| Summary: | 碩士 === 國立成功大學 === 臨床藥學研究所 === 92 === Part I
Topical corticosteroids are the most frequently prescribed products in dermatology and their potency is ranked in seven classes with Class I as the super-potent and Class VII as the mildest. The vasoconstrictor method has been adopted by the FDA as a means of assessing bioavailability (BA) and bioequivalence (BE) of topical dermatologic corticosteroids. Nevertheless, it has also been suggested that a dermatopharmacokinetic (DPK) characterization might provide an alternative approach for the determination of BE of topical dermatological products. This method has been proven to be consistent, objective and reproducible, while the applicability remained to be established. DPK studies provide information on drug concentration measurements with respect to time and should include validation of both analytical methods and the technique of skin stripping.
Hydrocortisone is the least potent topical corticosteroid. Previous studies have demonstrated that the skin blanching response to hydrocortisone is so weak that the vasoconstrictor assay is not appropriate for bioequivalence assessment. The purposes of this study were to evaluate the stratum corneum concentration-time profile of HC after topical application, to distinguish the difference of DPK and SC transport parameters between HC ointment and cream, and to examine the relationship between dermatopharmacokinetic parameters and pharmacodynamic responses.
The dermatopharmacokinetic profile of hydrocortisone formulations demonstrated that the DPK parameters ( Amax, Tmax, AUC0-30, ke, T1/2) of HC cream are significantly different from ointment. The vasoconstrictor effect of hydrocortisone was barely perceivable and only the effect of HC ointment can be differentiated from the untreated control, but not HC cream. As a result, the DPK method is more discriminative than pharmacodynamic assay for hydrocortisone formulations and is appropriate for bioequivalence assessment of HC formulations.
Furthermore, the stratum corneum (SC) transport parameters of HC formulations as a function of application time have been examined. For HC ointment, the partition coefficient (K) was independent of time duration and the variation in permeability with time duration was attributed to the changes in diffusion coefficient (D). In contrast, the permeability of HC cream was dependent on time duration, which was resulted from both the changes in the partition and diffusion coefficients with time duration. Results from in vitro skin penetration are consistent with the DPK parameters for HC cream with a higher Amax and larger AUC0-30 than ointment.
Part II
The rationale for PK/PD-modeling is to link pharmacokinetics and pharmacodynamics in order to establish and evaluate dose-concentration- response relationships and subsequently describe and predict the effect-time courses resulting from a drug dose. Our previous studies demonstrated that the SC uptake of clobetasol propionate (CP) from Dermovate 0.05% ointment exceeded the saturation of pharmacodynamic response, and may potentiate the risk of adverse effects after long-term use. The present studies aimed to develop a PK/PD combined model to correlate the relationship between drug uptake into the stratum corneum (SC) and pharmacodynamic response effect of topical CP. The difference between ointment and cream formulations was examined by comparing the parameters from the model analyses.
By indirect PKPD modeling, parameter estimates of the absorption rate constant (ko) and the transfer rate constant for drug removal into the effect compartment (keo) were greater with the ointment than the cream, while the elimination rate constant (k) was the same and negligible. A larger Emax (the maximum fitted value of a-AUEC) but a shorter ED50 (dose duration required to achieve 50% of the fitted Emax value) were obtained with the cream. The significant differences among parameters between ointment and cream may be attributed to different vehicle formulations.
In conclusion, the indirect pharmacokinetic/pharmacodynamic model with zero-order PK model and Emax PD model is an appropriate approach for correlating the exposure to topical CP and its pharmacodynamic effect. The established model can be applied to formulation design of topical CP for the optimization of drug delivery and clinical efficacy.
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