Effect of Caffeine on the Bioavailability and Pharmacokinetics of an Acetylsalicylic Acid-Paracetamol Combination: Results of a Phase I Study

Introduction: Caffeine is used as an adjuvant in analgesic combinations to enhance their efficacy. The present study aimed to determine the effect of caffeine on the pharmacokinetics of acetylsalicylic acid (ASA) and paracetamol when used as a fixed-dose ASA/paracetamol/caffeine combination. Methods: In this single-centre, two-way, cross-over phase I study, volunteers fasted overnight (>= 12 h) and randomly received single oral doses of 250 mg ASA/200 mg paracetamol (reference) or 250 mg ASA/200 mg paracetamol/50 mg caffeine (test). Blood samples were collected before and up to 24 h after dosing. The primary end points were the area under the concentration-time curve from zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C-max) for ASA, salicylic acid (SA) and paracetamol from the two combinations. The main secondary end points were AUC(0-infinity) and C-max of caffeine and time to reach C-max (t(max)) of all drugs. Results: Eighteen healthy male volunteers (32.5 +/- 10.5 years) participated in the study. The geometric means of C-max for ASA, SA and paracetamol were similar in the test (3.71, 15.8 and 2.42 mu g/ml, respectively) and reference groups (3.89, 15.8, 2.42 mu g/ml, respectively). The geometric mean of AUC(0-infinity) for ASA, SA and paracetamol from the test combination was 2.86, 60.5 and 7.68 mu g h/ml, respectively, and that for the reference was 2.96, 59.1 and 7.77 mu g h/ml, respectively. The medians of t(max) for ASA, SA and paracetamol were similar between the two groups. The point estimates for the ratios of AUC(0-infinity) and C-max for test versus reference regarding ASA, SA and paracetamol were within the predefined equivalence limits. The two treatments were well tolerated. Conclusion: Caffeine did not affect the pharmacokinetics of ASA and paracetamol when used as an adjuvant in ASA/paracetamol fixed-dose combination under fasting conditions, suggesting that caffeine enhances the analgesic efficacy of these drugs by pharmacodynamic rather than pharmacokinetic interactions.