FDA Guidance for Medical Industry on Bioavailability Studies

Bioequivalence and bioavailability studies are crucial elements for supporting the applications of NDAs, INDs, ANDAs, and their supplement products. As a part of the FDA regulatory requirements, all the orally-administered products need to be evaluated for their bioavailability. Such studies help in determining the overall process through the use of which the active pharmaceutical ingredient from the pharmaceutical product is released and reaches its intended site of action. What is meant by the bioavailability of drugs? Bioavailability studies of a given pharmaceutical product under analysis evaluates the rate and extent of active drug substance absorption from a given pharmaceutical product. Further, it also determines the exact concentration of the absorbed drug substance reaching its intended site of action. Besides, the BA studies help in characterizing a drug product, based on its rate of distribution, rate of elimination, the nutrient effect on drug absorption, dose proportionality, pharmacokinetic linearity, and so on. Factors influencing the bioavailability of drugs Here is a list of factors contributing to lowering the bioavailability of drugs. First pass metabolism produced by the liver *Intestinal motility *Chemical degradation by intestinal flora *Liver metabolism *Gastrointestinal function *Physical drug properties *Gastric emptying rate *Drug-drug interactions *Drug-food interactions *Efflux transporters substrates *Drug or food-induced enzyme induction or inhibition FDA requirements for evaluating bioequivalence and bioavailability of drugs The definitions of both the BA and BE studies emphasize the utilization of essential pharmacokinetic parameters. These are instead considered as bioassays for characterizing drug substance released from the pharmaceutical formulation under consideration. The sponsors of the clinical studies can make the best use of pilot level studies for validating analytical methodology, optimizing the time intervals for sample data collection, assessing the variability of the drug at different time intervals and supplementing useful information. FDA recommends the use of non-replicate study designs for evaluation of both the BA and BE study parameters. Such studies are majorly formulated in the event of use of either modified release or immediate release dosage forms. The significant advantage of these studies is that they are the best methods of evaluating the inter-species variations. Selection of the bioanalytical methods for both BA and BE studies should be precise, accurate, sensitive, selective, and reproducible in its overall approach. FDA has a separate guideline issued under the title of ‘Bioanalytical Method Validation’ for validating the bioanalytical methods under usage. Both direct and indirect methods for measuring bioavailability of drugs are limited in their resources. Thus, the FDA strongly recommends the applicability of systemic exposure measurements for quantifying bioavailability of drugs. Usually, in case of the orally administered drugs, there is no need for a pharmacodynamic approach for evaluating the drug’s bioavailability. Instead of it, a well-defined pharmacokinetic approach is used in the determination of both systemic exposure and BE establishment. According to the biopharmaceutics classification system, product quality assessed through the bioavailability and bioequivalence studies can be documented through the use of an in vitro approach, i.e. dissolution studies. Co-administration of food substances along with a particular pharmaceutical product under analysis may, in turn, affect its overall bioavailability and bioequivalence. Likewise, for BA studies of orally administered drug products, it is essential to adequately characterize half-life calls of the subject’s blood samples at definite time intervals of drug exposure.