1574P - Bioequivalence and absolute bioavailability of a single oral dose of two formulations of 0.75 mg palonosetron in healthy volunteers (HV)

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Supportive Care
Presenter Daniel Voisin
Authors D. Voisin1, C. Giuliano2, S. Baumann3
  • 1Helsinn Healthcare, 6915 - Pambio Noranco/CH
  • 2Preclinical, Helsinn Healthcare SA, 6912 - Lugano/CH
  • 3Clinical Research, CRS Clinical Research Services, 68167 - Mannheim/DE

Abstract

Background

Palonosetron HCl (PALO) is a potent 5-HT3 receptor antagonist (5HT3-RA) with a stronger receptor binding affinity and unique mechanism of action compared to older 5HT3-RAs. The primary objectives were to investigate the bioequivalence of two oral PALO 0.75 mg formulation(s) (F(s)) b1 and b2 and their absolute bioavailability when compared to b3 PALO 0.75 mg i.v F (see table for: b1, b2 and b3). Secondary objective was to evaluate the safety profile of the three PALO F(s).

Methods

36 male and female hv were randomized in this open-label, 3-treatment, cross-over study. 30 subjects received treatments b1, b2 and b3 in a 3- period randomized order (14-day interval set between periods). Treatments b1 and b2 were analyzed for bioequivalence by ANOVA CVs and defined bioequivalent if the 90% confidence intervals (CI) for the AUC0-∞, AUC0-t and Cmax treatment ratios lie within 80% to 125% range CI Absolute Ratios. Absolute bioavailability of the oral F(s) was calculated using the extent of exposure measure AUC0-∞ and AUC0-t.

Results

The oral 0.75 mg F(s) b1 and b2 showed bioequivalence in terms of rate and extent of absorption: The 90% CI for PALO AUC0-t, AUC0-∞ and Cmax are 97.91% to 109.47%, 96.47% to 107.76% and 93.40% to 103.59%, respectively. All CI's are well within the 80-125% equivalence limits. The absolute bioavailability of both oral and the i.v. F(s), calculated using AUC0-t is essentially not different (97% for b1, and 99% for b2 F(s)). Table: 1574P

Pharmacokineticparameter palonosetron Ratio Point estimateTest/Ref. ratio 90%Confidence Interval
AUC(0-t) [ng h/L] b1 / b3b2 / b3 96.5699.88 91.47 - 101-9394.61 - 105.44
AUC(0-inf) [ng h/L] b1 / b3b2 / b3 97.2698.99 92.33 - 102.4593.98 - 104.27
Cmax [ng/L] b1 / b3b2 / b3 72.6071.71 67.01 - 78.6766.18 - 77.70

b1: oral administration of 0.75 mg palonosetron as a softgel capsule (formulation A, clinical trial formulation).

b2: oral administration of 0.75 mg palonosetron as a softgel capsule (formulation B, Proposed commercial formulation).

b3: intravenous administration of 0.75 mg palonosetron (3 x 0.25 mg i.v. Aloxi® - reference for the bioavailability analysis).

ANOVA and 90% CIs for l0g-transformed.

All study F(s) were safe and well tolerated: constipation and headache were the main adverse events. No clinical influence was observed on safety laboratory or vital signs variability. No drop out was due to safety issue.

Conclusions

The study has shown bioequivalence of two PALO 0.75 mg oral formulations. No significant changes were observed in the absolute bioavailability between the two oral formulations and the i.v. 0.75 mg. All tested formulations showed a good safety profile.

Disclosure

D. Voisin: The Author is an Helsinn Employee,

C. Giuliano: The Author is an Helsinn Employee,

All other authors have declared no conflicts of interest.