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A Pharmacometric Approach to Investigate the Impact of Methylxanthine Abstinence and Caffeine Consumption on CYP1A2 Activity

This study aimed to investigate the impact of methylxanthine abstinence (MA) periods on CYP1A2 activity in individuals with varying levels of caffeine consumption through development of a population pharmacokinetic model of caffeine and its major metabolite paraxanthine. This study developed and evaluated a mixed-effects pharmacokinetic model for caffeine and paraxanthine concentration-time data derived from a sequential single-dose cross-over study in healthy male volunteers (n = 30) who received oral 100 mg caffeine doses. Participants received caffeine with and without a MA period. Participants were classified as low (0–100 mg/d), medium (100–200 mg/d), or high (>200 mg/d) caffeine consumers (LCCs, MCCs, or HCCs, respectively). All caffeine and paraxanthine concentration-time data were simultaneously modeled. Caffeine pharmacokinetics was described by a two-compartment model with first-order absorption and two first-order elimination pathways. Paraxanthine was described by a one-compartment model with first-order absorption and elimination. Among LCCs (n = 16) and MCCs (n = 9), there was no difference in the mean (95% confidence interval) total apparent caffeine clearance (CL) between the MA period [LCCs: 6.88 (5.61–8.16 l/h); MCCs: 10.09 (7.57–12.60 l/h)] versus the no MA period [LCCs: 6.22 (4.97–7.46 l/h); MCCs: 9.68 (7.12–12.24 l/h)]. The mean CL among HCCs (n = 5) was considerably higher in the MA period [10.48 (5.62–15.33 l/h)] compared with the no MA period [6.30 (3.40–9.20 l/h)] (P < 0.05). The decrease in CL in the no MA period among HCC appears to be due to alternative caffeine elimination pathways, rather than CYP1A2.