The comparative pharmacokinetics of modified-release and immediate-release paracetamol in a simulated overdose model

Background: Panadol Extend (PEx) is an over-the-counter, modified-release formulation of paracetamol. Each 665 mg tablet contains 69% slow-release and 31% immediate-release paracetamol. In simulated human overdose, PEx exhibits lower and later peak serum concentrations and a lower area-under-the-curve (AUC) than comparable doses of immediate-release paracetamol (APAP-IR). The lower AUC might result from incomplete absorption of paracetamol or simultaneous metabolism with absorption. Objective: Do differences in pharmacokinetics (PK) between PEx and APAP-IR result from incomplete absorption or simultaneous absorption and metabolism of paracetamol? Methods: Cross-over study of 80 mg/kg of PEx or APAP-IR in nine volunteers. Serial plasma paracetamol, glucuronide, sulphate and cysteine metabolite estimates performed over 24 h. Peak plasma concentration (Cmax), AUC((0-infinity)), time to peak concentration (Tmax) and elimination half-life (t(1/2)) were compared. Results: PEx exhibited significantly lower paracetamol Cmax (252.33 mu mol/L vs 565.56 mu mol/L, P = 0.0421), AUC((0-infinity)) (2133 mu mol/h/L vs 2637 mu mol/h/L, P = 0.0004) and delayed Tmax (2.889 h vs 1.389 h, P = 0.0189) than APAP-IR. Sulphate metabolite PK parameters for both preparations, PEx vs APAP-IR, showed similar AUC((0-infinity)) (1369 mu mol/h/L vs 1089 mu mol/h/L), Tmax (3.889 h vs 4.444 h), Cmax (95.889 mu mol/L vs 95.889 mu mol/L) and t(1/2) (3.895 h vs 3.810 h). Glucuronide metabolite concentrations revealed that PEx produced a lower Cmax (257.44 mu mol/L vs 335.22 mu mol/L, P = 0.0239) than APAP-IR. All other pharmacokinetic parameters were similar. Cysteine metabolite was not detected. Conclusion: There were minor differences between the PK parameters of the two major paracetamol metabolites of these two preparations in simulated overdose. The variability in paracetamol AUC seen between the two preparations in moderate overdose might be explained by concurrent metabolism of paracetamol during slower absorption with PEx.