Abstract

The bioequivalence of two lansoprazole 30 mg capsules was determined in healthy human, adult volunteers after a single dose in a randomized crossover study. The study was conducted at Pharmaconsult, Flemington Pharmaceutical Corporation, New Jersey, U.S.A. Reference (Lanzor®, Laboratoires Houde, Paris, France) and test (Lanfast®, Julphar, U.A.E.) products were administered to volunteers with 240 mL water after overnight fasting. Blood samples were collected at specified time intervals, plasma was separated, and analyzed for lansoprazole using a validated HPLC method. The pharmacokinetic parameters AUC0_,t, AUC0_, , Cmax, tand elimination rate constant were determined from plasma concentration-time profile of both formulations and found to be in good agreement with previously reported values. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by FDA. The ANOVA did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range (80-120%) for bioequivalence. Based on these statistical inferences, it was concluded that the two formulations exhibited comparable pharmacokinetic profiles and that Julphar's Lanfast is bioequivalent to Lanzor of Laboratoires Houde.

C.1.1. Introduction

Bioequivalence of two formulations of the same drug comprises equivalence with respect to the rate and extent of their absorption. While the area under concentration-time curve (AUC) generally serves as the characteristic of the extent of absorption, the peak concentration (Cmax) and the time of its occurrence (imax) reflect the rate of absorption, especially in fast-releasing drug formulations (1,2). The present study was conducted to evaluate the bioequivalence of two brands of lansoprazole 30 mg capsules in fasting, healthy human volunteers. Although several studies have been published regarding lansoprazole pharmacokinetics, very few of them have focussed on the proof of bioequivalence between two formulations.

Chemically lansoprazole is 2-({3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl} sulphi-nylbenzimidazole as shown in Figure C.1 (3).

It is a benzimidazole derivative with antisecretory and antiulcer activities. It inhibits the acid pump activity in the final stage of the enzyme process and therefore reduces the acid secretion of parietal cells. Lansoprazole is converted to active sulphenamide metabolites in the acidic environment of parietal cells; these metabolites inactivate H+,K+-ATPase (4). In vitro inhibition of H+,K+-ATPase activity and acid secretion by lansoprazole were found to be concentration dependent (5). Although lansoprazole alone has relatively low eradication effects on Helicobacter pylori, it may enhance the ability of other agents to eradicate the organism (6,7). Orally 30 mg/day of lansoprazole provided effective symptoms relief and healing of duodenal ulcer in 75% to 100% of patients after four weeks of therapy in non-comparative and comparative trials (8). In healthy volunteers, single and multiple oral doses of lansoprazole inhibited both basal and stimulated gastric acid secretions (9).

Since lansoprazole is acid labile, it is usually administered as capsules containing enteric-coated granules to prevent gastric decomposition and to increase the bioavailability. Its absolute bioavailability is 80% to 91%, which may be decreased if administered within 30 minutes of food intake. It has high protein binding (97%) which is decreased in renal function impairment (7,10). Lansoprazole has a half-life of about 1.5 hours; renal impairment decreases the half-life. After oral administration, peak concentration is achieved within one to two hours; a single 30 mg oral dose gives a peak concentration of 750 to 1150 ng/mL (7). Peak maxima (Cmax) and bioavailability were not significantly altered by administration of multiple doses of the drug for seven days (11) when compared with the first day of treatment, although bioavailability showed marked interindividual variability (11,12).

No significant difference was reported in the pharmacokinetics of lansoprazole in typical healthy individuals when compared with patient groups (13). The peak blood levels over the dosage range of 15, 30, and 60 mg appear relatively dose proportional. Time-to-peak concentration ranged from 1.0 to 2.0 hours and half-life ranged from 1.3 to 2.1 hours (12). Significant difference was observed in half-life when compared in young (1.4 hours) and elderly (1.9-2.9 hours) after multiple-day dosing. No effect of food on half-life was observed, although food delayed the time to peak concentration (3.3-3.7 hours) (13). Lansoprazole is extensively metabolized in the liver to two main excretory metabolites that are inactive (13,14). In the acid environment, lansoprazole is converted to two active metabolites that inhibit the acid secretion by H+,K+-ATPase within the parietal cells canaliculus, but that are not present in the systemic circulation (14). Therefore, in this study only the parent drug was estimated in plasma samples.

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