Bioequivalence and Safety of Twice‐Daily Sustained‐Release Paracetamol (Acetaminophen) Compared With 3‐ and 4‐Times‐Daily Paracetamol: A Repeat‐Dose, Crossover Pharmacokinetic Study in Healthy Volunteers

Abstract

Twice‐daily sustained‐release (SR) paracetamol (acetaminophen) offers convenient administration to chronic users. This study investigated at steady state (during the last 24 hours of a 3‐day dosing period) the pharmacokinetics, bioequivalence, and safety of twice‐daily SR paracetamol compared with extended‐release (ER) and immediate‐release (IR) paracetamol. In this open‐label, randomized, multidose, 3‐way crossover study, 28 healthy subjects received paracetamol SR (2 × 1000 mg twice daily), ER (2 × 665 mg 3 times daily), and IR (2 × 500 mg 4 times daily). At steady state, twice‐daily SR paracetamol was bioequivalent to ER and IR paracetamol. The 90% confidence intervals for the ratios of geometric means were within the acceptance interval for SR/ER paracetamol (AUC0–t, 0.973–1.033; AUC0–24, 0.974–1.034; AUC0–∞, 0.948–1.011; Cmax, 1.082–1.212; Cav, 1.011–1.106) and SR/IR paracetamol (AUC0–t, 0.969–1.029; AUC0–24, 0.968–1.027; AUC0–∞, 0.963–1.026; Cmax, 0.902–1.010; Cav, 1.004–1.098). Given twice daily, the SR formulation demonstrated SR properties as expected. Mean time at or above a 4 μg/mL plasma concentration of paracetamol from 2 daily doses of the SR formulation was significantly longer than that from 4 daily doses of IR paracetamol. SR formulation also had a greater Tmax, a longer half‐life, and lower Cmin compared with ER and IR paracetamol. All formulations were well tolerated.

Endoscopic comparison of gastroduodenal injury with over-the-counter doses of new fast-dissolving ibuprofen and paracetamol formulations: a randomized, placebo-controlled, 4-way crossover clinical trial

“…Results in that regard provided reassurance of the gastric safety of FD-APAP and indicate that the risk of elevated liver enzyme levels with the FD formulation of APAP is similar to that previously reported with standard APAP formulations 25 , 26 as well as with sustained-release paracetamol. 27 A previous study of paracetamol sodium bicarbonate, which is absorbed more quickly than standard paracetamol, found it to be well tolerated with no AEs that were considered treatment related; this study did not include endoscopic assessments of mucosal damage or routine liver enzyme monitoring, but no serious AEs were reported. 28 …”