OBJECTIVE: A new twice daily sustained-release (SR) paracetamol formulation was developed to improve convenience and enhance patient compliance for treatment of pain from chronic diseases. This research aimed to evaluate bioavailability and compare pharmacokinetic (PK) properties of the new SR paracetamol formulation (2x1,000 mg) with those of immediate-release (IR) paracetamol (2x500 mg) and existing extended-release (ER) paracetamol (2x665 mg). METHODS: Two randomized, single-dose, 4-way crossover studies were conducted. A total of 28 healthy male and female volunteers participated in each study. The relative bioavailability, partial extent of absorption, overall elimination, food effect, and safety were evaluated. RESULTS: The estimates of relative bioavailability of new SR with IR formulation based on dose-adjusted AUC0-inf were 91% (0.86-0.96) for the fasted state and 99% (0.95-1.02) for the fed state, while these estimates comparing new SR with ER formulation were 99% (0.96-1.03) in the fasted state and 98% (0.95-1.02) in the fed state. The accumulated mean time period at or above the minimal therapeutic plasma paracetamol concentration for the new SR was from 90% to 112% longer than that of the IR formulation, in fasted and fed state, respectively. Food significantly increased Cmax of SR formulation, with ratios fast vs. fed 0.79 (p<0.0001) and 0.77 (p<0.0001) in study I and II, respectively. CONCLUSIONS: The new SR formulation was well absorbed, with more than 90% relative bioavailability as compared to the currently marketed IR and ER products and better sustained-release PK characteristics, which make it suitable for twice-daily paracetamol treatment.
RCT Entities:
OBJECTIVE: A new twice daily sustained-release (SR) paracetamol formulation was developed to improve convenience and enhance patient compliance for treatment of pain from chronic diseases. This research aimed to evaluate bioavailability and compare pharmacokinetic (PK) properties of the new SRparacetamol formulation (2x1,000 mg) with those of immediate-release (IR) paracetamol (2x500 mg) and existing extended-release (ER) paracetamol (2x665 mg). METHODS: Two randomized, single-dose, 4-way crossover studies were conducted. A total of 28 healthy male and female volunteers participated in each study. The relative bioavailability, partial extent of absorption, overall elimination, food effect, and safety were evaluated. RESULTS: The estimates of relative bioavailability of new SR with IR formulation based on dose-adjusted AUC0-inf were 91% (0.86-0.96) for the fasted state and 99% (0.95-1.02) for the fed state, while these estimates comparing new SR with ER formulation were 99% (0.96-1.03) in the fasted state and 98% (0.95-1.02) in the fed state. The accumulated mean time period at or above the minimal therapeutic plasma paracetamol concentration for the new SR was from 90% to 112% longer than that of the IR formulation, in fasted and fed state, respectively. Food significantly increased Cmax of SR formulation, with ratios fast vs. fed 0.79 (p<0.0001) and 0.77 (p<0.0001) in study I and II, respectively. CONCLUSIONS: The new SR formulation was well absorbed, with more than 90% relative bioavailability as compared to the currently marketed IR and ER products and better sustained-release PK characteristics, which make it suitable for twice-daily paracetamol treatment.