ABSTRACT
BACKGROUND The realization of the importance of product formulation for the speed of onset, intensity, and duration of drug response occurred in the early 1960s. At that time, various scattered reports in the literature (1-5) indicated that formulation changes result in marked differences in maximum observed plasma concentration (Cmax) and area under the concentration-time curve (AUC), and the term “bioavailability” was coined to describe the fraction of dose reaching the general circulation. A few years later, dramatic bioavailability problems were observed with formulations of phenytoin in Australia and New Zealand in 1968 (6,7) and of digoxin in the United Kingdom and the United States in 1971 (8,9). Consequently, comparative bioavailability studies were introduced in the U.S. regulatory setting (10,11) and the term bioavailability was officially introduced by the Food and Drug Administration (FDA) (12) and defined as follows: “Bioavailability means the rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action.” Since the late 1970s, a test (T) formulation that meets statistical criteria for the measures of relative bioavailability is termed “bioequivalent” to, and therapeutically interchangeable with, the reference (R) formulation. For more details on the regulatory history of generic drug development, the reader is referred to relevant publications (13-15).
