Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data.

The chemokine ligand 2 (CCL2) promotes angiogenesis, tumor proliferation, migration, and metastasis. Carlumab is a human IgG1κ monoclonal antibody with high CCL2 binding affinity. Pharmacokinetic/pharmacodynamic data from 21 cancer patients with refractory tumors were analyzed. The PK/PD model characterized the temporal relationships between serum concentrations of carlumab, free CCL2, and the carlumab-CCL2 complex. Dose-dependent increases in total CCL2 concentrations were observed and were consistent with shifting free CCL2. Free CCL2 declined rapidly after the initial carlumab infusion, returned to baseline within 7 days, and increased to levels greater than baseline following subsequent doses. Mean predicted half-lives of carlumab and carlumab-CCL2 complex were approximately 2.4 days and approximately 1 hour for free CCL2. The mean dissociation constant (KD ), 2.4 nM, was substantially higher than predicted by in vitro experiments, and model-based simulation revealed this was the major factor hindering the suppression of free CCL2 at clinically viable doses.

Development of a preclinical PK/PD model to assess antitumor response of a sequential aflibercept and doxorubicin-dosing strategy in acute myeloid leukemia.

Timing of the anti-angiogenic agent with respect to the chemotherapeutic agent may be crucial in determining the success of combination therapy in cancer. We investigated the effects of sequential therapy with the potent VEGF inhibitor, aflibercept, and doxorubicin (DOX) in preclinical acute myeloid leukemia (AML) models. Mice were engrafted with human HL-60 and HEL-luciferase leukemia cells via S.C. and/or I.V. injection and treated with two to three doses of aflibercept (5-25 mg/kg) up to 3-7 days prior to doxorubicin (30 mg/kg) administration. Leukemia growth was determined by local tumor measurements (days 0-16) and systemic bioluminescent imaging (days 0-28) in animals receiving DOX (3 mg/kg) with or without aflibercept. A PK/PD model was developed to characterize how prior administration of aflibercept altered intratumoral DOX uptake. DOX concentration-time profiles were described using a four-compartment PK model with linear elimination. We determined that intratumoral DOX concentrations were 6-fold higher in the aflibercept plus DOX treatment group versus DOX alone in association with increased drug uptake rates (from 0.125 to 0.471 ml/h/kg) into tumor without affecting drug efflux. PD modeling demonstrated that the observed growth retardation was mainly due to the combination of DOX plus TRAP group; 0.00794 vs. 0.0043 h(-1). This PK/PD modeling approach in leukemia enabled us to predict the effects of dosing frequency and sequence for the combination of anti-VEGF and cytotoxic agents on AML growth in both xenograft and marrow, and may be useful in the design of future rational combinatorial dosing regimens in hematological malignancies.