Kerbusch T, Huitema A D, Ouwerkerk J, Keizer H J, Mathôt R A, Schellens J H, Beijnen J H
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Br J Clin Pharmacol. 2000 Jun;49(6):555-61. doi: 10.1046/j.1365-2125.2000.00217.x.
This study investigated the population pharmacokinetics of ifosfamide in 15 patients treated for soft tissue sarcoma with 9 or 12 g m-2 ifosfamide by means of a 72 h continuous i.v. infusion.
A model was developed using nonlinear mixed effects modelling (NONMEM) to describe the nonlinear pharmacokinetics of ifosfamide by linking the ifosfamide plasma concentrations to the extent of the autoinduction.
The proposed model revealed the effect of autoinduction on the disposition of ifosfamide. The initial clearance, volume of distribution, rate constant for enzyme degradation, induction half-life of the enzyme and the ifosfamide concentration at 50% of the maximum inhibition of enzyme degradation were estimated at 2.94 +/- 0.27 l h-1, 43.5 +/- 2.9 l, 0.0546 +/- 0. 0078 h-1, 12.7 h and 30.7 +/- 4.8 microM, respectively. Interindividual variabilities of initial clearance, volume of distribution, rate constant for enzyme degradation were 24.5, 23.4 and 22.7%, respectively. Proportional and additive variability not explained by the model were 13.6% and 0.0763 microM, respectively.
The absence of a lag time for the autoinduction of ifosfamide metabolism could be the result of an immediate inhibition of the enzymatic degradation of CYP3A4 by ifosfamide. By application of the autoinduction model individual pharmacokinetic profiles of patients were described with adequate precision. This model may therefore be used in the future development of a model to individualize dose selection in patients.
本研究通过72小时持续静脉输注，对15例接受9或12 g/m²异环磷酰胺治疗软组织肉瘤的患者进行了异环磷酰胺的群体药代动力学研究。
采用非线性混合效应模型（NONMEM）建立模型，通过将异环磷酰胺血浆浓度与自身诱导程度联系起来，描述异环磷酰胺的非线性药代动力学。
所提出的模型揭示了自身诱导对异环磷酰胺处置的影响。初始清除率、分布容积、酶降解速率常数、酶诱导半衰期以及酶降解最大抑制50%时的异环磷酰胺浓度分别估计为2.94±0.27 l/h、43.5±2.9 l、0.0546±0.0078 h⁻¹、12.7小时和30.7±4.8 μM。初始清除率、分布容积、酶降解速率常数的个体间变异分别为24.5%、23.4%和22.7%。模型未解释的比例变异和加性变异分别为13.6%和0.0763 μM。
异环磷酰胺代谢自身诱导无滞后时间可能是异环磷酰胺对CYP3A4酶促降解立即抑制的结果。通过应用自身诱导模型，能够以足够的精度描述患者的个体药代动力学特征。因此，该模型可用于未来个体化剂量选择模型的开发。
