BIOAVAILABILITY ASSESSMENT FROM PHARMACOLOGICAL DATA - METHOD AND CLINICAL-EVALUATION

A novel method is described for assessing drug bioavailability from ph armacologic data. The method is based upon a generalized model for the relationship between the observed effect (E) and the input rate (f): E = phi(c(e delta) f), where * denotes convolution, c(e delta) is ef fect site unit impulse response (''amount'' of drug at the effect site resulting from the instantaneous input of a unit amount of drug) and phi is transduction function (relates ''amount'' of drug at the effect site to E). The functions phi and c(e delta) are expressed as cubic s plines for maximum versatility. Pharmacologic data collected after the administration of two different doses by iv infusion are analyzed sim ultaneously to estimate the function parameters. This experimental des ign addresses the fact that phi and c(e delta) cannot be uniquely esti mated from the results of a single dose experiment. The unknown from a test treatment is then estimated by applying an implicit deconvolutio n method to the pharmacologic data collected during that treatment. Th e method was tested with simulated data. The method and the model were further evaluated by application to a clinical study of verapamil (V) pharmacodynamics in 6 healthy volunteers. Simulations showed that the method is accurate and precise in the presence of a high degree of me asurement error, bur large intrasubject variability in the model funct ions can result in biased estimates of the amount absorbed. The method produced reasonably accurate estimates of the V input rate and system ic availability (F) in the 6 human volunteers though there was a trend towards underestimation (estimated total F% = 93.6 +/- 14 vs. the tru e F% of 100).