Caffeine is primarily metabolized in the liver by the cytochrome P450 enzyme CYP1A2, the variability of which is influenced by genetic polymorphisms (such as CYP1A21F (rs762551)) and lifestyle factors. The aim of this study was to develop a population pharmacokinetic (PopPK) one-compartment model using R (N = 1000) to assess the influence of CYP1A21F, smoking, and oral contraceptive (OC) use on caffeine exposure. The mean clearance (CL) of caffeine was 2.59 ± 0.99 L/h in nonsmoking women with the C-allele and OC use and 8.31 ± 2.76 L/h in smokers with the A/A genotype. In nonsmoking women with the C-allele and OC use, the plasma half-life (t½) was 3.5-fold longer than that in smokers with the A/A genotype. The 200 mg twice-daily dosing regimen resulted in significant accumulation, exceeding the established safety threshold (Css,max > 10 mg/L) and carrying a risk of developing anxiety, restlessness, and cardiovascular stimulation. The model is able to quantify the interactions between genetics and lifestyle, providing a framework for personalized caffeine intake.
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