P. Chanu (1), L. Claret (1), M. Marchand (1), N. Losic (2), T.A. Puchalski (3), R. Bruno (1)
(1) Pharsight Consulting Services, Pharsight, a CertaraTM Company, Lyon and Marseille, France, (2) Genmab, Copenhagen, Denmark, (3) Janssen Research & Development, LLC, Spring House, PA, USA
Objectives: Daratumumab is a human CD38 monoclonal antibody with broad-spectrum antitumor activity. The aim of this project was to model the pharmacokinetics (PK), pharmacodynamic (PD) M-protein response induced by daratumumab given in patients with advanced multiple myeloma (MM) from a Phase I/II study. PK/PD modelling and simulation are used to guide dose selection of daratumumab in MM patients.
Methods: Data were available from 72 MM patients with measurable PK who received daratumumab 0.1 to 24 mg/kg at several dosing intervals (weekly to q4w) by intravenous infusion. A population PK model was developed to derive systemic exposure to daratumumab in patients. A concentration driven tumor growth inhibition model [1] was developed to describe M-protein response.
Results: A 2-compartment population PK model with parallel linear and Michaelis-Menten eliminations best described daratumumab pharmacokinetics [2]. The TGI model for M-protein confirmed a concentration dependent drug efficacy. Baseline M-Protein was found to follow a bimodal distribution. M-protein growth rate parameter was estimated similar to previous analysis [2].
Conclusions: Daratumumab was shown to inhibit tumor growth in a concentration-dependent manner in MM patients. PK/PD models are used to further optimize the dosing regimen for daratumumab and support Phase III design.
References:
[1] Bruno R, Jonsson F, Zaki M, Jacques C, Swern A, Richardson P, Rajkumar VS, Claret L. Simulation of clinical outcome for pomalidomide plus low-dose dexamethasone in patients with refractory multiple myeloma based on week 8 M-protein response. Blood (ASH Annual Meeting Abstracts), 118 (21), 1881, 2011.
[2] Marchand M, Claret L, Losic N, Puchalski TA, Bruno R. Population pharmacokinetics and exposure-response analyses to support dose selection of daratumumab in multiple myeloma patients PAGE 22 (2013) Abstr 2668 [www.page-meeting.org/?abstract=2668].
Reference: PAGE 23 (2014) Abstr 3281 [www.page-meeting.org/?abstract=3281]
Poster: Drug/Disease modeling - Oncology