RESUMO
OBJECTIVE: To assess the bioequivalence and safety of a new formulation of mycophenolate mofetil (MMF) 500 mg (Suprimun®, Clausen, Montevideo, Uruguay) marketed in Uruguay and other South American countries, and to test Cmax/AUC as a characteristic of its absorption rate. MATERIAL AND METHODS: A randomized, open-label, two-way, two-treatment, two-period crossover study in 24 healthy male volunteers was carried out. One tablet (500 mg) of each formulation was administered after an overnight fast. After dosing, serial blood samples were collected for a period of 36 hours. Plasma concentrations of MPA were determined by high-performance liquid chromatography and pharmacokinetic parameters were calculated. Analysis of variance was carried out using log-transformed AUC0-36, Cmax, and Cmax/AUC0-36. 90% confidence intervals and within-subject between-subject variance were calculated. The bioequivalence of the two formulations was established at the 80% - 125% acceptance limits and untransformed tmax medians were compared using Wilcoxon test. Subjects were monitored for adverse events throughout the study. RESULTS: The means (test and reference) were 21.14 and 20.86 µg × h × ml-1 for AUC0-36, 24.92 and 24.18 µg × h × ml-1 for AUC0-inf, 11.86 and 10.76 µg × ml-1 for Cmax and 0.51 and 0.54 h-1 for Cmax/AUC0-36. The geometric mean ratios (confidence interval 90%) of Test/Reference were 1.00 (0.95 - 1.06) for AUC0-36, 1.09 (0.96 - 1.24) for Cmax and 1.04 (0.99 - 1.09) for Cmax/ AUC0-36. The extra peaks observed are due to enterohepatic recycling of MPA. No serious or unexpected adverse events were observed during the study. CONCLUSIONS: The test formulation containing mycophenolate mofetil 500 mg met regulatory requirements for bioequivalence. Moreover, Cmax/AUC shows interesting features as a putative metric to evaluate the absorption rate of highly variable drugs like mycophenolate mofetil. Generally, both formulations were well tolerated.
Assuntos
Imunossupressores/farmacocinética , Ácido Micofenólico/análogos & derivados , Absorção , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Humanos , Imunossupressores/administração & dosagem , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/farmacocinética , UruguaiRESUMO
OBJECTIVE: The present study evaluates the acute effect of a single-dose itraconazole administration on CYP3A phenotype, as measured by cortisol MR ratio in urine. METHODS: Twenty-four healthy Uruguayan subjects recruited according to strict inclusion criteria participated in an open-label, randomized, two-period, crossover study designed to evaluate the bioequivalence of an itraconazole formulation (Traconal 100 mg, Achê Labs, São Paulo, Brazil). The study comprised two treatment periods separated by a wash-out period of 14 days. In each period a series of venous blood samples were drawn over 48 hours. Three urine samples were obtained for CYP3A phenotyping: pre-dose, 24 and 48 hours after dosing. Blood and urine samples were assayed for itraconazole, beta-hydroxycortisol and cortisol using a validated chromatographic method. RESULTS: The ratio of the mean AUC0-inf. T/AUC0-inf. R was included in the bioequivalence range, however, due to high variability, the CI90% was not. It was found that the cortisol metabolic ratio (MR) showed inhibition relative to basal activity in a proportion of subjects 24 hours (68 +/- 6.1%, mean +/- CI95%) and 48 hours (80 +/- 7.3%, mean +/- CI95%) after ingestion of itraconazole. A significant correlation was found between itraconazole AUC0-inf. and normalized basal CYP3A MR for the reference (r = 0.62, t = 3.72, p = 0.001) and the test product (r = 0.74, t = 5.22, p = 0.00003). A good correlation existed between basal cortisol MR and the elimination half-life of itraconazole. CONCLUSIONS: The findings are in line with the hypothesis that the determination of the bioavailability of highly variable CYP3A substrates might be improved by simultaneous non-interfering phenotyping. If this is confirmed, a new methodological paradigm may need to be developed in order to take account of metabolic variability in bioequivalence evaluation of this group of drugs.