Dataset Information

Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting.

ABSTRACT: OBJECTIVES:Aprepitant is effective for the prevention of chemotherapy-induced or postoperative nausea and vomiting (CINV/PONV). The aim of this study was to develop a population pharmacokinetic (PK) model of aprepitant in pediatric patients and to support dosing recommendations for oral aprepitant in pediatric patients at risk of CINV. METHODS:A population PK model was constructed based on data from 3 clinical studies in which children (6 months to 12 years) and adolescents (12-19 years) were treated with a 3-day regimen of oral aprepitant (capsules or suspension), with or without intravenous fosaprepitant on day 1 (CINV), or a single dose of oral aprepitant (capsules or suspension; PONV). Nonlinear mixed-effects modeling was used for model development, and a stepwise covariate search determined factors influencing PK parameters. Simulations were performed to guide final dosing strategies of aprepitant in pediatric patients. RESULTS:The analysis included 1326 aprepitant plasma concentrations from 147 patients. Aprepitant PK was described by a 2-compartment model with linear elimination and first-order absorption, with allometric scaling for central and peripheral clearance and volume using body weight, and a cytochrome P450 3A4 maturation component for the effect of ontogeny on systemic clearance. Simulations established that application of a weight-based (for those <12 years) and fixed-dose (for those 12-17 years) dosing regimen results in comparable exposures to those observed in adults. CONCLUSIONS:The developed population PK model adequately described aprepitant PK across a broad pediatric population, justifying fixed (adult) dosing for adolescents and weight-based dosing of oral aprepitant for children.

SUBMITTER: Chain A

PROVIDER: S-EPMC7439950 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting.

Chain Anne A Wrishko Rebecca R Vasilinin Grygoriy G Mouksassi Samer S

The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG 20200101 6

<h4>Objectives</h4>Aprepitant is effective for the prevention of chemotherapy-induced or postoperative nausea and vomiting (CINV/PONV). The aim of this study was to develop a population pharmacokinetic (PK) model of aprepitant in pediatric patients and to support dosing recommendations for oral aprepitant in pediatric patients at risk of CINV.<h4>Methods</h4>A population PK model was constructed based on data from 3 clinical studies in which children (6 months to 12 years) and adolescents (12-19 ...[more]

PMID: 32839657

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Project description:ImportanceThe prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment.ObjectiveTo evaluate whether adding aprepitant to palonosetron and dexamethasone can further prevent the incidence and severity of nausea and vomiting caused by FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy regimens among women with gastrointestinal cancer at higher risk.Design, setting, and participantsThis phase 3, double-blind, placebo-controlled randomized clinical trial recruited young women (age ≤50 years) who drank little or no alcohol and had gastrointestinal cancer for which they received FOLFOX or FOLFIRI chemotherapy. A total of 248 women were enrolled and assigned in the ratio 1:1 to intervention and control groups from August 4, 2015, to March 31, 2020. Intention-to-treat analysis was used to evaluate patient baseline characteristics and efficacy. The analysis was conducted on October 30, 2020.InterventionsPatients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1).Main outcomes and measuresThe primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase of the first cycle. Other efficacy indicators, such as no vomiting and no nausea, were measured as the secondary and exploratory end points.ResultsA total of 248 women from 4 clinical centers in China entered this study, and 243 patients (aprepitant regimen, 125 patients [51.4%]; placebo regimen, 118 patients [48.5%]) were evaluable for efficacy and safety; mean (SD) age of the total population was 40.1 (7.3) years. The CR rate was significantly higher in the aprepitant group vs the control group overall (107 [87.0%] vs 80 [66.7%]; P < .001) and in the acute (114 [92.7%] vs 91 [75.8%]; P = .001) and delayed (109 [88.6%] vs 84 [70.0%]; P = .001) phases of the trial. The incidence of adverse events was similar between the 2 groups (100 [80.0%] vs 96 [81.3%]; P = .79), and no grade 3 or 4 aprepitant treatment-related adverse events were observed. Multivariable analysis revealed that aprepitant use was the only independent factor associated with CR during the overall phase.Conclusions and relevanceThe combination of aprepitant with palonosetron and dexamethasone provided increased antiemetic efficacy in the FOLFOX or FOLFIRI chemotherapy regimen and was well tolerated by younger women with gastrointestinal cancer who have a history of little or no alcohol consumption.Trial registrationClinicalTrials.gov Identifier: NCT03674294.

Project description:BackgroundNeurokinin (NK) 1 receptor antagonists (RAs), administered in combination with a 5-hydroxytryptamine-3 (5-HT3 ) RA and dexamethasone (DEX), have demonstrated clear improvements in chemotherapy-induced nausea and vomiting (CINV) prevention over a 5-HT3 RA plus DEX. However, studies comparing the NK1 RAs in the class are lacking. A fixed combination of a highly selective NK1 RA, netupitant, and the 5-HT3 RA, palonosetron (NEPA), simultaneously targets two critical antiemetic pathways, thereby offering a simple convenient antiemetic with long-lasting protection from CINV. This study is the first head-to-head NK1 RA comparative study in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy (MEC).Materials and methodsThis was a pragmatic, multicenter, randomized, single-cycle, open-label, prospective study designed to demonstrate noninferiority of single-dose NEPA to a 3-day aprepitant regimen in preventing CINV in chemotherapy-naive patients receiving AC/non-AC MEC in a real-life setting. The primary efficacy endpoint was complete response (no emesis/no rescue) during the overall (0-120 hour) phase. Noninferiority was achieved if the lower limit of the 95% confidence interval (CI) of the difference between NEPA and the aprepitant group was greater than the noninferiority margin set at -10%.ResultsNoninferiority of NEPA versus aprepitant was demonstrated (risk difference 9.2%; 95% CI, -2.3% to 20.7%); the overall complete response rate was numerically higher for NEPA (64.9%) than aprepitant (54.1%). Secondary endpoints also revealed numerically higher rates for NEPA than aprepitant.ConclusionThis pragmatic study in patients with cancer receiving AC and non-AC MEC revealed that a single dose of oral NEPA plus DEX was at least as effective as a 3-day aprepitant regimen, with indication of a potential efficacy benefit for NEPA.Implications for practiceIn the absence of comparative neurokinin 1 (NK1 ) receptor antagonist (RA) studies, guideline committees and clinicians consider NK1 RA agents to be interchangeable and equivalent. This is the first head-to-head study comparing one NK1 RA (oral netupitant/palonosetron [NEPA]) versus another (aprepitant) in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy. Noninferiority of NEPA versus the aprepitant regimen was demonstrated; the overall complete response (no emesis and no rescue use) rate was numerically higher for NEPA (65%) than aprepitant (54%). As a single-dose combination antiemetic, NEPA not only simplifies dosing but may offer a potential efficacy benefit over the current standard-of-care.

Dataset Information

Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting.

Publications

Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting.

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