Evaluation of the effect of food and age on the pharmacokinetics of oral netupitant and palonosetron in healthy subjects: A randomized, open‐label, crossover phase 1 study
Abstract:Antiemetic treatment compliance is important to prevent chemotherapy-induced nausea and vomiting, a feared chemotherapy side effect. NEPA, a new oral fixed combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron, a second-generation 5-HT3 RA, targets dual antiemetic pathways with a single dose. This study investigated the effect of food intake and age on NEPA pharmacokinetics (PK) and safety. In this open-label, single-center, randomized, phase 1 study, 24 adults (18-45 yea… Show more
“…Pharmacokinetic disposition of palonosetron : Twenty articles evaluating palonosetron pharmacokinetics were included in this systematic review (Supplementary Table S12).…”
This update of the 2013 clinical practice guideline provides clinicians with guidance regarding the use of aprepitant and palonosetron for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) in children. The recommendations were based on three systematic reviews. Substantive changes were made to the guideline recommendations including the inclusion of palonosetron to the 5-HT antagonists recommended for children receiving highly emetogenic chemotherapy (HEC) and the recommendation of aprepitant for children 6 months of age or older receiving HEC. To optimize CINV control in children, future work must focus on closing critical research gaps.
“…Pharmacokinetic disposition of palonosetron : Twenty articles evaluating palonosetron pharmacokinetics were included in this systematic review (Supplementary Table S12).…”
This update of the 2013 clinical practice guideline provides clinicians with guidance regarding the use of aprepitant and palonosetron for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) in children. The recommendations were based on three systematic reviews. Substantive changes were made to the guideline recommendations including the inclusion of palonosetron to the 5-HT antagonists recommended for children receiving highly emetogenic chemotherapy (HEC) and the recommendation of aprepitant for children 6 months of age or older receiving HEC. To optimize CINV control in children, future work must focus on closing critical research gaps.
“…Despite the lack of controlling risk factors, new molecules with few pharmacokinetic advantages are being tested in adults (e.g. netupitant), and might be tested in the paediatric population in future studies .…”
Triple therapy decreased CIV risk, without increasing the occurrence of febrile neutropenia. However, this review could not address which subpopulations would most benefit from using this strategy. Future studies should focus on assessing risk factors for nausea and vomiting, as many patients did not achieve a complete antiemetic response.
“…Data used for PK/PD modeling of netupitant and palonosetron in this analysis were obtained from previous preclinical and clinical studies performed during the development of oral NEPA and palonosetron.Fig. 1Design of studies included for the PK/PD modeling and for the correlation with antiemetic clinical efficacy [17, 27, 28]. BMI, body mass index; CP, complete protection (CR and no significant nausea); CR, complete response (no emesis, no rescue medication); HEC, highly emetogenic chemotherapy; LEC, low emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; NK 1 , neurokinin-1; oral NEPA, 300 mg netupitant/0.50 mg palonosetron; PD, pharmacodynamic; PET, positron emission tomography; PK, pharmacokinetics…”
Section: Methodsmentioning
confidence: 99%
“…PK modeling of netupitant and palonosetron plasma concentration-time profiles was based on two-compartment model fitting to mean curves observed in an open-label, randomized phase I study in 22 healthy adults aimed at testing the effect of food on the PK of netupitant and palonosetron [28]. The subjects received single doses of oral NEPA in a fed or fasted state in the initial treatment period and in the alternative state in the following treatment period after a washout of 28 days.…”
Section: Methodsmentioning
confidence: 99%
“…Detailed design, methods, and patient eligibility criteria for the clinical studies have been published previously [17, 27, 28]. For each, the relevant study protocols were approved by the corresponding ethical review committees, and sites participating in the studies followed the International Conference on Harmonization E6 Good Clinical Practice guidelines, Declaration of Helsinki principles, and local laws and regulations.…”
Purpose
The administration timing of antiemetic and chemotherapeutic regimens is often determined by regulatory indications, based on registration studies. Oral NEPA, fixed combination of the neurokinin-1 receptor antagonist (NK
1
RA) netupitant and the 5-hydroxytryptamine-3 RA (5-HT
3
RA) palonosetron, is recommended to be administered approximately 60 min before chemotherapy. Reducing chair time for chemotherapy administration at oncology day therapy units would improve facility efficiency without compromising patient symptom management. The objective was to determine if oral NEPA can be administered closer to chemotherapy initiation without compromising patient symptom management.
Methods
NK
1
receptor occupancy (NK
1
RO) time course in the brain was determined using positron emission tomography; netupitant and palonosetron plasma concentration-time profiles were described by pharmacokinetic (PK) models; and the rate, extent, and duration of RO by netupitant and palonosetron were predicted by pharmacodynamic modeling. Clinical efficacy data from a pivotal study in cisplatin and oral NEPA-receiving patients were reviewed in the context of symptom management.
Results
Striatal 90% NK
1
RO, assumed to correlate with NK
1
RA antiemetic efficacy, was predicted at netupitant plasma concentration of 225 ng/mL, reached at 2.23 h following NEPA administration. Palonosetron 90% 5-HT
3
RO was predicted at a 188-ng/L plasma concentration, reached at 1.05 h postdose. The mean time to first treatment failure for the 1.5% of NEPA-treated patients without complete response receiving highly emetogenic chemotherapy was 8 h. Antiemetic efficacy was sustained over 5 days despite the expected decrease of NK
1
RO and 5-HT
3
RO.
Conclusions
Results suggest that administering oral NEPA closer to initiation of cisplatin administration would provide similar antiemetic efficacy. Prospective clinical validation is required.
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