Biowaiver Extension Potential for Class II Drugs

As discussed above, the rate-limiting step in the oral absorption of Class II drug substances is likely to be the in vivo dissolution [23-25]. For Class II dissolution rate limited drugs, hence, if in vivo dissolution can be estimated in vitro, an in vitro-in vivo correlation may be established. As discussed in Section 3.5, such media have been developed, and an adequate IVIVC was shown for number of Class II drugs. However, due to the numerous in vivo parameters involved, it appears that more research is needed to develop uniform dissolution media reflecting in vivo dissolution conditions, to establish an adequate IVIVC, and to asses the risk of bioinequivalence [86, 88], In addition, the relationship between the hydrodynamics in the currently available dissolution tests and the actual in vivo situation is not adequately characterized and might interfere to obtain the correlation. 

As discussed in detail above, the intestinal absorption of Class II drug substances may be limited by dissolution rate or solubility rate. In the latter case, when the absorption is limited by the drug equilibrium solubility, an IVIVC is not likely to be obtained. The GI tract drug concentrations in this case will be close to the saturation concentration, and since standard dissolution tests are carried out under sink conditions, they can predict only processes occurring well below the saturation concentration [85], Hence, at this point, Class II solubility rate limited drugs are probably poor candidates for BA/BE waiver. 

Looking into the future, more BCS Class II drug candidates are likely to be produced, and the delivery of these molecules through the oral route is expected to be a continuing challenge. 

In this chapter, we have reviewed the rate and extent of oral absorption of this class of drugs and discussed the numerous factors, physicochemical, physiological, and dosage form, that must be considered in effectively delivering these drug candidates. In-depth comprehension of these factors and their influence on the intestinal absorption process is essential in the effective oral delivery of BCS Class II drug substances. 

2 Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (2001) Experimental and computational approaches to estimate solubility and permeability 

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