Development of HPLC method for analysis of plasma simvastanin and simvastanin hydroxy acid and application to bioequivalence studies in dogs

Abstract

Four brands of 10 mg simvastatin film-coated tablets were evaluated. In vitro studies indicated that all brands met the general requirements of the USP 23 for content of active ingredient and uniformity of dosage units. The dissolution rate constants of all brands in 0.5 % sodium laury sulphate in 0.01 M monobasic sodium phosphate pH 5.5 ranged from 0.062 to 0.273 min⁻¹.. The value of brand C was significantly (p<0.05) lower than those of brands A (innovator’s product), B and D. The comparative bioavailability of brands B, C, and D relative to brand A were conducted in 12 healthy male mongrel dogs using a single dose of 200 mg simvastatin in a crossover design. Individual plasma drug concentration-time profiles of total simvastatin hydroxyl acid (SVA) were analyzed by HPLC for relevant pharmacokinetics parameters. There were no statistically significant differences in AUC (ANOVA. P<0.05) and t[subscript max] (Friedman test, p>0.05) values of brand B, C, and D with those of brand A. The 90% exact confidence intervals for the AUC ratios of brand B, C and D to those of brand A were within 80-125% bioequivalence range. Although, there were no significant differences (ANOVA,p<0.05) in C[subscript max] of brand B, C and D with those of brand A. The 90% exact confidence intervals for ratios of C[subscript max] of brand B, C, brabd B, C, and D relative to those of brand A were out of 80-125 % range. This implies that brands B, C, and D were considered to be equivalent to brand A with respect ot the extent of drug absorption. The elimination rate constants (K[subscript el]) of total SVA were between 1.05 and 1.92 hr⁻¹ whereas the elimination half-lives (t[subscript 1/2]) ranged from 0.47 to 1.66 hr. These values are in agreement with the previously reported half-life for total SVA of 1.9 hr. Although, all the four brands were capable of reducing blood cholesterol within 2 hr after administration, however, the values were not significantly different from the initial values. Correlative studies between the in vitro and in vivo data of all four brands indicates that there were no significant correlations between the two data (%Q₁₅ % Q₃₀ dissolution rae constants of drug versus C[subscript max], t[subscript max] and AUC values). This means that the in vitro data obtained under the present testing conditions could not be used to predict the bioavailability of simvastatin film-ciated tabkets,