Selection of 12‐Hour Sustained‐Release Acetaminophen (Paracetamol) Formulation Through Comparison of Pharmacokinetic Profiles of 4 Sustained‐Release Prototype Formulations and Standard Acetaminophen Formulation: An Open‐Label, Randomized, Proof‐of‐Principle Pharmacokinetic Study

Abstract

Acetaminophen (APAP; paracetamol), a widely used analgesic and antipyretic, is available in modified‐release and immediate‐release (IR) formulations requiring 3‐ or 4‐times‐daily dosing. This phase 1 open‐label crossover study compared pharmacokinetic profiles of single 2000‐mg doses of 4 different sustained‐release (SR) formulations of APAP (designed to allow twice‐daily dosing) against two 1000‐mg doses (taken 6 hours apart) of standard IR APAP in 14 healthy volunteers. The primary end point was duration of time that plasma APAP concentration exceeded a plasma concentration (TC) of 4 μg/mL. Of the 4 SR APAP formulations studied, a single 2000‐mg dose of a bilayer SR formulation had the longest mean TC>4μg/mL (8.1 hours), similar to that of 2 doses of IR APAP (8.3 hours). Mean TC>4μg/mL was 7.3 hours with a single‐layer SR APAP, 7.5 hours with another single‐layer SR APAP formulation using a different excipient, and 7.1 hours with an enteric‐coated SR APAP coupled with a fast‐dissolving IR APAP. Secondary pharmacokinetic analyses showed a similar extent of absorption and lower peak concentration for the bilayer SR formulation compared with IR APAP. Adverse events were all mild. Based on these results, the bilayer SR APAP formulation was selected for further development.

Prolonged use of paracetamol and the prescribing patterns on rehabilitation facilities

“…Several risk factors of ageing influence paracetamol pharmacokinetics such as absorption, distribution, metabolism and elimination even at the daily recommended doses (Mian et al, 2018; Yue & Liu, 2018). Decreased clearance of medications in older people has been reported in the literature, which may cause paracetamol toxicity at the daily recommended dose (Mian et al, 2018; Yue & Liu, 2018). Older age alone is not responsible for changes in paracetamol pharmacokinetics.…”

“…Although the frequency of SRP administration is less in this population compared to IRP, SRP may be a preferred option for the elderly to reduce the daily dosage while still providing continuous analgesia (Yue & Liu, 2018). Furthermore, the use of SRP can enhance compliance and improve pain management by preventing accidental overdose, as well as avoiding complications that may be caused by decreased clearance of the medication (Yue & Liu, 2018). A proportion of patients in both the IRP and SRP groups received more than the daily recommended dose (i.e.…”

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

“…The tubes were frozen at approximately −20°C within 1 hour of sampling and sent to the clinical laboratory (Celerion, Lincoln, Nebraska) for processing and analysis. Plasma samples were analyzed by validated methods, as described in the accompanying work by Yue et al …”

“…The tubes were frozen at approximately −20°C within 1 hour of sampling and sent to the clinical laboratory (Celerion, Lincoln, Nebraska) for processing and analysis. Plasma samples were analyzed by validated methods, as described in the accompanying work by Yue et al 13 The primary PK outcome was the duration of time for which plasma acetaminophen concentration was at or above 4 μg/mL (T Cࣙ4μg/mL ) during the 18-hour blood sampling period. Previous studies, primarily conducted in febrile children, have indirectly suggested that the minimum acetaminophen concentration for a therapeutic effect lies between 3 and 5 μg/mL, 14,15 and the United Kingdom Over-the-Counter monograph for acetaminophen recognizes a threshold of 3 to 5 μg as the minimal concentration for provision of analgesia.…”

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

“…Validated methods were used to analyze plasma samples. 13 High-performance liquid chromatographymass spectrometry was used to quantify plasma concentrations of paracetamol in an assay developed by Celerion (Lincoln, Nebraska). Liquid-liquid extraction was performed using methyl tertbutyl ether as the extraction solvent.…”