Application of population pharmacokinetic modeling in early clinical development of the anticancer agent E7820.

Investigational New Drugs
Ron J KeizerAlwin D R Huitema

Abstract

The aim of this study was to assess the population pharmacokinetics (PopPK) of the novel oral anti-cancer agent E7820. Both a non-linear mixed effects modeling analysis and a non-compartmental analysis (NCA) were performed and results were compared. Data were obtained from a phase I dose escalation study in patients with malignant solid tumors or lymphomas. E7820 was administered daily for 28 days, followed by a washout period of 7 days prior to the start of subsequent cycles. A one compartment model with linear elimination from the central compartment was shown to give adequate fit, while absorption was described using a turnover model. Final population parameter estimates of basic PK parameters obtained with the PopPK method were (RSE): clearance, 6.24 L/h (7.1%), volume of distribution, 66.0 L (8.5%), mean transit time to the absorption compartment, 0.638 h (6.5%). The intake of food prior to dose administration slowed absorption (2.8-fold, RSE 13%) and increased relative bioavailability of E7820 by 36% (RSE 14%), although the effect on C (max) and AUC was not significant. Comparison with the NCA approach showed approximately equal PK parameter estimates and food effect measures, although specific advantages of PopPK include...Continue Reading

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Citations

Jun 2, 2009·Seminars in Cancer Biology·Liangru ContoisPeter C Brooks
Mar 13, 2014·Chemistry : a European Journal·Changduo PanChengjian Zhu
Jun 4, 2015·Pharmacology Research & Perspectives·Ron J KeizerAlwin D R Huitema
Jan 10, 2018·Organic & Biomolecular Chemistry·Changduo PanJin-Tao Yu
Jan 7, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Monica MitaChris Takimoto

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