Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting

Sant P. Chawla, Steven M. Grunberg, Richard J. Gralla, Paul J. Hesketh, Cindy Rittenberg, Mary E. Elmer, Carrie Schmidt, Arlene Taylor, Alexandra D. Carides, Judith K. Evans, Kevin J. Horgan

Research output: Contribution to journalArticle

194 Citations (Scopus)

Abstract

BACKGROUND. The neurokinin-1 antagonist aprepitant (EMEND™; Merck Research Laboratories, West Point, PA) has been shown to reduce chemotherapy-induced nausea and vomiting when it is given with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The current study sought to define the most appropriate dose regimen of oral aprepitant. METHODS. This multicenter, randomized, double-blind, placebo-controlled study was conducted in patients with cancer who were receiving initial cisplatin (≥ 70mg/m2) and standard antiemetic therapy (intravenous ondansetron plus oral dexamethasone). Patients were randomized to receive standard therapy plus either aprepitant 375 mg on Day 1 and 250 mg on Days 2-5, aprepitant 125 mg on Day 1 and 80 mg on Days 2-5, or placebo. Due to an apparent interaction with dexamethasone suggested by pharmacokinetic data obtained while the study was ongoing, the aprepitant 375/250 mg dose was discontinued and replaced with aprepitant 40 mg on Day 1 and 25 mg on Days 2-5, and a new randomization schedule was generated. Patients recorded nausea and emesis in a diary. The primary endpoint was complete response (no emesis and no rescue therapy), which was analyzed using an intent-to-treat approach with data obtained after the dose adjustment. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments, and included all available data. RESULTS. The percentages of patients who achieved a complete response in the overall study period were 71.0% for the aprepitant 125/80-mg group (n = 131 patients), 58.8% for the aprepitant 40/25-mg group (n = 119 patients), and 43.7% for the standard therapy group (n = 126 patients; P < 0.05 for either aprepitant regimen vs. standard therapy). Rates for Day 1 were 83.2% for the aprepitant 125/80-mg group, 75.6% for aprepitant 40/25-mg group, and 71.4% for the standard therapy group (P < 0.05 for aprepitant 125/80 mg vs. standard therapy), and rates on Days 2-5 were 72.7% for the aprepitant 125/80-mg group, 63.9% for the aprepitant 40/25-mg group, and 45.2% for the standard therapy group (P < 0.01 for either aprepitant group vs. standard therapy). The efficacy of the aprepitant 375/250-mg regimen was similar to that of the aprepitant 125/80-mg regimen. The overall incidence of adverse events was generally similar across treatment groups: 85% in the aprepitant 375/250-mg group (n = 34 patients), 76% in the aprepitant 125/80-mg group (n = 214 patients), 71% in the aprepitant 40/25-mg group (n = 120 patients), and 72% in the standard therapy group (n = 212 patients), with the exception of a higher incidence of infection in the aprepitant 125/80-mg group (13%) compared with the standard therapy group (4%). CONCLUSIONS. When it was added to a standard regimen of intravenous ondansetron and oral dexamethasone in the current study, aprepitant reduced chemotherapyinduced nausea and vomiting and was generally well tolerated, although increases in infection were noted that were assumed to be due to elevated dexamethasone levels as a result of the pharmacokinetic interaction. The aprepitant 125/80-mg regimen had the most favorable benefit: risk profile.

Original languageEnglish (US)
Pages (from-to)2290-2300
Number of pages11
JournalCancer
Volume97
Issue number9
DOIs
StatePublished - May 1 2003
Externally publishedYes

Fingerprint

aprepitant
Nausea
Vomiting
Drug Therapy
Group Psychotherapy
Dexamethasone
Ondansetron

Keywords

  • Antiemetic
  • Clinical trial
  • Neurokinin
  • Substance P

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Chawla, S. P., Grunberg, S. M., Gralla, R. J., Hesketh, P. J., Rittenberg, C., Elmer, M. E., ... Horgan, K. J. (2003). Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting. Cancer, 97(9), 2290-2300. https://doi.org/10.1002/cncr.11320

Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting. / Chawla, Sant P.; Grunberg, Steven M.; Gralla, Richard J.; Hesketh, Paul J.; Rittenberg, Cindy; Elmer, Mary E.; Schmidt, Carrie; Taylor, Arlene; Carides, Alexandra D.; Evans, Judith K.; Horgan, Kevin J.

In: Cancer, Vol. 97, No. 9, 01.05.2003, p. 2290-2300.

Research output: Contribution to journalArticle

Chawla, SP, Grunberg, SM, Gralla, RJ, Hesketh, PJ, Rittenberg, C, Elmer, ME, Schmidt, C, Taylor, A, Carides, AD, Evans, JK & Horgan, KJ 2003, 'Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting', Cancer, vol. 97, no. 9, pp. 2290-2300. https://doi.org/10.1002/cncr.11320
Chawla, Sant P. ; Grunberg, Steven M. ; Gralla, Richard J. ; Hesketh, Paul J. ; Rittenberg, Cindy ; Elmer, Mary E. ; Schmidt, Carrie ; Taylor, Arlene ; Carides, Alexandra D. ; Evans, Judith K. ; Horgan, Kevin J. / Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting. In: Cancer. 2003 ; Vol. 97, No. 9. pp. 2290-2300.
@article{32986d1f18914cb48fa8d81c213441c8,
title = "Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting",
abstract = "BACKGROUND. The neurokinin-1 antagonist aprepitant (EMEND™; Merck Research Laboratories, West Point, PA) has been shown to reduce chemotherapy-induced nausea and vomiting when it is given with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The current study sought to define the most appropriate dose regimen of oral aprepitant. METHODS. This multicenter, randomized, double-blind, placebo-controlled study was conducted in patients with cancer who were receiving initial cisplatin (≥ 70mg/m2) and standard antiemetic therapy (intravenous ondansetron plus oral dexamethasone). Patients were randomized to receive standard therapy plus either aprepitant 375 mg on Day 1 and 250 mg on Days 2-5, aprepitant 125 mg on Day 1 and 80 mg on Days 2-5, or placebo. Due to an apparent interaction with dexamethasone suggested by pharmacokinetic data obtained while the study was ongoing, the aprepitant 375/250 mg dose was discontinued and replaced with aprepitant 40 mg on Day 1 and 25 mg on Days 2-5, and a new randomization schedule was generated. Patients recorded nausea and emesis in a diary. The primary endpoint was complete response (no emesis and no rescue therapy), which was analyzed using an intent-to-treat approach with data obtained after the dose adjustment. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments, and included all available data. RESULTS. The percentages of patients who achieved a complete response in the overall study period were 71.0{\%} for the aprepitant 125/80-mg group (n = 131 patients), 58.8{\%} for the aprepitant 40/25-mg group (n = 119 patients), and 43.7{\%} for the standard therapy group (n = 126 patients; P < 0.05 for either aprepitant regimen vs. standard therapy). Rates for Day 1 were 83.2{\%} for the aprepitant 125/80-mg group, 75.6{\%} for aprepitant 40/25-mg group, and 71.4{\%} for the standard therapy group (P < 0.05 for aprepitant 125/80 mg vs. standard therapy), and rates on Days 2-5 were 72.7{\%} for the aprepitant 125/80-mg group, 63.9{\%} for the aprepitant 40/25-mg group, and 45.2{\%} for the standard therapy group (P < 0.01 for either aprepitant group vs. standard therapy). The efficacy of the aprepitant 375/250-mg regimen was similar to that of the aprepitant 125/80-mg regimen. The overall incidence of adverse events was generally similar across treatment groups: 85{\%} in the aprepitant 375/250-mg group (n = 34 patients), 76{\%} in the aprepitant 125/80-mg group (n = 214 patients), 71{\%} in the aprepitant 40/25-mg group (n = 120 patients), and 72{\%} in the standard therapy group (n = 212 patients), with the exception of a higher incidence of infection in the aprepitant 125/80-mg group (13{\%}) compared with the standard therapy group (4{\%}). CONCLUSIONS. When it was added to a standard regimen of intravenous ondansetron and oral dexamethasone in the current study, aprepitant reduced chemotherapyinduced nausea and vomiting and was generally well tolerated, although increases in infection were noted that were assumed to be due to elevated dexamethasone levels as a result of the pharmacokinetic interaction. The aprepitant 125/80-mg regimen had the most favorable benefit: risk profile.",
keywords = "Antiemetic, Clinical trial, Neurokinin, Substance P",
author = "Chawla, {Sant P.} and Grunberg, {Steven M.} and Gralla, {Richard J.} and Hesketh, {Paul J.} and Cindy Rittenberg and Elmer, {Mary E.} and Carrie Schmidt and Arlene Taylor and Carides, {Alexandra D.} and Evans, {Judith K.} and Horgan, {Kevin J.}",
year = "2003",
month = "5",
day = "1",
doi = "10.1002/cncr.11320",
language = "English (US)",
volume = "97",
pages = "2290--2300",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "9",

}

TY - JOUR

T1 - Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting

AU - Chawla, Sant P.

AU - Grunberg, Steven M.

AU - Gralla, Richard J.

AU - Hesketh, Paul J.

AU - Rittenberg, Cindy

AU - Elmer, Mary E.

AU - Schmidt, Carrie

AU - Taylor, Arlene

AU - Carides, Alexandra D.

AU - Evans, Judith K.

AU - Horgan, Kevin J.

PY - 2003/5/1

Y1 - 2003/5/1

N2 - BACKGROUND. The neurokinin-1 antagonist aprepitant (EMEND™; Merck Research Laboratories, West Point, PA) has been shown to reduce chemotherapy-induced nausea and vomiting when it is given with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The current study sought to define the most appropriate dose regimen of oral aprepitant. METHODS. This multicenter, randomized, double-blind, placebo-controlled study was conducted in patients with cancer who were receiving initial cisplatin (≥ 70mg/m2) and standard antiemetic therapy (intravenous ondansetron plus oral dexamethasone). Patients were randomized to receive standard therapy plus either aprepitant 375 mg on Day 1 and 250 mg on Days 2-5, aprepitant 125 mg on Day 1 and 80 mg on Days 2-5, or placebo. Due to an apparent interaction with dexamethasone suggested by pharmacokinetic data obtained while the study was ongoing, the aprepitant 375/250 mg dose was discontinued and replaced with aprepitant 40 mg on Day 1 and 25 mg on Days 2-5, and a new randomization schedule was generated. Patients recorded nausea and emesis in a diary. The primary endpoint was complete response (no emesis and no rescue therapy), which was analyzed using an intent-to-treat approach with data obtained after the dose adjustment. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments, and included all available data. RESULTS. The percentages of patients who achieved a complete response in the overall study period were 71.0% for the aprepitant 125/80-mg group (n = 131 patients), 58.8% for the aprepitant 40/25-mg group (n = 119 patients), and 43.7% for the standard therapy group (n = 126 patients; P < 0.05 for either aprepitant regimen vs. standard therapy). Rates for Day 1 were 83.2% for the aprepitant 125/80-mg group, 75.6% for aprepitant 40/25-mg group, and 71.4% for the standard therapy group (P < 0.05 for aprepitant 125/80 mg vs. standard therapy), and rates on Days 2-5 were 72.7% for the aprepitant 125/80-mg group, 63.9% for the aprepitant 40/25-mg group, and 45.2% for the standard therapy group (P < 0.01 for either aprepitant group vs. standard therapy). The efficacy of the aprepitant 375/250-mg regimen was similar to that of the aprepitant 125/80-mg regimen. The overall incidence of adverse events was generally similar across treatment groups: 85% in the aprepitant 375/250-mg group (n = 34 patients), 76% in the aprepitant 125/80-mg group (n = 214 patients), 71% in the aprepitant 40/25-mg group (n = 120 patients), and 72% in the standard therapy group (n = 212 patients), with the exception of a higher incidence of infection in the aprepitant 125/80-mg group (13%) compared with the standard therapy group (4%). CONCLUSIONS. When it was added to a standard regimen of intravenous ondansetron and oral dexamethasone in the current study, aprepitant reduced chemotherapyinduced nausea and vomiting and was generally well tolerated, although increases in infection were noted that were assumed to be due to elevated dexamethasone levels as a result of the pharmacokinetic interaction. The aprepitant 125/80-mg regimen had the most favorable benefit: risk profile.

AB - BACKGROUND. The neurokinin-1 antagonist aprepitant (EMEND™; Merck Research Laboratories, West Point, PA) has been shown to reduce chemotherapy-induced nausea and vomiting when it is given with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The current study sought to define the most appropriate dose regimen of oral aprepitant. METHODS. This multicenter, randomized, double-blind, placebo-controlled study was conducted in patients with cancer who were receiving initial cisplatin (≥ 70mg/m2) and standard antiemetic therapy (intravenous ondansetron plus oral dexamethasone). Patients were randomized to receive standard therapy plus either aprepitant 375 mg on Day 1 and 250 mg on Days 2-5, aprepitant 125 mg on Day 1 and 80 mg on Days 2-5, or placebo. Due to an apparent interaction with dexamethasone suggested by pharmacokinetic data obtained while the study was ongoing, the aprepitant 375/250 mg dose was discontinued and replaced with aprepitant 40 mg on Day 1 and 25 mg on Days 2-5, and a new randomization schedule was generated. Patients recorded nausea and emesis in a diary. The primary endpoint was complete response (no emesis and no rescue therapy), which was analyzed using an intent-to-treat approach with data obtained after the dose adjustment. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments, and included all available data. RESULTS. The percentages of patients who achieved a complete response in the overall study period were 71.0% for the aprepitant 125/80-mg group (n = 131 patients), 58.8% for the aprepitant 40/25-mg group (n = 119 patients), and 43.7% for the standard therapy group (n = 126 patients; P < 0.05 for either aprepitant regimen vs. standard therapy). Rates for Day 1 were 83.2% for the aprepitant 125/80-mg group, 75.6% for aprepitant 40/25-mg group, and 71.4% for the standard therapy group (P < 0.05 for aprepitant 125/80 mg vs. standard therapy), and rates on Days 2-5 were 72.7% for the aprepitant 125/80-mg group, 63.9% for the aprepitant 40/25-mg group, and 45.2% for the standard therapy group (P < 0.01 for either aprepitant group vs. standard therapy). The efficacy of the aprepitant 375/250-mg regimen was similar to that of the aprepitant 125/80-mg regimen. The overall incidence of adverse events was generally similar across treatment groups: 85% in the aprepitant 375/250-mg group (n = 34 patients), 76% in the aprepitant 125/80-mg group (n = 214 patients), 71% in the aprepitant 40/25-mg group (n = 120 patients), and 72% in the standard therapy group (n = 212 patients), with the exception of a higher incidence of infection in the aprepitant 125/80-mg group (13%) compared with the standard therapy group (4%). CONCLUSIONS. When it was added to a standard regimen of intravenous ondansetron and oral dexamethasone in the current study, aprepitant reduced chemotherapyinduced nausea and vomiting and was generally well tolerated, although increases in infection were noted that were assumed to be due to elevated dexamethasone levels as a result of the pharmacokinetic interaction. The aprepitant 125/80-mg regimen had the most favorable benefit: risk profile.

KW - Antiemetic

KW - Clinical trial

KW - Neurokinin

KW - Substance P

UR - http://www.scopus.com/inward/record.url?scp=0037403701&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037403701&partnerID=8YFLogxK

U2 - 10.1002/cncr.11320

DO - 10.1002/cncr.11320

M3 - Article

VL - 97

SP - 2290

EP - 2300

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 9

ER -