Population pharmacokinetic/pharmacodynamic models to support dose selection of daratumumab in multiple myeloma patients
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].
