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

Ron J. Keizer, Miren K. Zamacona, Mendel Jansen, David Critchley, Jantien Wanders, Jos H. Beijnen, Jan H.M. Schellens, Alwin D.R. Huitema

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21 Citations (Scopus)


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 included efficiency in use of data and more appropriate assessment of variability.

Original languageEnglish
Pages (from-to)140-152
Number of pages13
JournalInvestigational New Drugs
Issue number2
Publication statusPublished - Apr 2009
Externally publishedYes


  • Alpha2-integrin
  • E7820
  • Mixed-effects modeling
  • Non-compartmental analysis
  • Oncology
  • Population pharmacokinetics


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