Bioavailability and Bioequivalence

Bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation in an unchanged, pharmacologically active form. For an intravenous dose, bioavailability is by definition 1.0 (100%), as the drug is delivered directly into the bloodstream. For all other routes, F < 1 due to incomplete absorption, first-pass metabolism, or pre-systemic degradation.

Absolute bioavailability is determined by comparing the AUC after extravascular administration (e.g., oral) to the AUC after IV administration of the same dose: F = AUC_oral / AUC_IV × (Dose_IV / Dose_oral). Relative bioavailability compares two extravascular formulations without an IV reference: F_rel = AUC_test / AUC_reference. This is the basis for bioequivalence testing.

Factors governing oral bioavailability: (1) Formulation properties — particle size, dissolution rate, excipients, and coating all affect the rate and extent of drug release. Poorly soluble drugs (BCS Class II, e.g., itraconazole, ketoconazole) may have highly variable and food-dependent absorption. (2) Membrane permeability — highly lipophilic drugs cross membranes readily; hydrophilic drugs may rely on transporters. (3) First-pass effect — hepatic and gut wall extraction during portal transit. High-extraction drugs (morphine, glyceryl trinitrate, propranolol, lignocaine) have very low and variable oral bioavailability. (4) Gut wall metabolism — CYP3A4 in enterocytes metabolises many drugs before they reach portal blood (midazolam, cyclosporin, nifedipine). (5) P-glycoprotein efflux — returns drug from enterocytes to gut lumen, reducing absorption. (6) Gastric emptying rate — rapid emptying delivers drug to the small intestine (main absorption site) faster; food typically slows emptying, delaying but often not reducing overall absorption.

Bioequivalence is the regulatory standard used to establish that a generic formulation delivers equivalent drug exposure to the reference (innovator) product. Two formulations are bioequivalent if the 90% confidence interval for the ratio of AUC and Cmax (geometric mean test/reference) falls within 80–125%. This criterion is used by Medsafe in New Zealand for generic medicine approval. Bioequivalence studies are conducted in healthy volunteers under controlled conditions (typically crossover design).

The 80–125% rule means that within a study, individual patients may experience somewhat more or less exposure from a generic compared to the innovator. For most drugs with wide therapeutic indices, this is clinically irrelevant. However, for narrow therapeutic index drugs (NTI drugs) — including phenytoin, warfarin, digoxin, lithium, cyclosporin, tacrolimus, and carbamazepine — Medsafe applies tighter criteria (90% CI for AUC within 90–111%) to reduce the risk of therapeutic failure or toxicity during brand switching. In NZ clinical practice, patients stabilised on NTI drugs should generally not be switched between brands without medical review and additional TDM. Community pharmacists encountering brand substitution for NTI drugs should alert the prescriber and arrange follow-up monitoring.

The Biopharmaceutics Classification System (BCS) categorises drugs by solubility and permeability: Class I (high solubility/high permeability, e.g., metoprolol) — generally bioequivalent and eligible for biowaiver from in vivo studies; Class II (low solubility/high permeability, e.g., itraconazole) — dissolution-limited, sensitive to formulation; Class III (high solubility/low permeability, e.g., cimetidine) — permeability-limited; Class IV (low solubility/low permeability, e.g., amphotericin B) — problematic absorption.