Validation of a semi-physiological model for caffeine in healthy subjects and cirrhotic patients

Abstract The objective of this paper was to validate a previously developed semi physiological model to simulate bioequivalence trials of drug products. The aim of the model was to ascertain whether the measurement of the metabolite concentration–time profiles would provide any additional information in bioequivalence studies (Fernandez-Teruel et al., 2009a,b; Navarro-Fontestad et al., 2010). The semi-physiological model implemented in NONMEM VI was used to simulate caffeine and its main metabolite plasma levels using caffeine parameters from bibliography. Data from 3 bioequivalence studies in healthy subjects at 3 different doses (100, 175 and 400 mg of caffeine) and one study in cirrhotic patients (200 or 250 mg) were used. The first aim was to adapt the previous semi-physiological model for caffeine, showing the hepatic metabolism with one main metabolite, paraxanthine. The second aim was to validate the model by comparison of the simulated plasma levels of parent drug and metabolite to the experimental data. The simulations have shown that the proposed semi-physiological model was able to reproduce adequately the pharmacokinetic behavior of caffeine and paraxanthine in both healthy subjects and cirrhotic patients at all the assayed doses. Therefore, the model could be used to simulate plasma concentrations vs . time of drugs with the same pharmacokinetic scheme as caffeine, as long as their population parameters are known, and it could be useful for bioequivalence trial simulation of drugs that undergo hepatic metabolism with a single main metabolite.