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


CONCLUSIONS
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.
Flouvat
B
B
Laboratoire de Toxicologie, Hôpital Ambroise Paré, Rueil-Malmaison, France.
Leneveu
A
A
Fitoussi
S
S
Delhotal-Landes
B
B
Gendron
A
A
D000082:Acetaminophen / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005602:France; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007267:Injections; D008297:Male; D009339:Needles; D010146:Pain / Q000209:etiology; D019999:Pharmaceutical Solutions / Q000008:administration & dosage*; D013056:Spectrophotometry, Ultraviolet; D013810:Therapeutic Equivalency; D013997:Time Factors; D014950:Wounds, Penetrating
D018712:Analgesics, Non-Narcotic; D019999:Pharmaceutical Solutions; D000082:Acetaminophen; C063776:propacetamol