van Ruth Serge, Mathôt Ron A A, Sparidans Rolf W, Beijnen Jos H, Verwaal Vic J, Zoetmulder Frans A N
Department of Surgical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Clin Pharmacokinet. 2004;43(2):131-43. doi: 10.2165/00003088-200443020-00005.
During recent years, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin has been used for various malignancies.
To characterise the population pharmacokinetics and pharmacodynamics of mitomycin during HIPEC.
Forty-seven patients received mitomycin 35 mg/m2 intraperitoneally as a perfusion over 90 minutes. Mitomycin concentrations were determined in both the peritoneal perfusate and plasma. The observed concentration-time profiles were used to develop a population pharmacokinetic model using nonlinear mixed-effect modelling (NONMEM). The area under the plasma concentration-time curve (AUC) was related to the haematological toxicity.
Concentration-time profiles of mitomycin in perfusate and plasma were adequately described with one- and two-compartment models, respectively. The average volume of distribution of the perfusate compartment (V1) and rate constant from the perfusate to the systemic circulation (k12) were 4.5 +/- 1.1L and 0.014 +/- 0.003 min(-1), respectively (mean +/- SD, n = 47). The average volume of distribution of the central plasma compartment (V2), clearance from the central compartment (CL) and volume of distribution of the peripheral plasma compartment (V3) were 28 +/- 16L, 0.55 +/- 0.18 L/min and 36 +/- 8L, respectively. The relationship between the AUC in plasma and degree of leucopenia was described with a sigmoidal maximum-effect (Emax) model.
The pharmacokinetics of mitomycin during HIPEC could be fitted successfully to a multicompartment model. Relationships between plasma exposure and haematological toxicity were quantified. The developed pharmacokinetic-pharmacodynamic model can be used to simulate different dosage schemes in order to optimise mitomycin administration during HIPEC.
近年来，减瘤手术联合丝裂霉素热灌注腹腔化疗（HIPEC）已用于多种恶性肿瘤。
描述HIPEC期间丝裂霉素的群体药代动力学和药效学特征。
47例患者接受35mg/m²丝裂霉素腹腔内灌注90分钟。测定腹腔灌洗液和血浆中的丝裂霉素浓度。利用非线性混合效应建模（NONMEM），将观察到的浓度-时间曲线用于建立群体药代动力学模型。血浆浓度-时间曲线下面积（AUC）与血液学毒性相关。
丝裂霉素在灌洗液和血浆中的浓度-时间曲线分别用单室和双室模型进行了充分描述。灌洗液相室的平均分布容积（V1）和从灌洗液到体循环的速率常数（k12）分别为4.5±1.1L和0.014±0.003min⁻¹（均值±标准差，n = 47）。中央血浆相室的平均分布容积（V2）、中央室清除率（CL）和外周血浆相室的分布容积（V3）分别为28±16L、0.55±0.18L/min和36±8L。血浆AUC与白细胞减少程度之间的关系用S型最大效应（Emax）模型进行了描述。
HIPEC期间丝裂霉素的药代动力学可以成功地拟合到多室模型。血浆暴露与血液学毒性之间的关系得到了量化。所建立的药代动力学-药效学模型可用于模拟不同的给药方案，以优化HIPEC期间丝裂霉素的给药。
