Lee Carlton K K, Rowinsky Eric K, Li Jing, Giles Francis, Moore Malcolm J, Hidalgo Manuel, Capparelli Edmund, Jolivet Jacques, Baker Sharyn D
Department of Oncology, Johns Hopkins University and Department of Pharmacy, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2158-65. doi: 10.1158/1078-0432.CCR-05-2249.
To develop and validate a population pharmacokinetic model for troxacitabine, a novel l-nucleoside analogue, administered by short infusion; to characterize clinical covariates that influence pharmacokinetic variability; and to design a dosage rate for continuous infusion administration to achieve low micromolar concentrations, which may be more efficacious than shorter infusions.
Plasma samples from 111 cancer patients receiving troxacitabine (0.12-12.5 mg/m(2)) as a 30-minute infusion in phase I trials were used to develop the model with NONMEM. Clinical covariates evaluated included creatinine clearance, body surface area, age, and sex. From the model, a troxacitabine dosage rate of 2.0 to 3.0 mg/m(2)/d was expected to achieve a target concentration of 0.1 micromol/L; plasma samples were obtained during the infusion from eight patients receiving troxacitabine as a 3-day infusion.
Troxacitabine pharmacokinetics were characterized by a three-compartment linear model. The mean value for systemic clearance [interindividual variability (CV%)] from the covariate-free model was 9.1 L/h (28%). Creatinine clearance and body surface area accounted for 36% of intersubject variation in clearance. Troxacitabine 2.0 mg/m(2)/d (n = 3) and 3.0 mg/m(2)/d (n = 5) for 3 days produced mean +/- SD end of infusion concentrations of 0.12 +/- 0.03 and 0.15 +/- 0.03 micromol/L, respectively.
Renal function and body surface area were identified as sources of troxacitabine pharmacokinetic variability. The population pharmacokinetic model model-derived dosage rates for continuous infusion administration successfully achieved predetermined target plasma concentrations. The present model may be used to optimize treatment with troxacitabine by developing a dosing strategy based on both renal function and body size.
建立并验证一种用于曲扎西他滨（一种新型左旋核苷类似物）的群体药代动力学模型，该药物通过短时间输注给药；确定影响药代动力学变异性的临床协变量；并设计一种连续输注给药的剂量率，以达到低微摩尔浓度，这可能比短时间输注更有效。
在I期试验中，从111例接受曲扎西他滨（0.12 - 12.5 mg/m²）30分钟输注的癌症患者中采集血浆样本，用于使用NONMEM建立模型。评估的临床协变量包括肌酐清除率、体表面积、年龄和性别。根据该模型，预计曲扎西他滨剂量率为2.0至3.0 mg/m²/d时可达到0.1微摩尔/升的目标浓度；在8例接受3天曲扎西他滨输注的患者输注期间采集血浆样本。
曲扎西他滨药代动力学特征为三室线性模型。无协变量模型的全身清除率平均值[个体间变异性（CV%）]为9.1 L/h（28%）。肌酐清除率和体表面积占清除率个体间变异的36%。曲扎西他滨2.0 mg/m²/d（n = 3）和3.0 mg/m²/d（n = 5）持续3天，输注结束时的平均±标准差浓度分别为0.12±0.03和0.15±0.03微摩尔/升。
肾功能和体表面积被确定为曲扎西他滨药代动力学变异性的来源。群体药代动力学模型得出的连续输注给药剂量率成功达到了预定的目标血浆浓度。本模型可用于通过基于肾功能和体型制定给药策略来优化曲扎西他滨的治疗。
