Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after
single intravenous infusion in healthy subjects.
Int J Clin Pharmacol Ther. 2004 Jan; 42(1):[Link]
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.
Authors+Show Affiliations
Flouvat B
Leneveu A
Fitoussi S
Delhotal-Landes B
Gendron A
MeSH
AcetaminophenAdultAnalgesics, Non-NarcoticArea Under CurveBiological AvailabilityChemistry,
PharmaceuticalChromatography, High Pressure LiquidCross-Over StudiesDrug Administration
ScheduleFranceHalf-LifeHumansInfusions, IntravenousInjectionsMaleNeedlesPainPharmaceutical
SolutionsSpectrophotometry, UltravioletTherapeutic EquivalencyTime FactorsWounds, Penetrating
Pub Type(s)
Clinical Trial
Comparative Study
Journal Article
Randomized Controlled Trial
Language
eng
PubMed ID
14756388