Related to the science of clinical pharmacology, biopharmaceutics can be thought of as the body of scientific principles applied to convert a well-characterized drug substance to an appropriate, and potentially optimized, drug product. At the heart of biopharmaceutics is a thorough understanding of the physical, chemical and biological properties of the drug substance related to absorption (e.g., solubility, stability and intestinal permeability) and how to utilize these data to decide on the best route of administration and to develop a successful dosage form. The development of an initial formulation for a drug substance entails the study of drug product dissolution under a variety of environmental conditions (e.g., pH), and linking the resulting rate and extent of dissolution to the subsequent rate and extent of absorption (i.e., bioavailability or BA). These so-called in vitro-in vivo correlations (IVIVC) are important to early optimization of formulation performance in order to achieve systemic plasma drug concentration-time profiles later in human clinical trials with the greatest chance for therapeutic success.
Not infrequently, the final, to-be-marketed formulation of the active drug substance is different than the initial formulations used in either early or late clinical trial phases of development. Biopharmaceutics plays a critical role in linking the in vivo performance or BA of each of the early formulations (i.e., reference formulations) to the final (i.e., test formulations) formulations.
The standard study to assess comparative BA of the test and reference formulations is the bioequivalence (BE) study. Often, the results of BE studies are expressed as measures of exposure, such as area under the plasma concentration-time curve (AUC) and peak or maximum plasma concentration (Cmax). The ratio of these in vivo measurements (test/ reference) are usually statistically reported as 90% confidence intervals (CI). BE is declared if the 90% CI is between 80 and 125% ("goalposts"). However, if the 90% CI is either partially or completely outside these "goalposts", therapeutic equivalence is determined by integrating the clinical pharmacology information about exposure-response relationships into the regulatory decision-making process.
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