Bioequivalence Study Of Montelukast Sodium Chewable Tablets In Healthy Volunteers

Objectives:With montelukast sodium chewable tablets produced by a pharmaceutical enterprise in China as the test preparation and the original drug montelukast sodium chewable tablets developed by the Merck Sharp&Dohme Ltd.as the reference preparation,the objectives are aimed at evaluating bioequivalence and safety of the two preparations in healthy adult volunteers in a fasting state and a fed state by studying pharmacokinetic parameters and bioavailability.Methods:The design featuring randomness,crossover,single dosage,two periods and two sequences was adopted.24 healthy volunteers in a fasting state and another 24 healthy volunteers in a fed state were grouped in the experiments.Each of the volunteers was randomized into one of the two groups according to the random table generated before the volunteers were grouped.Then each volunteer was orally administered 5mg of the test preparation or the reference preparation in a fasting state or a fed state after they were in a fasting state for at least ten hours.The wash-out period lasted for seven days.Sixteen tubes of venous blood were collected from each volunteer in each period.Drug concentrations in plasma were determined with the HPLC-MS/MS method after the collected blood samples were treated properly.The pharmacokinetic parameters were calculated with the Win Nonlin 7.0^?software according to the non-compartment model.Bioequivalence of the two preparations was evaluated with the SAS 9.4 statistical software.All the volunteers lived in the research center during the experiments and guarded by medical staff of the research team in the whole course.The safety of the test preparation and the reference preparation was evaluated by analyzing the incidence rate of adverse events,vital signs,physical examination,the 12-leads electrocardiogram results in a resting state and laboratory test results obtained after the volunteers took the corresponding preparation.Results:Experiment in a fasting state:AUC_0-tof the test preparation and that of the reference preparation were（1862.74±409.99）ng·h/m L and（1937.62±436.24）ng·h/m L respectively;AUC_0-∞of the test preparation and that of the reference preparation were（1939.89±442.26）ng·h/m L and（2012.45±480.69）ng·h/m L respectively;T_max of the test preparation and that of the reference preparation were（3.15±1.40）h and（2.79±0.94）h respectively;C_maxof the test preparation and that of the reference preparation were（247.83±65.49）ng/m L and（277.08±56.09）ng/m L respectively.The 90%CIs of the geometric mean value ratios of C_max,AUC_0-t and AUC_0-∞were 81.03%～96.20%,89.78%～102.69%and 89.99%～103.12%respectively,which all fell into the bioequivalence range（80.00%～125.00%）required in the guidelines for human bioavailability and bioequivalence testing of pharmaceutical preparations.Four adverse events including upper respiratory tract infection,T-wave changes,sinus tachycardia and syncope happened to three volunteers in total during the experiment and all came into complete remission.Serious adverse events or adverse events resulting in exiting the test never happened in the whole experiment.Experiment in a fed state:AUC_0-t of the test preparation and that of the reference preparation were（1969.17±703.74）ng·h/m L and（2118.88±719.01）ng·h/m L respectively;AUC_0-∞of the test preparation and that of the reference preparation were（2072.47±870.40）ng·h/m L and（2242.64±873.52）ng·h/m L respectively;T_max of the test preparation and that of the reference preparation were（4.00±1.76）h and（4.35±1.80）h respectively;C_max of the test preparation and that of the reference preparation were（241.33±61.38）ng/m L and（247.58±62.91）ng/m L respectively.The 90%CIs of the geometric mean value ratios of C_max,AUC_0-t and AUC_0-∞were 91.12%～104.92%,89.89%～96.05%and 90.20%～96.51%respectively,which all fell into the bioequivalence range（80.00%～125.00%）required in the the guidelines for human bioavailability and bioequivalence testing of pharmaceutical preparations.Eleven adverse events including profuse sweating,elevated total bilirubin,two cases of dizziness,two cases of elevated triglyceride,atrial premature beat,decreasing of leukocyte,nausea,pityriasis rosea and urinary tract infection happened to eight volunteers in total during the experiment.Except for two volunteers with elevated triglyceride and one volunteer with atrial premature beat who refused to be rechecked,the other adverse events came into complete remission.Serious adverse events or adverse events resulting in exiting the test never happened in the whole experiment.Conclusions:Through the bioequivalence tests of the two preparations in a fasting state and a fed state respectively,the montelukast sodium chewable tablets（5mg）produced by a pharmaceutical enterprise in China and montelukast sodium chewable tablets produced by the Merck,Sharp&Dohme Ltd.are judged to be bioequivalent and have good safety for the healthy volunteers.