Population PK-PD modeling of E7820 and α2-integrin expression on platelets in patients with solid tumors and lymphomas
RJ Keizer (1), MK Zamacona (2), M Jansen (2), DJ Critchley (2), J Wanders (2), JH Beijnen (1,4), JHM Schellens (3,4), ADR Huitema (1)
(1) Department of Pharmacy & Pharmacology, the Netherlands Cancer Institute / Slotervaart Hospital, Amsterdam, the Netherlands; (2) Eisai Limited, London, United Kingdom; (3) Division of Clinical Pharmacoloy, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; (4) Division of Drug Toxicology, Section of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Introduction: The novel angiogenesis inhibitor E7820 was evaluated in a phase I dose escalation study in patients with malignant solid tumors or lymphomas, the clinical results of which have been reported previously. Its anti-angiogenetic effects are exerted mainly by inhibition of the mRNA expression of α2-integrin. E7820 was administered daily for 28 days, followed by a washout period of 7 days prior to starting subsequent cycles. It is hypothesized that α2-integrin expression on platelets may be a biomarker for tumor growth inhibition in response to treatment with E7820. The aim of this study was to develop a population PK-PD model for E7820 and its effect on α2-integrin platelet levels.
Methods: 1421 E7820 plasma samples were available from 37 patients, while 462 α2-integrin level measurements at 209 unique timepoints were available from 29 patients, collected from up to 9 treatment cycles. The population analysis was performed in NONMEM VI. First, a PK model was built and evaluated. Subsequently, effects of E7820 concentration on α2-integrin levels were modeled using an indirect response model with inhibition of input rate. Both linear and Emax-models for the concentration-effect relationship were tested. It was assessed if incorporation of delays in onset of PD response to drug exposure, or development of tolerance could be shown. By simulation from the developed model, several dosing strategies were evaluated for their effect on integrin expression levels.
Results: The final PK model was a one compartment model with linear elimination from the central compartment, while absorption was modeled using a turnover model. Final population parameter estimates were (RSE): clearance (CL/F) = 6.22 L/hr (13 %), volume of distribution (V/F) = 66.0 L (11%), mean transition time to the absorption compartment = 0.636 hours (7 %) and 3 transition compartments. Significant drug effects were observed, using either linear or Emax models. A sigmoid Emax model fitted the data best, with parameters estimates (RSE): Emax = 0.80 (20 %), IC50 = 755 ng/mL (8 %), and baseline integrin expression on platelets = 9060 molecules of equivalent soluble fluorochrome (9 %). Incorporation of transition compartments to model delays in drug-effect did not improve the model, nor did a model that incorporated development of tolerance to E7820. Marked differences in PD response (decrease of integrin expression levels) were observed for different simulated dosing regimens. Increasing dose frequency to bid or tid at the MTD level of 100 mg, shows small increases in PD response. When dosed at 50 mg, median PD response was <20% compared with dosing at MTD.
Conclusions: A population PK-PD model was developed describing the disposition of E7820 and the effects of exposure on expression of α2-integrin on platelets. This model was subsequently used for evaluation of different dosing strategies. For α2-integrin levels on platelets to serve as a biomarker for tumor growth inhibition in humans, the relationship between α2-levels on platelets, tumor growth and disease progression should be assessed further.
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