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
D. Voisin1, C. Giuliano2, S. Baumann3
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.