Interrelations between plasma caffeine concentrations and neurobehavioural effects in healthy volunteers: model analysis using NONMEM

Abstract

The objective was to develop a population pharmacokinetic-pharmacodynamic model of caffeine's psychomotor effects in healthy, non-habitual users of caffeine. Twenty Chinese males each received a single dose of 250 mg of caffeine orally. Plasma concentrations of caffeine were determined at various times within 24 h after dosing. The subjects' psychomotor performance was evaluated before and at various times after dosing by a test battery consisting of oculomotor assessment (saccadic velocity) as well as the computerised Swedish Performance Evaluation System. Nonlinear mixed-effects modelling to analyse the pharmacokinetic-pharmacodynamic relationships was performed using NONMEM. Model robustness was assessed by a nonparametric bootstrap. The results showed that caffeine caused significant improvements in psychomotor functioning. The time course of these effects was best described by pharmacokinetic/pharmacodynamic models involving an effect compartment. The transfer half-lives between plasma and effect site for different domains of psychomotor functioning were in the range 24.8-49.5 min. Evaluation of the final models showed close agreement between pairs of bootstrapped and final model parameter estimates (all differences<10%). These results provided the first suggestive evidence that caffeine effects on psychomotor performance occur after some time delay relative to changes in plasma caffeine concentration. The models for the neurobehavioural tests provided similar transfer half-lives between plasma and effect site.

Population Pharmacokinetic Pharmacodynamic Modeling of Caffeine Using Visual Analogue Scales

“…A different rate parameter was estimated for each occasion to avoid the use of interoccasion variability (IOV) as the normality assumption around the rate parameter was not deemed appropriate. Pharmacokinetic parameters of caffeine estimated in the current model are in agreement with previous reports [3] [5] [10]. Based on estimated apparent elimination rate constant (K), population half-life was determined to be approximately 4.3 hours which is in the range consistent with reported values [2] [10].…”

“…Therefore, as a similar approach to modeling other pharmacodynamic properties of caffeine has been explored by others, we chose to fix Ke0 to 1.73, a value which was reported by a previous publication [2] to allow for a more stable model. A local grid search for Ke0 was conducted by varying the Ke0 value between 1 -2 (range based on previously published values for Ke0 [3] [5]) and change in objective function was recorded. PD parameters modeled include E0 (baseline response on VAS) on each occasion and slope ( Table 2).…”

“…energy drinks, colas) for the same purpose. Pharmacodynamic effects of caffeine have been evaluated using various assessments such as reflex speed [3], stylus tapping [4], or through blood pressure changes [5]. Visual analogue scores (VAS) are widely used in behavioral research and are particularly attractive because of simple administration of the method and the effective use of VAS for evaluation of the caffeine pharmacodynamics has been reported [6].…”

Skill execution and sleep deprivation: effects of acute caffeine or creatine supplementation - a randomized placebo-controlled trial

“…responders and non-responders). The absorption of caffeine in plasma following consumption has been estimated at between 30 and 90 min with half life of several hours [16], so the time between consumption and testing (90 min) in this study may have been too long to see all effects of differing caffeine dose, or any effect on non-sleep deprived performance. Nonetheless, at 90 min there was still clear evidence of a reduction in the effect of sleep deprivation on the skill measured and no evidence this was different between the 1 and 5 mg/kg dose.…”

“…Creatine does however readily cross the blood brain barrier and chronic systemic loading does appear to increase brain stores [13,14]. Acute doses of caffeine appear most beneficial at around 30-90 min prior performance [16] and while the timing of an acute dose of creatine has yet to be determined, it appears to take at least an hour for absorption into the bloodstream [17-19]. …”