第一部份
　　皮質類固醇製劑為皮膚科領域最常使用之外用治療藥品，其效價共分為七級，以第一級最強，第七級最弱。美國藥物食品管理局「外用皮質類固醇製劑生體相等性試驗規範」建議以人體藥效血管收縮檢定法進行生體相等性評估，此外亦建議可採用皮膚藥動試驗法來評估外用皮膚製劑的生體相等性，此法亦曾被證明具有一致性、客觀性及再現性，而其可行性仍待評估。皮膚藥動試驗法（Dermatopharmacokinetic, DPK）包含了皮膚層撕法和藥物活性成份之分析，以角質層上的活性成分藥量之動態變化作評估。

　　Hydrocortisone（HC）是外用皮質類固醇中效價最弱的藥品，若干研究結果顯示HC之血管收縮反應表現不明顯，故以血管收縮檢定法來評估其生體相等性並不適當。本研究之目的在利用皮膚層撕法評估局部投與HC外用製劑後HC在角質層上的藥動變化，分析HC乳軟膏在藥動學上的差異性並檢視其皮膚藥動與藥效之關聯性，以探討DPK做為評估HC外用製劑生體相等性試驗法之可行性。

　　研究結果顯示，根據角質層中Hydrocortisone含量的經時變化（DPK profile）顯示乳軟膏之各皮膚藥動參數（Amax、Tmax、AUC0-30、ke、T1/2）具有顯著差異且乳膏之變異度較大。然而HC血管收縮檢定法之結果相當不明顯，僅能分辨軟膏與未用藥部位之差異，因此對於Hydrocortisone製劑，皮膚藥動試驗法之鑑別度較高，故此法應可作為Hydrocortisone製劑生體相等性評估之方法。

　　進一步分析軟膏及乳膏的角質層滲透性參數，軟膏之分配係數（K）幾乎不受用藥時間的影響，因此滲透性（P）隨用藥時間增加而降低主要來自擴散係數（D）的經時變化。乳膏之分配係數及擴散係數同樣受到用藥時間的影響，導致乳膏之滲透性隨用藥時間的變化較大。此外，體外經裸鼠皮滲透試驗之結果與DPK profile所呈現之乳膏具有較高的最大吸收量（Amax）及經時吸收量（AUC0-30）結果相符。

第二部分
　　近年來有關藥動藥效模式的分析被廣泛地討論，主要依生理狀況下身體對藥效反應的時間歷程加以描述，以期能夠預測藥效反應並且調整治療策略。過去的研究結果顯示Dermovate 0.05 % ointment（Clobetasol）角質層上的吸收量已使血管收縮反應達到飽和，基於安全性的考量，本研究選用最強效之Clobetasol 17-propionate（CP）作為模式藥物，建立皮膚藥動學與藥效反應之關係，並且探討乳軟膏藥動、藥效參數之異同。

　　藥動藥效模式分析的結果顯示，以零階次藥動模式與Emax藥效模式合併之Indirect藥動藥效模式可適當地描述外用皮質類固醇Clobetasol 17-propionate皮膚上藥量與藥效反應結果之關連性，並且可分辨CP乳軟膏之差異。CP軟膏之吸收速率常數ko及藥品進入藥效作用腔室之速率常數keo均高於CP乳膏，而藥品自角質層排除之速率常數k則相等且可忽略不計。藥效參數方面，CP乳膏之Emax較軟膏稍大且ED50較短。未來將可進一步探討此模式應用在其他類外用製劑之可行性，並可作為改良處方的依據。

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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