Flouvat B, Leneveu A, Fitoussi S, Delhotal-Landes B, Gendron A
Laboratoire de Toxicologie, Hôpital Ambroise Paré, Rueil-Malmaison, France.
Int J Clin Pharmacol Ther. 2004 Jan;42(1):50-7. doi: 10.5414/cpp42050.
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.
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.
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.
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.
已研发出一种新型即用型对乙酰氨基酚注射液（必理通10mg/ml），无需预先复溶。本研究的目的是确定静脉输注0.5g和1g必理通15分钟后对乙酰氨基酚的血药浓度曲线，并证明1g必理通剂量与市售注射用参比制剂丙帕他莫2g（普罗达非林2g，相当于1g对乙酰氨基酚）之间的生物等效性。次要目的是评估局部耐受性以及临床和生物学安全性。
本研究根据开放标签、随机、单剂量、3期交叉设计，在24名健康男性志愿者中进行，各剂量之间有1周的洗脱期。在每次给药前以及每次输注开始后的24小时内的18个时间点采集血样。采用经过验证的配有紫外检测的高效液相色谱法测定对乙酰氨基酚的血清浓度。根据血药浓度-时间数据，进行非房室药代动力学分析，以计算Cmax、tmax、AUC(inf)、t(1/2)、MRT、Cl(T)和Vd。对经对数转换的AUC(inf)和Cmax进行生物等效性检验。使用从0（无）到3（严重）的4级分类量表评估输注部位的局部疼痛强度。通过体格检查、生命体征和心电图测量以及包括血液学和生物化学在内的实验室检查评估临床和生物学安全性。
输注0.5g和1g新型对乙酰氨基酚溶液后，C(max)和AUC(inf)与剂量成比例增加。将剂量校正为1g对乙酰氨基酚后，AUC比值的平均（±标准差）Cmax比值分别为0.98±0.24和0.94±0.08。两种对乙酰氨基酚剂量的t(max)相同，t(1/2)、MRT、Cl(T)和V(d)的90%置信区间在可接受区间0.8 - 1.25内。新溶液（必理通1g）与市售溶液（丙帕他莫2g）比值的计算90%置信区间，C(max)为1.11 - 1.31（点估计值1.20），AUC(inf)为1.10 - 1.16（点估计值1.13）。这些值在Cmax的0.75至1.33和AUC(inf)的0.80 - 1.25的可接受生物等效性区间内。应用部位疾病是最常观察到的不良事件，但与丙帕他莫（20%）相比，必理通治疗后受试者报告的输注部位局部疼痛较少（2%）。三种治疗的临床和生物学安全性良好且相当。
静脉注射0.5g和1g对乙酰氨基酚溶液后，对乙酰氨基酚的药代动力学呈线性。所有结果表明，以10mg/ml必理通形式给药的1g对乙酰氨基酚与2g丙帕他莫生物等效，且局部安全性更好。
