A double-blind, randomized, two-part, two-period crossover study to evaluate the pharmacokinetics of caffeine versus d9-caffeine in healthy subjects

The deuterium kinetic isotope effect has been used to affect the cytochrome P450 metabolism of the deuterated versions of substances. This study compares the pharmacokinetics of caffeine, a Generally Recognized As Safe food and beverage ingredient, versus d9-caffeine, a potential caffeine alternative, and their respective metabolites at two dose levels in 20 healthy adults. A single dose of 50 mg or 250 mg of caffeine, or a molar-equivalent dose of d9-caffeine, were orally administered in solution with blood samples collected for up to 48 h post-dose. Plasma concentrations of parent and metabolites were analyzed using validated LC-MS/MS methods. Both d9-caffeine and caffeine were rapidly absorbed; however, d9-caffeine exhibited a higher (ca. 29%–43%) Cmax and 4-5-fold higher AUClast than caffeine, and lower Cmax, lower AUClast, and a 5-10-fold reduction in the relative exposure to the active metabolites of caffeine. Results were consistent in normal and rapid metabolizers, and both substances were well tolerated. •d9-Caffeine produced a similar Tmax, 28%–44% higher Cmax, and a 4-fold greater AUC0-48h than a similar dose of caffeine.•d9-Caffeine demonstrated a 5–10-fold lower relative exposure to the active metabolites of caffeine.•Exposure to caffeine and d9-caffeine was 32%-62% and 0-18% higher, respectively, in normal metabolizers versus hyperinducers.•Metabolizer phenotype had a lesser impact on exposure to d9-caffeine, suggesting a lower role for CYP1A2 in its elimination.•Both products were well tolerated. No adverse events for insomnia were reported during the study.