A novel method is described for assessing drug bioavailability from pharmacologic data. The method is based upon a generalized model for the relationship between the observed effect (E) and the input rate (f): E =φ(C(eδ) * f)) were * denotes convolution, c(eδ) is effect site unit impulse response ('amount' of drug at the effect site resulting from the instantaneous input of a unit amount of drug) and φ is transduction function (relates 'amount' of drug at the effect site to E). The functions φ and c(eδ) are expressed as cubic splines for maximum versatility. Pharmacologic data collected after the administration of two different doses by iv infusion are analyzed simultaneously to estimate the function parameters. This experimental design addresses the fact that φ and c(eδ) cannot be uniquely estimated from the results of a single dose experiment. The unknown f from a test treatment is then estimated by applying an implicit deconvolution method to the pharmacologic data collected during that treatment. The 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 measurement error, but large intrasubject variability in the model functions can result in biased estimates of the amount absorbed. The method produced reasonably accurate estimates of the V input rate and systemic availability (F) in the 6 human volunteers though there was a trend towards underestimation (estimated total F% = 93.6 ± 14 vs. the true F% of 100).
- Computer simulation
- Pharmacologic data
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology (medical)