評估口服速放劑型核准上市後變更是否需再執行生體相等性之研究：心臟血管藥品   全文下載

Assessing the Potential Bioequivalence Requirement for Oral Immediate Release Dosage Form: Post Approval Changes for Cardiovascular Drugs

藥品核准後經常會發生配方必需改變的情形，因此美國制定了一套規定，稱為SUPAC guidance （Scale Up and Post Approval Change Guidance），來規範與管理藥品在核准後發生配方改變時所需之基本試驗要求。在此規範中，藥品品項分類的觀念BCS （Biopharmaceutical Classification System）被提出，藥品根據溶解度與穿透度的不同，而被區分為高溶解度／高穿透度藥品，高溶解度／低穿透度藥品，低溶解度／高穿透度藥品，低溶解度／低穿透度藥品等四大類。根據規範，當藥品配方改變後，此四類藥品均需作溶離試驗。而且其中的低溶解度／低穿透度的藥品，則更需加作生體相等性試驗。除此之外，製程、配方及原料的第三層次變更，也需要作生體相等性試驗。然而在此藥品品項分類系統中，只有少數一些藥品被列入，因此要廣泛的應用這個規定，則需要有更多的藥品被補充收集在內。本研究之目標是收集有關藥品釋放及吸收方面之資料，再加以評估，以了解是否能用溶離試驗來取代生體相等性試驗。由於心臟血管系統藥品彼此間的物理化學與藥物動力學性質差異頗大，因此本研究的基礎是特別依據台灣的藥物發展情況來作的。謹慎考慮後，本研究的資料收集，已知的藥品資料如藥品的物理化學性質，體外體內之藥物動力學資訊，並參考下列項目：（1）有效濃度及產生毒性濃度，（2） 溶解度與pKa，（3） 藥品及其代謝物之吸收百分比，（4） 半衰期（t1／2）與到達最高血中濃度的時間（tmax），（5） 德國的建議進行藥品生體相等性藥品清單，WHO及FDA的狹窄治療指標藥品（NTI）清單等。最後根據這些資料作出判斷性的結論。

Formulation changes can occur during drug development before approval or after approval. Recently, the FDA issued several guidances regarding scale up and post approval changes (SUPAC). The first of the series addresses the requirements for determining and evaluating those changes for immediate release (IR) oral dosage form. In that guidance, the concepts of Biopharmaceutical Classification System (BCS) were introduced. Based on their solubility (S) and permeability (P), the drugs are classified as high (H) and low (L), and thus are divided into four classes (HS/HP, HS/LP, LS/HP, and LS/LP). Only LS/LP drugs are required to perform a bioequivalence (BE) study. The other classes of drugs are required to perform a BE study only when they fail their dissolution testing, under level 3 changes in manufacturing process, components and composition. In addition, only a handful of drugs were classified under the BCS system. In order for the industry to extensively apply the BCS system, more drugs need to be classified. The objective of this study is to compile the pertinent information relating to the drug release from the formulation and absorption through the gut wall. By evaluating the information collectively, an educational guess can be made as to whether the formulation can be rapidly converted to solution in the gastrointestinal tract and therefore behave as such. Under those conditions, a BE study may not be needed if in vitro dissolution performance can be demonstrated. Cardiovascular drugs were studied for their vastly different safety profiles, physicochemical properties and pharmacokinetic behaviors. This report is written for the Taiwan regulatory authority (Bureau of Pharmaceutical Affairs, Department of Health) considering the uniqueness of the Asian pharmaceutical environment. The final judgement was made based on the following information: 1) effective and toxic concentrations; 2) solubility and pKa; 3) total % absorption as both drug and metabolite(s); 4) half-life and its peak time as indication of in vivo solubility and permeability of drug; and 5) German BA list, WHO list9 and the FDA narrow therapeutic index drug list. The reason(s) for the judgement was provided. 藥品核准後經常會發生配方必需改變的情形，因此美國制定了一套規定，稱為SUPAC guidance （Scale Up and Post Approval Change Guidance），來規範與管理藥品在核准後發生配方改變時所需之基本試驗要求。在此規範中，藥品品項分類的觀念BCS （Biopharmaceutical Classification System）被提出，藥品根據溶解度與穿透度的不同，而被區分為高溶解度／高穿透度藥品，高溶解度／低穿透度藥品，低溶解度／高穿透度藥品，低溶解度／低穿透度藥品等四大類。根據規範，當藥品配方改變後，此四類藥品均需作溶離試驗。而且其中的低溶解度／低穿透度的藥品，則更需加作生體相等性試驗。除此之外，製程、配方及原料的第三層次變更，也需要作生體相等性試驗。然而在此藥品品項分類系統中，只有少數一些藥品被列入，因此要廣泛的應用這個規定，則需要有更多的藥品被補充收集在內。本研究之目標是收集有關藥品釋放及吸收方面之資料，再加以評估，以了解是否能用溶離試驗來取代生體相等性試驗。由於心臟血管系統藥品彼此間的物理化學與藥物動力學性質差異頗大，因此本研究的基礎是特別依據台灣的藥物發展情況來作的。謹慎考慮後，本研究的資料收集，已知的藥品資料如藥品的物理化學性質，體外體內之藥物動力學資訊，並參考下列項目：（1）有效濃度及產生毒性濃度，（2） 溶解度與pKa，（3） 藥品及其代謝物之吸收百分比，（4） 半衰期（t1／2）與到達最高血中濃度的時間（tmax），（5） 德國的建議進行藥品生體相等性藥品清單，WHO及FDA的狹窄治療指標藥品（NTI）清單等。最後根據這些資料作出判斷性的結論。