Background: The goal of this study was to develop an in vivo-in vitro (IVIV) correlation, both in men and\nwomen, which allows constructing a model to predict bioequivalence assessments for drugs with narrow\nabsorption windows. Besides, pharmacokinetic and pharmacodynamic equivalences were also investigated.\nFurosemide was chosen as a prototype.\nMethods: Twelve healthy Caucasian volunteers (8 women and 4 men) participated in a relative\nbioavailability study. Two oral formulations [Lasix�® (Reference, R) and Furosemide EFA�® (Test, T)] were\nadministered under fasting conditions. Urinary excretion of unchanged drug (PK), and of chloride, sodium\nand potassium (PD) wasmonitored throughout time. PK and PD parameters were calculated from each\nrespective excretion rate versus time curve. In vitro dissolution testing of both formulations was carried out\nusing the USP apparatus 2 and 4 with fixed and variable dissolution media.\nResults: T and R could be considered bioequivalent since the 90% confidence intervals for the T/R ratio of\ngeometric means for the area under the urinary drug excretion rate versus time curve and for the maximum\nexcretion rate were within the 0.80-1.25 bioequivalence interval. However, T had faster initial absorption\nand higher levels in women, while R displayed such characteristics in men. Closer IVIV correlations in\nwomen were obtained when apparatus 4 with variable biorelevant dissolution media were used [going\nfrom fasting state simulated gastric fluid to fasting state simulated intestinal fluid]. Since R had faster\ndisintegration time than T, a shorter stay of R under gastric conditions was required in order to obtain a\ngood IVIV correlation in men. Saluretic effect displayed a typical clockwise hysteresis loop for the PKPD\ncorrelation assessed through chloride-versus-furosemide urinary excretion rates. Even though a higher\namount of furosemide was excreted with the urine in men, differences in the excretion of electrolytes\nbetween sexes were almost negligible.\nConclusions: Sex-differences in the gastrointestinal transit of formulations, under fasting conditions,\ndetermined the extent and the rate of furosemide absorption. The prolongation of the absorption process\nby mean of slowing the gastric emptying would make the formulation more effective. The USP-4 apparatus\nwith variable dissolution media was able to discriminate the formulations even between sexes, becoming a\npromissory in vitro dissolution testing to predict bioequivalence.
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