Lortholary O, Tod M, Rizzo N, Padoin C, Biard O, Casassus P, Guillevin L, Petitjean O
Service de Médecine Interne, Hôpital Avicenne, Université Paris-Nord, Bobigny, France.
Antimicrob Agents Chemother. 1996 May;40(5):1242-7. doi: 10.1128/AAC.40.5.1242.
The teicoplanin pharmacokinetics (PK) of 30 febrile and severely neutropenic patients (polymorphonuclear count, < 500/mm3) with hematologic malignancies were compared with those determined for five healthy volunteers (HV). Neutropenic patients were given piperacillin combined with amikacin, and teicoplanin was added to the regimen the day fever developed in patients suspected of having a staphylococcal infection or 48 h later. Teicoplanin was given intravenously at a dosage of 6 mg/kg of body weight at 0, 12, and 24 h and once a day thereafter. Five to eleven blood samples per patient were collected. Teicoplanin concentrations were measured by liquid chromatography. A bicompartmental model was fitted to the data by a nonlinear mixed-effect-model approach. Multiple-linear regression analysis was applied in an attempt to correlate PK parameters to nine covariates. The mean trough concentrations of teicoplanin 48 h after the onset of treatment and 24 h after the last injection (last trough) +/- standard deviations were 8.8 +/- 4.1 and 17.5 +/- 13.5 mg/liter, respectively. A significant increase was noted in the mean rate of elimination clearance of teicoplanin in neutropenic patients compared with that of HV (0.86 versus 0.73 liter/h, P = 0.002), as was the case with rates of distribution clearance (5.89 versus 4.94 liter/h, P = 0.002); the mean half-life of distribution was significantly shorter in patients than in HV (0.43 versus 0.61 h, P = 0.002). In contrast, the volumes of the central compartment (ca. 5.8 liters for both groups), the volumes of distribution at steady state (HV, 37.6 liters; patients, 55.9 liters), and the elimination half-lives (HV, 39.6 h; patients, 52.7 h) were not significantly different between HV and neutropenic patients. Interindividual variabilities of rates of clearance (coefficient of variation [CV], 43%) and elimination half-lives (CV, 56%) were mainly explained by the variabilities among rates of creatinine clearance. Interindividual variabilities of the volumes of the central compartment (CV, 33%) and the volumes of distribution at steady state (CV = 51%) were correlated to interindividual variabilities among numbers of leukocytes and the ages of patients, respectively. On the basis of the population PK model of teicoplanin, simulations were made to optimize the dosing schedule. A supplemental 6 mg/kg dose of teicoplanin at 36 h resulted in a trough concentration at 48 h of 16.0 +/- 4.5 mg/liter, with only 7% of patients having a trough concentration of less than 10 mg/liter, compared with 46% of patients on the usual schedule.
将30例患有血液系统恶性肿瘤且发热、严重中性粒细胞减少（多形核细胞计数<500/mm³）的患者的替考拉宁药代动力学（PK）与5名健康志愿者（HV）的进行比较。中性粒细胞减少的患者接受哌拉西林联合阿米卡星治疗，在怀疑有葡萄球菌感染的患者发热当天或48小时后，在治疗方案中加入替考拉宁。替考拉宁以6mg/kg体重的剂量在0、12和24小时静脉注射，此后每天一次。每位患者采集5至11份血样。通过液相色谱法测量替考拉宁浓度。采用非线性混合效应模型方法将双室模型拟合到数据中。应用多元线性回归分析试图将PK参数与9个协变量相关联。治疗开始后48小时和最后一次注射后24小时（末次谷浓度）替考拉宁的平均谷浓度±标准差分别为8.8±4.1和17.5±13.5mg/L。与HV相比，中性粒细胞减少患者中替考拉宁的平均清除率显著增加（0.86对0.73L/h，P=0.002），分布清除率也是如此（5.89对4.94L/h，P=0.002）；患者的平均分布半衰期明显短于HV（0.43对0.61h，P=0.002）。相比之下，中央室容积（两组均约为5.8L）、稳态分布容积（HV为37.6L；患者为55.9L）和消除半衰期（HV为39.6h；患者为52.7h）在HV和中性粒细胞减少患者之间无显著差异。清除率的个体间变异性（变异系数[CV]，43%）和消除半衰期的个体间变异性（CV，56%）主要由肌酐清除率的变异性解释。中央室容积的个体间变异性（CV，33%）和稳态分布容积的个体间变异性（CV=51%）分别与白细胞数量和患者年龄的个体间变异性相关。基于替考拉宁的群体PK模型进行模拟以优化给药方案。在36小时补充6mg/kg剂量的替考拉宁，48小时时的谷浓度为16.0±4.5mg/L，只有7%的患者谷浓度低于10mg/L，而常规给药方案的患者为46%。
