Population PK/PD model for diflomotecan, a new E-ring modified camptothecin analogue, in patients of a phase I study

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Abstract
2046 Background: To develop a semimechanistic population PK/PD model of neutropenic effects of diflomotecan, to establish the concentration-effect relationship and to quantify the degree of interpatient variability. Methods: PK data were obtained from 24 patients with advanced cancer receiving diflomotecan as 20 min i.v. infusion every 3 weeks at planned starting doses of 2, 4, 5 and 6 mg/m2. The number of cycles ranged from 1 to 7. Diflomotecan was measured in 258 plasma samples after the 1st administration. Neutrophil cell counts in peripheral blood were followed every 3–7 days for the entire course of the trial with a total of 505 counts. Population PK/PD analysis was done with NONMEM. Dose, demographic and biochemical variables were tested as covariates. Results: Plasma levels-time data were described with a 3-compartment model and first order elimination. Typical estimates of distribution volumes were 41.5, 39.2 and 12.8 L for central (Vc), shallow (VP1) and deep (VP2) compartments, respectively. Bod...

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