Caffeine is a commonly ingested psychoactive substance which affects alertness and cognition. A\nclinical study was conducted to determine the effect of orally ingested caffeine on visual analogue\nscale (VAS) responses in healthy, moderate caffeine-consuming volunteers through the use of\npopulation pharmacokinetic-pharmacodynamic (PK-PD) modeling. Twelve subjects were recruited\nfor a three-period cross-over study which utilized caffeine containing beverages. Each visit\nincluded 8-hour blood plasma and VAS response collection for PK and PD assessment respectively.\nThe VAS used in the study, also called the caffeine analog scale, has been previously validated for\ncaffeine. Population PK-PD modeling was conducted with NONMEM 7.2. Simultaneous and sequential\nmodeling of PK-PD was attempted. Final model selection was based on parameter estimate\nprecision, diagnostic plots, and visual predictive check (VPC) plots. Results showed that a\none-compartment open model with first-order absorption and elimination best described the\npharmacokinetics of caffeine. Sequential PK-PD modeling was successful and an effect compartment\nmodel with linear slope and baseline parameter best described caffeine pharmacodynamics.\nDiagnostic plots showed no major bias and VPC plots showed agreement between observations\nand predictions. The model was able to link VAS responses to caffeine concentration in healthy\nvolunteers and may be useful in clinical trial simulations and design.
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