Palmer G M, Atkins M, Anderson B J, Smith K R, Culnane T J, McNally C M, Perkins E J, Chalkiadis G A, Hunt R W
Department of Paediatric Anaesthesia and Pain Management, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, VIC 3052, Australia.
Br J Anaesth. 2008 Oct;101(4):523-30. doi: 10.1093/bja/aen208. Epub 2008 Jul 15.
Pharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation.
Neonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28-32 weeks, 10 mg kg(-1); 32-36 weeks, 12.5 mg kg(-1); and > or =36 weeks, 15 mg kg(-1). A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time-concentration profiles using population modelling (NONMEM).
Fifty neonates, median (range) PMA 38.6 (32-45) weeks, mean (SD) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h(-1) 70 kg(-1) and volume of distribution (V) 76 (29.6%) litre 70 kg(-1). CL increased with PMA from 4.4 litre h(-1) 70 kg(-1) at 34 weeks to 6.3 litre h(-1) 70 kg(-1) at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 micromol litre(-1) associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre(-1) at steady state are predicted after 15 mg kg(-1) 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled.
The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.
据报道，对乙酰氨基酚的静脉前体药物（丙帕他莫）在新生儿重复给药后的药代动力学情况，而静脉注射对乙酰氨基酚制剂的数据较少。
来自重症监护病房的新生儿根据孕龄（PMA）每6小时按需静脉注射对乙酰氨基酚：28 - 32周，10 mg/kg；32 - 36周，12.5 mg/kg；≥36周，15 mg/kg。最多采集五份血样进行分析和肝功能测试（LFTs）。使用群体建模（NONMEM），采用一室线性处置模型（零级输入；一级消除）来描述时间 - 浓度曲线。
50名新生儿，PMA中位数（范围）为38.6（32 - 45）周，平均（标准差）体重2.9（0.7）kg，在中位数4天内平均接受15次给药，进行了189次血清对乙酰氨基酚和231次LFT测量。足月儿的标准化群体参数估计值为清除率（CL）5.24（变异系数30.5%）升·小时⁻¹·70kg⁻¹，分布容积（V）76（29.6%）升·70kg⁻¹。CL随PMA增加，从34周时的4.4升·小时⁻¹·70kg⁻¹增加到46周时的6.3升·小时⁻¹·70kg⁻¹。未结合高胆红素血症的存在与CL降低有关：胆红素水平150μmol/L时CL降低40%。对于PMA 40周的新生儿，每6小时静脉注射15mg/kg后，预测稳态时对乙酰氨基酚浓度在10至23mg/L之间。一名患者的丙氨酸转氨酶浓度增加两倍，其每日样本的肝酶分析有显著变化。
参数估计值与丙帕他莫所描述的相似。没有肝毒性的证据。未结合高胆红素血症影响CL，需要减少剂量。
