Differential time course of action of 5-HT3 and NK1 receptor antagonists when used with highly and moderately emetogenic chemotherapy (HEC and MEC).
BACKGROUND
Cisplatin-based highly emetogenic chemotherapy (HEC) displays a biphasic pattern of emesis with both an early and delayed period. In contrast, moderately emetogenic chemotherapy (MEC) has a monophasic pattern. The objective of this analysis was to further investigate the impact of the NK1-receptor antagonist aprepitant on these patterns.


METHODS
Three phase III HEC (patients scheduled to receive cisplatin-based chemotherapy) and one phase III MEC (breast cancer patients scheduled to receive anthracycline plus cyclophosphamide (AC)) trials of aprepitant were included. In all studies, patients were randomized in a 1:1 ratio to an aprepitant regimen (aprepitant plus ondansetron plus dexamethasone) or the standard regimen (ondansetron plus dexamethasone). The exact dosing regimen for ondansetron and dexamethasone was different in each study. In a post hoc analysis, multivariate logistic regression models were used to assess the impact on first emesis at different time intervals after chemotherapy.


RESULTS
One thousand five hundred twenty-seven patients and 856 patients were randomized and assessed for efficacy in the HEC and MEC trials, respectively. For HEC, aprepitant reduced the risk of first emesis by 38-77% vs. standard regimen, beginning 15-18 h after cisplatin and extending to 60 h. For MEC, aprepitant reduced the risk of first emesis by 38-61% vs. active control, beginning 3 h after AC and for up to 12 h.


CONCLUSIONS
Time of onset and duration of enhanced control of emesis with the addition of aprepitant differed between HEC and MEC. This suggests that the pattern of NK1-sensitive mechanisms may vary for different chemotherapy regimens.
Hesketh
Paul J
PJ
Department of Hematology Oncology, Lahey Clinic Medical Center, 41 Mall Road, Burlington, MA 01805, USA. paul.hesketh@lahey.org
Warr
David G
DG
Street
James C
JC
Carides
Alexandra D
AD
D000932:Antiemetics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D000077608:Aprepitant; D002945:Cisplatin / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015999:Multivariate Analysis; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D064729:Neurokinin-1 Receptor Antagonists; D017294:Ondansetron / Q000008:administration & dosage / Q000627:therapeutic use; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000627:therapeutic use; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
D000932:Antiemetics; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D000077608:Aprepitant; D017294:Ondansetron; D003907:Dexamethasone; D002945:Cisplatin