Thesis
Estudio de Bioequivalencia de Dos Formulaciones Orales de Sibutramina en Voluntarios Sanos
Autor
DR. VILLAGRANA ZESATI, JESÚS ROBERTO
Institución
Resumen
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.