Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects

Abstract

Objectives: A new, ready-to-use solution for injection of paracetamol (Perfalgan 10 mg/ml) without previous reconstitution has been developed. The aim of the study was to determine the serum concentration profiles of paracetamol after 15 min infusion of Perfalgan 0.5 g and 1 g doses and to demonstrate the bioequivalence between Perfalgan 1 g dose and a marketed reference formulation for injection, propacetamol 2 g (Pro-Dafalgan 2 g) equivalent to 1 g of paracetamol. The secondary objective was to evaluate local tolerance, and clinical and biological safety.

Methods: The study was performed in 24 healthy, male volunteers, according to an open-label, randomized, single-dose, 3-period crossover design, with a 1-week washout period between the doses. Blood samples were taken prior to each administration and at 18 time points within the 24-hour period following the beginning of each infusion. Serum concentrations of paracetamol were determined by validated high-performance liquid chromatography with UV detection. From serum concentration-time data, a non-compartmental pharmacokinetic analysis was performed to calculate Cmax, tmax, AUC(inf), t(1/2), MRT, Cl(T) and Vd. Log-transformed AUC(inf) and Cmax were tested for bioequivalence. The local pain intensity at infusion site was assessed using a 4-point categorical scale from 0 (none) to 3 (severe). The clinical and biological safety was evaluated by physical examination with measurements of vital signs and ECG and laboratory tests including hematology and biochemistry.

Results: After infusion of 0.5 g and I g of the new paracetamol solution, C(max) and AUC(inf) increased proportionally with dosage. After dose correction to 1 g of paracetamol, the mean (+/- SD) Cmax ratio was 0.98 +/- 0.24 and 0.94 +/- 0.08 for AUC ratio. Identical t(max) was observed for the 2 paracetamol dosages and 90% confidence intervals for t(1/2), MRT, Cl(T) and V(d) were within the acceptable interval 0.8-1.25. The calculated 90% confidence intervals of the new solution (Perfalgan 1 g) to marketed solution (propacetamol 2 g) ratios were 1.11-1.31 (point estimate 1.20) for C(max) and 1.10-1.16 (point estimate 1.13) for AUC(inf). These values were within the acceptable bioequivalence intervals of 0.75 to 1.33 for Cmax and 0.80-1.25 for AUC(inf). Application site disorders were the most frequently observed adverse events but local pain at infusion site was less reported by subjects after Perfalgan (2%) compared to propacetamol (20%). The clinical and biological safety was good and equivalent for the 3 treatments.

Conclusion: After administration of paracetamol solution for injection 0.5 g and 1 g, the pharmacokinetics of paracetamol is linear. All results indicate that 1 g of paracetamol administered as Perfalgan 10 mg/ml is bioequivalent to propacetamol 2 g with a better local safety.