Estudio de Bioequivalencia de Dos Formulaciones Orales de Sibutramina en Voluntarios Sanos

Abstract

INTRODUCTION An interchangeable drug is defined as a drug that have following compared to the innovative drug: - contains the same amount of the drug - possesses comparable pharmacokinetic properties - have the same clinically significant formulations characteristics and - is to be administered for the same way. Considering all these conditions in the context that the effect and security of a drug are directly proportional to the blood concentration and therefore with the active principle level. OBJECTIVE Cuantify blood levels of two oral formulations of sibutramine, establishing the pharmacocinetics, gastrointestinal absorption, maximun concentration and elimination time, that define if both products have equivalent bioavailability. MATERIAL AND METHODS Design Randomized, open, comparative, single-dose, 2 period, 2-way cross-over study. Population - 30 healthy volunteers where included - Males 18 to 55 years old - Clinically healthy (clinical laboratory and cabinet tests between normal values) - Weight body between ± 10 % of ideal - With signed Informed Consent 20 Treatment 30 subjects where randomly divided in 2 groups (15 subjects for group) the treatments where assigned in two secuences A-B and B-A in two experimental session separated with two week. In first experimental session the Group 1 subjects (treatment A-B) received orally one tablet of sibutramine 15 mg, and the Group 2 subjects (treament B-A) received orally one tablet of sibutramine 15 mg. In second experimental session treatments were inverted. The drug administration was considered as time cero (0 hrs). Blood samples were taking alter drug consumption at 0, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 24.0, 48.0 and 72 hrs. The active metabolite of sibutramine plasma concentration was quantified using High Power Liquid Chromatography Method with ultraviolet detection. Pharmacokinetic and Statistical Analysis The individual plasma concentration vs. time curves were constructed and the maximal concentration (Cmax) and the time of this concentration (tmax) were directly obtained frorm these curves. The area under curve were obtained of the plasma concentration vs time curve (AUC) by the trapezoidal method. In order to demonstrate the bioequivalence of both formulations, analysis of variance for a cross-over design for log transformed of Cmax and AUC was carried out. Then, ratios of Cmax and AUC of the formulations tested were calculated and 90% confidence intervals were obtained, the probability of exceeding the limits of acceptance (80-125%) was obtained by the two one-sided t tests described by Schuirman. RESULTS 21 30 healthy males where included on a randomized, open, comparative, singledose, 2 period, 2-way cross-over, for the bioavalability study of sibutramina (15 mg: IFA Certez® vs Raductil® 15 mg ). No adverse effects where observed. Pharmacokinetics Analysis Win NonLin statistical software was used for calculate the following pharmacokinetic parameters based in the plasmatic concentration data vs time. Cmax (ng/mL) AUCINF_obs (hr*ng/mL) Tmax (hr) Form Form Form Vol P R P R P R Media 14.610 15.344 250.320 256.610 3.933 4.400 SD 5.171 5.276 59.630 65.845 2.333 2.313 CV% 35.4 34.4 23.8 25.7 59.3 52.6 Media Geo 13.868 14.548 243.629 249.718 3.429 3.873 Statistical Analysis Comparison of 90% confidence limits of Cmax and AUC and probability of exceeding the limits of acceptance, considering that the two formulations are bioequivalents. Pharmacokinetic Parameter Unit Classic Interval Westlake Interval Anderson- Hauck Test Power Log10 (Cmax) ng/mL 92.2349 – 115.3355 87.20028 - 112.7972 0.0143 0.9056 Log10 (ABC0→∞) (observed) ng*h/mL 95.2218 – 110.3901 91.2827 – 108.7173 0.0006 0.9976 CONCLUSION Based in the pharmacokinetics dates, tmax, Cmax and AUC0→t we concluded that IFA Certez® tablets of 15 mg is bioequivalent with Raductil® tablets of 15 mg.