Bioavailability and Bioequivalence Studies

Bioavailability and Bioequivalence Studies

1. Definitions and conceptual overview

• Drug product performance, in vivo, is defined as the release of the drug substance from the drug product leading to bioavailability of the drug substance (and thence to a pharmacodynamic response); BA and BE are the two in vivo measures of drug product performance (Shargel 8e Ch.8).
• Bioavailability (BA) — "the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action" (US-FDA/CDER 2014 definition adopted by Shargel) (Shargel 8e Ch.8) [FDA].
  • G&G frames it as "the fractional extent to which an administered dose of drug reaches its site of action or a biological fluid (usually the systemic circulation) from which it has access to the site of action"; if the metabolic/excretory capacity of liver and intestine for the drug is large, BA is reduced substantially (first-pass effect) (G&G 14e Ch.2).
  • KDT: BA is "the rate and extent of absorption of a drug from a dosage form as determined by its concentration–time curve in blood or by its excretion in urine"; it is a measure of the fraction (F) of an administered dose that reaches the systemic circulation in the unchanged form (KDT 8e Ch.2).
  • CDSCO: "the relative amount of drug from an administered dosage form which enters the systemic circulation and the rate at which the drug appears in the systemic circulation" (CDSCO 2005 §2) [CDSCO].
  • Symbol F = bioavailable fraction; F = 1 (100%) for an IV dose by definition; F < 1 orally because of (a) incomplete absorption and (b) presystemic/first-pass metabolism in gut wall or liver, or biliary excretion (KDT 8e Ch.2; G&G 14e Ch.2).
• Bioequivalence (BE) — "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study" (Shargel 8e Ch.8) [FDA].
  • A BE study is a special case of a relative-bioavailability study — it compares the BA of the same active ingredient from a test product to a reference product (Shargel 8e Ch.8).
  • CDSCO: BE is achieved "if its extent and rate of absorption are not statistically significantly different from those of the reference product when administered at the same molar dose" (CDSCO 2005 §2) [CDSCO].
• Why BA/BE matter: BA studies establish the in vivo performance of a new drug product and relate the physicochemical properties of the drug/formulation/manufacturing process to expected clinical efficacy and safety; BE studies compare the to-be-marketed product with the formulation used in the pivotal safety/efficacy trials, and underpin generic approval (Shargel 8e Ch.8).
• Bioequivalence vs relative bioavailability (terminology): during new-drug development, comparisons between different dosage forms of the same drug are usually called relative bioavailability; the term bioequivalence is reserved for the formal test/reference comparison that supports marketing (Shargel 8e Ch.8).
• KDT's core teaching point: different manufacturers' (or different batches') formulations may be chemically equivalent (same amount of drug) yet biologically inequivalent (do not yield the same blood levels); two preparations are bioequivalent when the rate and extent of BA are not significantly different under suitable test conditions (KDT 8e Ch.2).
• When BE documentation must be established between formulation versions: (a) early and late clinical-trial formulations; (b) clinical-trial vs stability-study formulations, if different; (c) clinical-trial vs to-be-marketed products; (d) product-strength equivalence; and for new fixed-dose combinations or modified-release (MR) versions of an approved immediate-release (IR) product (Shargel 8e Ch.8; CDSCO 2005 §3.1.1) [CDSCO].
• Postapproval changes (SUPAC — scale-up and postapproval changes): after approval, a manufacturer may change the API supplier, formulation, manufacturing process, or manufacturing site; for each, drug-product performance must be shown unchanged, demonstrated in vivo by BE or in vitro by comparative dissolution (Shargel 8e Ch.8, Ch.26).