This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative methods for evaluation of BE was discussed. The outcome of the workshop emphasized both a need for greater attention to quality, possibly, via a Quality-By-Design (QBD) approach and a need to develop a "whole toolkit" approach towards the problem of determination of rate and extent in the assessment of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical industry and regulators work together to evaluate and validate alternative methods that are based on both the underlying science and are adapted to the drug product itself instead of single "universal" method.
An HPLC method for the determination of diclofenac (DCF) and four of its metabolites (3'-hydroxydiclofenac, 4'-hydroxydiclofenac, 5-hydroxydiclofenac, and 3'-hydroxy-4'-methoxydiclofenac) in human urine is described. Following base hydrolysis, the samples were neutralized and extracted. Evaporated extracts were reconstituted in mobile phase containing ascorbic acid, and chromatographed, using flow-rate programming, on a reversed-phase column. Absolute recovery (average), was at least 78% for diclofenac and ranged from 75 to 85% for the four metabolites. Standard curves showed linearity over the range of concentrations of 0.2 to 40 ug/mL, using 0.25 mL of urine. Specificity was demonstrated by examining chromatograms of extracts of blank urine from 8 volunteers and 24 study subjects. Good accuracy was observed for all compounds over the concentration range of 0.2 to 40 ug/mL using 0.25 mL of urine. Based on accuracy and precision criteria, the limit of quantitation for all 5 analytes was 0.4 ug/mL, using 0.25 mL of urine. Analysis of urine from subjects with normal and reduced renal function who received diclofenac orally demonstrated that total diclofenac and metabolites excreted in the urine represented approximately 31% and 4% of an oral dose of diclofenac, respectively.
Using a pharmacokinetic model recently proposed to explain ibuprofen disposition in man, plasma concentrations of pure ibuprofen enantiomers were simulated following oral administration of (-)-(R)-ibuprofen, (+)-(S)-ibuprofen, or rac-ibuprofen. Simulated and literature values for AUC's were used to compare S/R ratios for different cases of the model and for different methods of calculating the fraction of R bioinverted to S. Numerical simulation using STELLA confirmed previous results for different cases of bioinversion. Simulated S/R AUC ratios, for administration of the racemate, ranged from 4.0 (presystemic bioinversion) to 1.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 1.53 +/- 0.2 for administration of the racemate; therefore, systemic bioinversion was concluded to be representative of ibuprofen disposition. Additional simulations of S/R AUC ratios, for administration of (-)-(R)-ibuprofen only, ranged from 1.5 (presystemic bioinversion) to 0.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 0.50 +/- 0.9 for administration of (-)-(R)-ibuprofen only, which again supported conclusions of systemic bioinversion. Using different equations for estimation of fraction of R inverted to S (FR----S), results based on simulated data were identical; however, FR----S values based on literature data were different. Therefore, assumptions made for different FR----S equations do not appear to be rigorous. Calculations of FR----S, based on literature data, averaged 0.52 overall, indicating bioavailability of (+)-(S)-ibuprofen may be similar for a 150 mg dose of (+)-(S)-ibuprofen compared to a 200 mg dose of racemate.
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