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

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.

Pharmacokinetics and pharmacodynamics of aprepitant for the prevention of postoperative nausea and vomiting in pediatric subjects.

BACKGROUND/PURPOSE: This multicenter, randomized, partially-blinded phase IIb study evaluated the pharmacokinetics (PK)/pharmacodynamics, safety, and tolerability of aprepitant in pediatric subjects for the prevention of postoperative nausea and vomiting (PONV). METHODS: Subjects aged birth to 17 years scheduled to undergo surgery and receive general anesthesia with ≥1 risk factor for PONV were randomly assigned to 1 of 3 aprepitant dose regimens (a single oral dose of aprepitant equivalent to adult doses of 10 mg, 40 mg, or 125 mg), or a control regimen of ondansetron before anesthesia. Assessments included PK, safety, and exploratory efficacy (complete response [CR; no emesis, retching, or dry heaves and no rescue therapy within 0-24 h following surgery] and no vomiting [NV; no emesis, retching, or dry heaves within 0-24 h following surgery]). RESULTS: Of 220 randomized and treated subjects, 119 receiving a single aprepitant dose were sampled for PK analysis and had evaluable aprepitant plasma concentrations. A dose-dependent relationship in exposure (AUC0-8 h and Cmax) was observed. Aprepitant was generally well tolerated, and the CR and NV rates were high (>80%) across treatment groups. CONCLUSIONS: PK, safety, and preliminary efficacy analyses support further clinical evaluation of aprepitant for PONV prophylaxis in pediatric patients. CLINICALTRIALS. GOV ID: NCT01732458 LEVEL OF EVIDENCE: Therapeutic, Level I.

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in paediatric subjects: An analysis by age group.

BACKGROUND: This was a subgroup analysis of age group, dexamethasone use, and very highly emetogenic chemotherapy (VHEC) use from a randomised, multicentre, double-blind, Phase 3 study of oral aprepitant in paediatric subjects. METHODS: Subjects aged 6 months to 17 years scheduled to receive chemotherapeutic agents associated with at least moderate risk for emesis were randomly assigned to receive either aprepitant plus ondansetron (aprepitant regimen) or placebo plus ondansetron (control regimen); both could be administered with or without dexamethasone. This secondary analysis evaluated subjects stratified by pre-specified age groups, dexamethasone use, and VHEC use. The primary endpoint of this analysis was the proportion of subjects who experienced complete response (CR) during the delayed phase. RESULTS: CR rates in the delayed phase were numerically higher with the aprepitant than the control regimen across all age categories, and reached significance for subjects aged 12-17 years (51% vs. 10%; P < 0.0001). In subjects receiving dexamethasone, CR was twice as high for the aprepitant versus control regimen in the 6 months to <2 year group (50% vs. 25%) and significantly higher in the 12-17 year group (40% vs. 7%, P < 0.05). CR was also significantly higher with aprepitant in the 6 months to <2 year and 12-17 year age groups who received VHEC. Similar proportions of subjects experiencing at least one adverse event were seen in both regimens across age categories. CONCLUSION: A 3 day aprepitant regimen seemed effective and safe for prevention of chemotherapy-induced nausea and vomiting in paediatric subjects across subgroups (ClinicalTrials.gov NCT01362530).

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial.

BACKGROUND: Oral aprepitant, a neurokinin-1 receptor antagonist, is recommended in combination with other anti-emetic agents for the prevention of nausea and vomiting associated with moderately or highly emetogenic chemotherapy in adults, but its efficacy and safety in paediatric patients are unknown. We did this phase 3 trial to examine the safety and efficacy of such treatment in children. METHODS: In this final analysis of a phase 3, randomised, multicentre, double-blind study, patients aged 6 months to 17 years with a documented malignancy who were scheduled to receive either moderately or highly emetogenic chemotherapy were randomly assigned with an interactive voice response system to an age-based and weight-based blinded regimen of aprepitant (125 mg for ages 12-17 years; 3·0 mg/kg up to 125 mg for ages 6 months to <12 years) plus ondansetron on day 1, followed by aprepitant (80 mg for ages 12-17 years; 2·0 mg/kg up to 80 mg for ages 6 months to <12 years) on days 2 and 3, or placebo plus ondansetron on day 1 followed by placebo on days 2 and 3; addition of dexamethasone was allowed. Randomisation was stratified according to patient age, planned use of chemotherapy associated with very high risk of emetogenicity, and planned use of dexamethasone as an anti-emetic. Ondansetron was dosed per the product label for paediatric use or local standard of care. The primary efficacy endpoint was the proportion of patients who achieved complete response (defined as no vomiting, no retching, and no use of rescue medication) during the 25-120 h (delayed phase) after initiation of emetogenic chemotherapy. Efficacy and safety analyses were done with all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01362530. FINDINGS: Between Sept 22, 2011, and Aug 16, 2013, 307 patients were randomly assigned at 49 sites in 24 countries to either the aprepitant group (155 patients) or to the control group (152 patients). Three patients in the aprepitant group and two in the control group did not receive study medication, and thus were excluded from analyses. 77 (51%) of 152 patients in the aprepitant group and 39 (26%) of 150 in the control group achieved a complete response in the delayed phase (p<0·0001). The most common grade 3-4 adverse events were febrile neutropenia (23 [15%] of 152 in the aprepitant group vs 21 [14%] of 150 in the control group), anaemia (14 [9%] vs 26 [17%]), and decreased neutrophil count (11 [7%] vs 17 [11%]). The most common serious adverse event was febrile neutropenia (23 [15%] patients in the aprepitant group vs 22 [15%] in the control group). INTERPRETATION: Addition of aprepitant to ondansetron with or without dexamethasone is effective for the prevention of chemotherapy-induced nausea and vomiting in paediatric patients being treated with moderately or highly emetogenic chemotherapy. FUNDING: Merck & Co., Inc.

Primary early thoracoscopy and reduction in length of hospital stay and additional procedures among children with complicated pneumonia: results of a multicenter retrospective cohort study.

OBJECTIVE: To determine the effect of initial procedure type on the length of hospital stay (LOS) and on the requirement for additional pleural fluid drainage procedures in a large multicenter cohort of children with pneumonia complicated by pleural effusion. DESIGN: Retrospective cohort study. SETTING: Administrative database containing inpatient resource use data from 27 tertiary care children's hospitals. PARTICIPANTS: Patients between 12 months and 18 years of age diagnosed as having complicated pneumonia were eligible for the study if they were discharged from the hospital between January 1, 2001, and December 31, 2005, and underwent early (within 2 days of the index hospitalization) pleural fluid drainage. INTERVENTION: Pleural fluid drainage, categorized as chest tube placement, video-assisted thoracoscopic surgery (VATS), or thoracotomy. MAIN OUTCOME MEASURES: The LOS and the requirement for additional pleural fluid drainage. RESULTS: Nine hundred sixty-one of 2862 patients (33.6%) with complicated pneumonia underwent early pleural fluid drainage. Initial procedures included chest tube placement (n = 714), VATS (n = 50), and thoracotomy (n = 197). The median patient age was 4.0 years (interquartile range, 2.0-8.0 years). The median LOS was 10 days (interquartile range, 7-14 days). Two hundred ninety-eight patients (31.0%) required at least 1 additional pleural fluid drainage procedure, and 44 patients (4.6%) required more than 2 pleural fluid drainage procedures. In linear regression analysis, children undergoing primary VATS had a 24% (adjusted beta coefficient, -0.24; 95% confidence interval, -0.41 to -0.07) shorter LOS than patients undergoing primary chest tube placement; this translated into a 2.8-day reduction in the LOS for those undergoing early primary VATS. In logistic regression analysis, patients undergoing primary VATS had an 84% (adjusted odds ratio, 0.16; 95% confidence interval, 0.06-0.42) reduction in the requirement for additional pleural fluid drainage procedures compared with patients undergoing primary chest tube placement. CONCLUSION: Our large retrospective multicenter study demonstrates that, compared with primary chest tube placement, primary VATS is associated with shorter LOS and fewer additional procedural interventions.