Fig. 1

(A) Reported (plots) and estimated (lines) plasma concentrations of caffeine and paraxanthine in male volunteers administered single oral doses of 100 mg caffeine, and (B) measured (plots) and estimated (lines) concentrations of caffeine and paraxanthine in a female patient who took an oral overdose of 5900 mg caffeine. (A) Plasma concentrations of caffeine (closed symbols) and paraxanthine (open symbols) were taken from the literature (circles, from 4 Japanese volunteers [3]; triangles, from 30 Caucasian volunteers [4]). The plasma concentrations of caffeine (solid line) and paraxanthine (dash-dot line) estimated using the current simplified PBPK model and the estimated caffeine concentrations for virtual Japanese (dashed line) and Causation (dotted line) populations generated by the Simcyp simulator are also shown. (B) Measured plasma concentrations of caffeine (closed squares) and paraxanthine (open squares) in a patient who took a single oral caffeine overdose of 5900 mg. Solid and dashed lines are estimated plasma caffeine concentrations generated by the current simplified PBPK model and by the Simcyp simulator, respectively. The dash-dot line shows the PBPK-modeled paraxanthine concentrations