months and older. Procedure The pharmacokinetic (PK)/pharmacodynamic (PD) profile, safety, and tolerability of a single intravenous dose of fosaprepitant administered concomitantly with ondansetron with/without dexamethasone were evaluated in pediatric patients with cancer receiving emetogenic chemotherapy. PK/PD from three doses of fosaprepitant (3.0, 1.2, and 0.4 mg/kg, up to 150, 60, and 20 mg, respectively) were compared with placebo in 2‐ to 17‐year‐old subjects; an open‐label amendment evaluated a fourth dose (5.0 mg/kg, up to 150 mg) in those under 12 years old. Historical adult PK data were used for comparison. Efficacy was measured as an exploratory endpoint. Results PK data were evaluable for 167/234 subjects who completed cycle one. Aprepitant exposures were dose proportional; adolescents (12 to 17 years) receiving fosaprepitant 150 mg had exposures similar to adults at the same dose. Higher weight‐normalized doses (5 mg/kg) were necessary for children aged < 12 years to achieve comparable adult exposures. The adverse event profile was typical of cancer patients receiving emetogenic chemotherapy. Drug‐related adverse events were reported in 16 (6.8%) subjects, with hiccups being most common (n = 5; 2.1%). Conclusions Intravenous fosaprepitant was well tolerated by pediatric subjects with cancer, and dose‐proportional exposures were observed. Subjects < 12 years old required higher doses to achieve comparable adult exposures.

Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors

“…It aids in prevention of both delayed and acute nausea and vomiting associated with cancer chemotherapy 24 . Fosaprepitant is a neurokinin 1 receptor (NK-1R) antagonist that binds and deactivate NK-1R leading to downstream effect such as Ca 2+ signaling through the g-protein coupled receptor (GPCR) cascade, which in turn leads to cellular sequestration resulting in vomiting [24][25][26] . Fosaprepitant exerts its effect on targeted cells by passing across the blood brain barrier (BBB) to its target destination 23 .…”

Factors Associated With Chemotherapy-Induced Vomiting Control in Pediatric Patients Receiving Moderately or Highly Emetogenic Chemotherapy: A Pooled Analysis

“…Individual patient-level demographic and efficacy data from five prospective phase I to phase III pediatric clinical trials were pooled for analysis. [14][15][16][17][18] All trials were approved by the research ethics boards at participating institutions. Informed consent and assent, where appropriate, were obtained from participants and/or their guardians.…”

“…Informed consent and assent, where appropriate, were obtained from participants and/or their guardians. The methods of each trial have been published 14,[16][17][18] or are available elsewhere. 15 Trial characteristics are presented in the Data Supplement.…”

Chemotherapy-induced nausea and vomiting in children – the missing evidence

“…9 NK 1 receptor antagonists Antagonists targeting NK 1 receptors inhibit substance P in binding to the receptor and are characterised by their long duration of action, significant antiemetic efficacy against acute and delayed CINV, and a favourable safety profile. 8,15 Aprepitant is an oral NK 1 receptor antagonist approved in children aged 6 months and older. In children receiving highly emetogenic chemotherapy, the combination of aprepitant, dexamethasone, and ondansetron was found to protect 48% of patients from acute vomiting compared with only 12% of patients receiving dexamethasone and ondansetron (P < 0.001).…”