Woo Sukyung, Gardner Erin R, Chen Xiaohong, Ockers Sandra B, Baum Caitlin E, Sissung Tristan M, Price Douglas K, Frye Robin, Piekarz Richard L, Bates Susan E, Figg William D
Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2009 Feb 15;15(4):1496-503. doi: 10.1158/1078-0432.CCR-08-1215.
Romidepsin is a potent histone deacetylase inhibitor under clinical development. The objective of this study was to evaluate the effect of demographic, clinical, and pharmacogenetic covariates on the pharmacokinetics of romidepsin in patients with T-cell lymphoma.
Pharmacokinetic assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m2 of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLCO1B3, and ABCB1, all of which encode genes thought to be involved in romidepsin disposition.
A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9 L/h with between-patient variability of 37%. ABCB1 2677G>T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure.
The population pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population.
罗米地辛是一种正在临床开发的强效组蛋白脱乙酰酶抑制剂。本研究的目的是评估人口统计学、临床和药物遗传学协变量对罗米地辛在T细胞淋巴瘤患者体内药代动力学的影响。
对98名参加II期研究的患者进行了药代动力学评估，这些患者在第一个治疗周期的第1天接受14或18mg/m²的罗米地辛，静脉输注4小时。采用非线性混合效应建模方法进行群体建模，以探讨CYP3A4、CYP3A5、SLCO1B3和ABCB1基因多态性变异的影响，这些基因均被认为参与罗米地辛的处置过程。
具有线性动力学的二室模型能充分描述罗米地辛的处置过程。群体清除率为15.9L/h，患者间变异为37%。ABCB1 2677G>T/A变异等位基因倾向于清除率降低和组织分布容积减小，但这未得到统计学显著性支持。CYP3A4/5和SCLO1B3的基因变异对全身暴露无影响。
群体药代动力学分析表明罗米地辛药代动力学存在中度个体间变异性，且在该群体中没有与罗米地辛无法解释的药代动力学变异性相关的临床相关协变量。
