Abstract 1651
Background
NEPA, a fixed oral combination of NETU (neurokinin-1 receptor antagonist [NK1 RA]) and PALO (5-hydroxytryptamine-3 [5-HT3] RA), has been studied in > 1150 patients in phase 2/3 trials (with 83% of patients being Caucasian). NEPA has shown higher efficacy over PALO in preventing CINV associated with cisplatin and AC chemotherapy, and a good safety profile. In a recent Asian registration phase 3 trial, with patient eligibility criteria similar to those of pivotal trials in Caucasians, an oral dose of NEPA was found to be noninferior to a 3-day oral aprepitant/granisetron regimen in CINV prevention. This presentation discusses PK behaviors of NETU and PALO in Chinese and Caucasian HV.
Methods
Results from one phase 1 trial in 18 Chinese HV and five phase 1 trials in Caucasian HV (NETU, N = 232; PALO, N = 205) were analyzed. HV received an oral dose of NEPA (NETU 300 mg/PALO 0.5 mg), and NETU and PALO plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. PK parameters were estimated from plasma concentration-time curves by noncompartmental analysis using WinNonlin v6.3 software (Certara USA, Inc.).
Results
The PK profiles of NETU and PALO for Chinese and Caucasian HV are shown (Table). Mean body weight (BW) of Chinese HV was 15–19% lower than that of Caucasians, as expected. The PK profile of NETU was comparable between Chinese and Caucasian HV. For PALO, mean Cmax and overall exposure were higher in Chinese HV. The lower mean BW and higher incidence of nonfunctional CYP2D6 alleles (main enzyme responsible for the metabolism of PALO) in Chinese could be postulated to explain these differences.
Conclusions
The similar efficacy and safety of PALO and NEPA in pivotal trials in both populations suggest that some PK differences between Chinese and Caucasian are probably unlikely to affect the clinical outcome.
Clinical trial identification
Not applicable
Legal entity responsible for the study
Helsinn Healthcare SA
Funding
Helsinn Healthcare SA
Disclosure
M. Aapro: Advisor for Eisai, Helsinn, Merck, Mundipharma, Roche, and Tesaro; honoraria from Eisai, Helsinn, Merck, Mundipharma, Roche, and Tesaro; and has received grants from Helsinn, Merck, Roche, and Tesaro. A. Bernareggi: Employee of Helsinn Healthcare SA.Table: 514P
Netupitant and palonosetron PK parameters in Chinese and Caucasian healthy volunteers
| Study population (N, mean BW) | Netupitant dose (mg) | Netupitant PK parameters, mean (CV%) | |||
| Cmax (ng/mL) | tmax (h) | AUCinf (ng·h/mL) | t1/2 (h) | ||
| Chinese (18, 62.9 kg) | 300 | 698 (31.1) | 4.36 (14.6) | 22000 (20.0) | 73.1 (37.1) |
| Caucasian (232, 74.2 kg) | 300 | Range of mean (CV%) values | |||
| 374 (37.1) – 650 (21.8) | 5.01 (35.4) – 5.66 (17.1) | 13303 (34.5) – 22391 (38.6) | 76.6 (37.6) – 101.2 (52.2) | ||
| Study population (N, mean BW) | Palonosetron dose (mg) | Palonosetron PK parameters, mean (CV%) | |||
| Cmax (ng/L) | tmax (h) | AUCinf (ng·h/L) | t1/2 (h) | ||
| Chinese (18, 62.9 kg) | 0.5 | 1800 (14.0) | 3.25 (43.3) | 81000 (17.3) | 45.1 (25.0) |
| Caucasian (205, 73.4 kg) | 0.5 | Range of mean (CV%) values | |||
| 768 (20.7) – 1530 (25.6) | 3.76 (40.6) – 4.96 (24.3) | 33199 (20.9) – 56710 (32.8) | 36.9 (23.6) – 48.3 (46.7) | ||
AUCinf, area under the plasma concentration-time curve from time 0 to infinity; BW, body weight; Cmax, maximum plasma concentration; CV, coefficient of variation; t1/2, plasma half-life; tmax, time to Cmax.