Evaluation of a 12‐Hour Sustained‐Release Acetaminophen (Paracetamol) Formulation: A Randomized, 3‐Way Crossover Pharmacokinetic and Safety Study in Healthy Volunteers

Acetaminophen (paracetamol) is a first‐line treatment for mild and moderate pain. A twice‐daily sustained‐release (SR) formulation may be more convenient for chronic users than standard immediate‐release (IR) acetaminophen. This randomized, 3‐way crossover study evaluated pharmacokinetics and safety of single‐dose 1500‐ and 2000‐mg SR acetaminophen formulations and 2 doses of IR acetaminophen 1000 mg given 6 hours apart in healthy adults (n = 14). Primary outcome was time that plasma acetaminophen concentration was ≥4 μg/mL (T(C≥4μg/mL)). Key secondary outcomes were area under the plasma concentration–time curve (AUC) from time 0 to time t, when plasma acetaminophen was detectable (AUC(0–t)), AUC from 0 to infinity (AUC(0–inf)), and maximum plasma acetaminophen concentration (C(max)). T(C≥4μg/mL) from 2000‐mg SR acetaminophen was similar to that from 2 doses of IR acetaminophen, whereas T(C≥4μg/mL) for 1500‐mg SR acetaminophen was significantly shorter than that for IR acetaminophen (P = .004). The extent of acetaminophen absorption from 2000‐mg SR and 2 doses of the IR formulation was similar and within bioequivalence limits with regard to AUC(0–12), AUC(0–t), and AUC(0–inf). The extent of acetaminophen absorption from 1500‐mg SR was significantly lower than that from IR acetaminophen. The 2000‐mg SR represents a potential candidate formulation for 12‐hour dosing with acetaminophen.