Abstract
Background: The goal of this study was to develop an in vivo-in vitro (IVIV) correlation, both in men and women, which allows constructing a model to predict bioequivalence assessments for drugs with narrow absorption windows. Besides, pharmacokinetic and pharmacodynamic equivalences were also investigated. Furosemide was chosen as a prototype.
Methods: Twelve healthy Caucasian volunteers (8 women and 4 men) participated in a relative bioavailability study. Two oral formulations [Lasix® (Reference, R) and Furosemide EFA® (Test, T)] were administered under fasting conditions. Urinary excretion of unchanged drug (PK), and of chloride, sodium and potassium (PD) wasmonitored throughout time. PK and PD parameters were calculated from each respective excretion rate versus time curve. In vitro dissolution testing of both formulations was carried out using the USP apparatus 2 and 4 with fixed and variable dissolution media.
Results: T and R could be considered bioequivalent since the 90% confidence intervals for the T/R ratio of geometric means for the area under the urinary drug excretion rate versus time curve and for the maximum excretion rate were within the 0.80-1.25 bioequivalence interval. However, T had faster initial absorption and higher levels in women, while R displayed such characteristics in men. Closer IVIV correlations in women were obtained when apparatus 4 with variable biorelevant dissolution media were used [going from fasting state simulated gastric fluid to fasting state simulated intestinal fluid]. Since R had faster disintegration time than T, a shorter stay of R under gastric conditions was required in order to obtain a good IVIV correlation in men. Saluretic effect displayed a typical clockwise hysteresis loop for the PKPD correlation assessed through chloride-versus-furosemide urinary excretion rates. Even though a higher amount of furosemide was excreted with the urine in men, differences in the excretion of electrolytes between sexes were almost negligible.
Conclusions: Sex-differences in the gastrointestinal transit of formulations, under fasting conditions, determined the extent and the rate of furosemide absorption. The prolongation of the absorption process by mean of slowing the gastric emptying would make the formulation more effective. The USP-4 apparatus with variable dissolution media was able to discriminate the formulations even between sexes, becoming a promissory in vitro dissolution testing to predict bioequivalence.
Methods: Twelve healthy Caucasian volunteers (8 women and 4 men) participated in a relative bioavailability study. Two oral formulations [Lasix® (Reference, R) and Furosemide EFA® (Test, T)] were administered under fasting conditions. Urinary excretion of unchanged drug (PK), and of chloride, sodium and potassium (PD) wasmonitored throughout time. PK and PD parameters were calculated from each respective excretion rate versus time curve. In vitro dissolution testing of both formulations was carried out using the USP apparatus 2 and 4 with fixed and variable dissolution media.
Results: T and R could be considered bioequivalent since the 90% confidence intervals for the T/R ratio of geometric means for the area under the urinary drug excretion rate versus time curve and for the maximum excretion rate were within the 0.80-1.25 bioequivalence interval. However, T had faster initial absorption and higher levels in women, while R displayed such characteristics in men. Closer IVIV correlations in women were obtained when apparatus 4 with variable biorelevant dissolution media were used [going from fasting state simulated gastric fluid to fasting state simulated intestinal fluid]. Since R had faster disintegration time than T, a shorter stay of R under gastric conditions was required in order to obtain a good IVIV correlation in men. Saluretic effect displayed a typical clockwise hysteresis loop for the PKPD correlation assessed through chloride-versus-furosemide urinary excretion rates. Even though a higher amount of furosemide was excreted with the urine in men, differences in the excretion of electrolytes between sexes were almost negligible.
Conclusions: Sex-differences in the gastrointestinal transit of formulations, under fasting conditions, determined the extent and the rate of furosemide absorption. The prolongation of the absorption process by mean of slowing the gastric emptying would make the formulation more effective. The USP-4 apparatus with variable dissolution media was able to discriminate the formulations even between sexes, becoming a promissory in vitro dissolution testing to predict bioequivalence.
| Original language | English |
|---|---|
| Article number | 2 |
| Journal | Journal of Pharmaceutical Technology and Drug Research |
| Volume | 5 |
| DOIs | |
| Publication status | Published - 19 Oct 2016 |