Background: Dermatopharmacokinetic (DPK) bioequivalence (BE) evaluation required assessments of stratum corneum (SC) drug content.The SC samples are normally collected using adhesive stripping tapes.However, such procedure is susceptible to potential inter-operator variability, which weakens the conclusion for bioavailability.Aim: In this study, we simulated the SC content of a non-steroidal anti-inflammatory drug (drug A) after application of two types of topical patches (R and T) through a mathematic model built upon estimated subject-and time-point-specific parameters.The purpose was to verify the conclusion of DPK bioequivalence obtained from actual measurements.Method: This was an open-label, self-controlled trial in 20 males.Subjects were applied two pieces of each patch (3.2×3.2 cm2) on their back at randomly assigned positions.Stratum comeum (SC) samples were taken for bioassay with adhesive stripping tapes prior to patch application, and at 20h and 24h post-dose following removal of each patch.In addition to primary bioequivalence evaluation using a power model, we modeled the measured SC drug content data based on the appropriate solution of Ficks second law of diffusion [1].The SC content of drug A in each sampled SC layer was regarded as drug concentration in a certain thickness of SC at the No.X SC sampling batches (i.e.the SC depth).Subject-and time-point-specific parameters for distribution fraction (D), diffusion constant (K), and the hypothesized maximal number of SC-sample batches (L) were estimated with this model and then used to simulate the amount of drug A in the sampled SC layers and the unsampled SC layers, respectively.Bioequivalence evaluation was repeated the estimated values of total SC drug content (including the residual amount of drug in the unsampled SC layers).Results: Bioequlvalence was established on actual measurements of the total SC drug content at each postapplication time point and on the decrement of SC drug content from 20h to 24h post-application (Table).With the estimated subject-and time-point-specific values for K, D, and L, the diffusion model showed acceptable goodness-of-fit for each subject.The R2 value of the established model agai(s)t the actual measurements ranges from 0.8371 to 0.9992.Based on the simulations, theproportion of unsampled SC drug content comprises less than 8% of the estimated total SC content at any single time point with either of the two patches.Bioequivalence evaluations performed on the estimated total SC drug content were in line with the results obtained from actual measurements (Table).Conclusion: The diffusion model has good compliance with the actual data and hence reliable for the simulation of residual SC drug amount.Since minimal proportion of drug was estimated in the residual SC samples, influence of inter-operator variability was considered ignorable.Bioequivalence evaluation for the estimated values further supported the conclusion derived from the measures of SC drug content.