L Zhu, A Roy, P Statkevich, L Cohen, G Kroog, A Bello
Bristol-Myers Squibb Company
Objectives: Chemokine receptor 4 (CXCR4) is essential for homing and maintenance of hematopoietic stem cells in the bone marrow. Ulocuplumab (BMS-936564; ULO) is a first-in-class, fully human IgG4 monoclonal antibody, which inhibits the binding of CXCR4 to CXCL12. It is hypothesized that by mobilizing leukemic cells from the bone marrow to the peripheral blood, ULO could improve the response to chemotherapy. The objectives of the analysis were to develop a population PK model (PPK) for ULO and to identify key covariates in patients with hematological malignancies.
Methods: Data were assembled from 2 phase I multiple dose escalation studies in patients with relapsed/refractory acute myeloid leukemia (AML, N=73) and multiple myeloma (MM, N=35). ULO doses of 0.3, 1, 3 and 10 mg/kg were given weekly as 60-minute infusions. AML patients received 1 week ULO monotherapy followed by combination treatment with MEC (mitoxantrone/etoposide/cytarabine); MM patients received 2 weeks ULO monotherapy followed by combination with lenalidomide/dexamethasone or bortezomib/dexamethasone. A PPK model was developed using NONMEM (V7.2) in which body weight, gender, baseline albumin, white blood cell count (WBC), and combination chemotherapies were evaluated as covariates. A full model approach followed by a stepwise backward search was used for the covariate analysis.
Results: ULO serum concentration-time profiles and model diagnostics suggested concentration dependent disposition. A two-compartment model with parallel linear and nonlinear elimination pathways adequately described the data. Central (Vc) and peripheral volume of distribution were 4.37 L (%RSE: 3%) and 3.6 L (16%) respectively; the linear clearance (CL) was 0.015 L/h (9%) and the maximum nonlinear clearance was 0.29 L/h (Vmax/Km). WBC, which expresses the target CXCR4 receptor, was influential on Vmax. In the full model, the allometric coefficients of body weight for ULO CL and Vc were estimated to be 0.33 and 0.41, respectively, suggesting a modest effect of body weight. Simulations indicated that an ULO flat dosing regimen could provide relatively uniform exposures over a wide body weight range.
Conclusions: ULO PK was well described by a PPK model with parallel linear and nonlinear elimination. Covariate analysis indicated a modest effect of body weight. The population PK model provided the basis for evaluating flat dosing regimens in additional clinical studies.
Reference: PAGE 25 (2016) Abstr 5798 [www.page-meeting.org/?abstract=5798]
Poster: Drug/Disease modeling - Oncology