Permeability details of be exempt varieties requiring self certification of BCS classification

On November 11, 2017, it was a night of shopping spree The official flagship store of CDE also released the new product "list of 289 base drugs that can exempt or simplify human bioequivalence test (be) varieties (Draft for comments)" It is noteworthy that this is only the first batch to be released, and there should be at least 2-3 batches left behind After all, experts have to relax For this draft, according to the API category statistics, do a simple summary without distinguishing the dosage form differences 20 varieties recommend be exemption, 13 varieties recommend BCS classification of self certification, and then apply for be exemption The safety of bismuth preparation needs to be evaluated by PK method It is recommended to simplify be study for 12 varieties, and only after meal be study is needed For the 20 recommended be exempt varieties, the basic problem is not big and it is easy to understand The oral rehydration salt powder is a mixture of inorganic salt and sugar, without auxiliary materials and complex preparation process Vitamin B, calcium preparation, iron preparation, folic acid and potassium chloride granules are all endogenous or foodborne components Cyclophosphamide is BCS class I or class III, which is toxic and should not be evaluated Montmorillonite powder, polyethylene glycol 4000, phenolphthalein and sodium bicarbonate are non absorbable and locally active drugs, which can not be evaluated by be method Levofloxacin, propranolol and metoprolol are all FDA and / or EMA recommended be exempt varieties CDE only gives the varieties and specifications of the 13 varieties of BCS, but does not explain the reasons for BCS classification It can be inferred that the existing BCS classification is not clear or controversial (for example, at the critical point of classification) In this paper, according to the reported content of bioequivalence exemption monograph on rapid release oral solid preparations, the permeability research reports of these 13 varieties are summarized, and the special situation in the permeability research is illustrated by citing examples One For the permeability in BCS classification, the most authoritative method is the absolute bioavailability (BA) However, the result of low absolute Ba does not mean that the absorption in vivo is low or it must belong to low permeability, which may be caused by the metabolic transformation in vivo, the stability of gastrointestinal tract or the loss of drugs on membrane transporters (such as P-glycoprotein), etc It is necessary to analyze the specific reasons and come to the correct conclusion Case 1: in vivo results contradict the results of Caco-2 cell model - there is limited information on the permeability of ribavirin in the literature of ribavirin The absolute Ba of ribavirin ranges from about 33% to 52% This may be at least partly due to first pass metabolism Other reports show that about 85% of oral drugs are absorbed, which will put ribavirin at the boundary of high permeability and low permeability (85%) in who and EMA regulations, but it can not meet the "high permeability" (90%) stipulated by FDA It is reported that the apparent permeability of ribavirin Caco-2 cells is about 0.18 × 10-6cm / s The low permeability of Caco-2 cell model may be due to the lack of high level hCNT2 in the transport system 2 The second is the experimental model (such as Caco-2 cell model or intestinal perfusion test), but sometimes the results of Caco-2 cell model or intestinal perfusion test are quite different Case 2: the results of Caco-2 cell model and in vivo intestinal perfusion test are quite different - atenolol is reported to be absorbed orally by about 50%, so it is considered as a low permeability drug Caco-2 cell transport studies also showed similar permeability values However, the permeability value obtained by intestinal perfusion is 500 times higher than that obtained by Caco-2 The possible reasons are as follows: (1) atenolol is a kind of hydrophilic drug which is transported by the way of close connection through the paracellular pathway The higher permeability observed in the intestinal perfusion technique may be due to the lower extracellular transport and / or the larger absorption area available to the human body in vivo (2) The gut has mucus to form goblet cells, which affect tight junctions When Caco-2 cells mixed with mucogenic cells (HT29-MTX), the permeability of atenolol increased When the generative cells replace Caco-2, the permeability increases to 30 times (3) The difference of extracellular Ca + + concentration can lead to the change of cell structure integrity and the change of atenolol cell bypass permeability It is reported that the permeability of atenolol increases about 7 times by reducing the concentration of extracellular Ca + (4) Finally, the cell tissue of the intestine has a transepithelial resistance (Teer) of 50-100 Ω cm2 The Caco-2 cell line has a Teer of > 200-300 Ω cm2 Higher Teer in Caco-2 cells may result in lower permeability than in intestinal cells However, the permeability data obtained by intestinal perfusion technique is reasonable and consistent, with an average of 2.10-5cm/s, indicating that atenolol has low permeability 3 Parameters such as logP or clopp can only be used as auxiliary reference, because there are many errors and counter examples, it is not recommended to be used as the basis for permeability judgment and evaluation Case 3: the results of permeability based on logP or clopp contradict the results in vivo - zidovudine, codeine phosphate and metronidazole (1) zidovudine - were initially classified into BCS III based on the data of clopp, but later, zidovudine was finally classified into bcs i based on the results of absolute Ba study and the study of internal mass balance (2) Codeine phosphate Caco-2 monolayer cell model results in high permeability, belonging to BCS I, but because the log P (1.1) value of codeine phosphate is lower than the reference drug metoprolol (2.3), codeine phosphate is also classified into BCS III drugs (3) Metronidazole - if distribution coefficient data are used to predict metronidazole permeability, it is concluded that the permeability is low and therefore classified as BCS III However, the permeability of this calculation forecast is not a reliable forecast index, nor is it recognized by the official regulatory agencies 4 If the result of absolute BA in vivo is just at the edge of hypertonic and hypotonic (for example, more than 85%, but less than 90%), FDA will adopt the standard of "high not low" For example, metronidazole, stavudine, lamivudine, paracetamol, ribavirin In conclusion, the absolute BA in vivo is the absolute reference for the classification of permeability, and the conservative standard of high or low is adopted The Caco-2 cell model in vitro is a good evaluation model, which is less inconsistent with the absolute be in vivo Even if it is encountered, specific problems need to be analyzed Generally, it is recommended to use at least two methods for evidence assessment Table 1 Summary of BCS classification and permeability studies of be exempt varieties requiring self certification BCS classification