Molecular Electrophilicity Index - A Promising Descriptor for Predicting Toxicological Property

Abstract

In the treatment of asthma, salmeterol xinafoate and fluticasone propionate are known to be effective and well accepted. These studies determined the bioequivalence between the test and reference formulations of salmeterol xinafoate/fluticasone propionate HFA pMDI, in healthy volunteers. Four pharmacokinetic studies were performed with the two higher strengths (25/250 mcg per actuation) and the two lower strengths (25/125 mcg per actuation) of the test and reference formulation. In all studies, the evaluation was based on a single dose, randomized, crossover design with a minimum washout period of 14 days. Out of the four studies, two studies also evaluated pulmonary deposition by blocking gastrointestinal absorption using charcoal administration for each strength. Examinations for safety included monitoring of adverse events and vital signs along with clinical laboratory assessments. A validated LC-MS/MS technique was used to determine the plasma concentrations of salmeterol xinafoate and fluticasone propionate. For the studies without charcoal blockade for salmeterol, the 90% CI for C max and AUC 0-t for 25/250 mcg was 83.44-100.29 and 104.08-120.08 respectively, while for 25/125 mcg it was 88.33-106.08 and 100.49-114.88 respectively. Similarly, in the studies with charcoal blockade for salmeterol, the 90% CI for C max and AUC 0-t for 25/250 mcg was 94.10-113.20 and 96.44-116.69 respectively, while for 25/125 mcg it was 100.70-115.72 and 104.99-122.70 respectively. For fluticasone, the 90% CI for C max and AUC 0-t for 25/250 mcg was 91. 08-105.07 and 99.86-115.61 respectively and for 25/125 mcg, it was 87. 04-105.03 and 85.38-103.42 respectively. Since the 90% CI for C max and AUC 0-t for both salmeterol and fluticasone were within the 80-125% interval in all the studies, it was concluded that test and reference formulations of salmeterol xinafoate/fluticasone propionate HFA pMDI are bioequivalent in their rate and extent of absorption with and without charcoal blockade for both the strengths.