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Background: Darunavir is an inhibitor of the human immunodeficiency virus (HIV-1) protease. Darunavir exists in various pseudo polymorphs such as alcohol solvates, hydrate solvates, alkane solvates. Darunavir was approved in US in the form of Darunavir ethanolate (RLD). Aurobindo Pharma Ltd, India developed Darunavir as Darunavir propylene glycolate tablets. Both Darunavir ethanolate and Darunavir propylene glycolate are alcohol solvates used to improve stability and bioavailability of Darunavir; however pharmacokinetic and bioequivalence data of Darunavir propylene glycolate tablets in healthy volunteers is not available. Objective: This study was designed to evaluate the bioequivalence of Darunavir Propylene Glycolate tablets manufactured by Aurobindo Pharma Ltd, India with PREZISTA (Darunavir ethanolate) Tablets 800 mg reference formulation of Janssen Ortho LLC, USA in healthy volunteers under fed conditions. This study compared dissolution profiles, relative bioavailability, pharmacokinetics, safety and tolerability of Darunavir ethanolate and Darunavir propylene glycolate tablet formulations. Methods: To evaluate the pharmaceutical equivalence of the test and reference products, in vitro dissolution test was performed using the US Pharmacopeia (USP) dissolution apparatus-II, paddle method and a simple model independent approach using the difference factor (f1) and the similarity factor (f2) were adopted to compare dissolution profiles. After an overnight fasting of at least 10.0 hours and exactly 30 minutes after serving of a high fat high calorie meal, a single oral 800-mg dose of the 2 formulations were administered to 14 healthy volunteers under fed conditions in a randomized, open- label, 2-treatment, 2-sequence, 2-period crossover study with washout period of 7 days. In addition, 100 mg Ritonavir (NORVIR) was administered every 12 hours for two days prior to administration of Darunavir and till sampling of 36.00 hours post dose in each period. Darunavir plasma concentrations were quantified using a validated LC-MS/MS detection method and were used to determine the pharmacokinetic parameters. As mandated by the US Food and Drug Administration, the test and reference formulations were considered bioequivalent if the T/R ratios and 90% CI’s of the geometric mean ratios for the log-transformed values of pharmacokinetic parameters were within the predetermined range of 80.00 to 125.00. Results: When subjected to a simple model independent approach of dissolution profile comparison, f1 (difference) and f2 (similarity factor) were found to be 4.44 and 66.64 respectively. Similarly, the two Darunavir Tablet formulations were safe and well tolerated by all the volunteers. The T/R ratios (90% CI’s) for the ratios of Cmax, AUC0-t and AUC0-inf respectively were 111.40 (97.44-127.35), 108.81 (97.81-121.05) and 112.31 (96.04-131.33). Conclusion: The results of this single-dose fed study showed that test formulation developed with Darunavir propylene glycolate solvate form was found to be predictive bioequivalent to reference formulation in healthy volunteers. Both test and reference formulations were safe and well tolerated. |
