A single-dose, randomized, two-way crossover study comparing two olanzapine tablet products in healthy adult male volunteers under fasting conditions.
BACKGROUND
Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class.


OBJECTIVE
The aim of this study was to assess the bioequivalence of 2 commercial 10-mg tablet formulations of olanzapine by statistical analysis of the pharmacokinetic parameters C(max), AUC from 0 to 72 hours after dosing (AUC(0-72)), and AUC(0-infinity) as required by the Egyptian health authority for the marketing of a generic product.


METHODS
This bioequivalence study was carried out in healthy male volunteers using a single-dose, randomized, 2-way crossover design under fasting conditions. Statistical analysis of the pharmacokinetic parameters C(max), AUC(0-72), and AUC(0-infinity) was conducted to determine bioequivalence (after log-transformation of data using analysis of variance and 90% CIs) and to gain marketing approval in Egypt. The formulations were considered to be bioequivalent if the log-transformed ratios of the 3 pharmacokinetic parameters were within the predetermined bioequivalence range (ie, 80%-125%), as established by the US Food and Drug Administration (FDA). Both the test product (Trademark: Integrol((R)) [Global Napi Pharmaceuticals, Cairo, Egypt]) and the reference product (Trademark: Zyprexa((R)) [Eli Lilly and Company, Basingstoke, Hampshire, United Kingdom]) were administered as 10-mg tablets with 240 mL of water after an overnight fast on 2 treatment days, separated by a 2-week washout period. After dosing, serial blood samples were collected for 72 hours. Plasma samples were analyzed using a sensitive, reproducible, and accurate liquid chromatography-tandem mass spectrometry method capable of quantitating olanzapine in the range of 0.167 to 16.7 ng/mL, with a lower limit of quantitation of 0.167 ng/mL. Adverse events were reported by the volunteers as instructed or observed by the resident physician, and were recorded, tabulated, and evaluated.


RESULTS
Twenty-four healthy adult male volunteers participated in this study. Their mean (SD) age was 24.7 (6.2) years (range, 19-41 years), mean weight was 73.4 (6.7) kg (range, 64-89 kg), and mean height was 174.25 (4.6) cm (range, 168-186 cm). Values for C(max), AUC(0-72), AUC(0-infinity), T(max), t(1/2), and the terminal disposition rate constant were found to be in agreement with previously reported values. The differences between the 2 products did not reach statistical significance at P <or= 0.05 (90% CIs: C(max), 101.82-124.79; AUC(0-72), 93.36-102.04; and AUC(0-infinity), 88.57-101.77). The test/reference ratio of these parameters was within the acceptance range of the FDA criterion for bioequivalence. Both formulations were apparently well absorbed from the gastrointestinal tract (ie, no specific gastrointestinal tract-related adverse events were reported).


CONCLUSIONS
In this small study in healthy male volunteers, there were no statistically significant differences in any of the calculated pharmacokinetic parameters between the 10-mg test and reference tablets of olanzapine. The 90% CIs for the ratios of mean C(max), AUC(0-72), and AUC(0-infinity) were within the range of 80% to 125% (using log-transformed data), meeting the FDA regulatory criterion for bioequivalence. Both formulations were well tolerated.
Elshafeey
Ahmed H
AH
Pharmaceutics Department, College of Pharmacy, Cairo University, Cairo, Egypt. Ah_elshafeey@hotmail.com
Elsherbiny
Mohamed A
MA
Fathallah
Mohsen M
MM
D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004534:Egypt; D005215:Fasting / Q000097:blood*; D006207:Half-Life; D006801:Humans; D008297:Male; D000077152:Olanzapine; D012016:Reference Values; D013607:Tablets; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D055815:Young Adult
D014150:Antipsychotic Agents; D013607:Tablets; D001569:Benzodiazepines; D000077152:Olanzapine