Population Pharmacokinetics and Exposure-Response Analyses to Support Dose Selection of Daratumumab in Multiple Myeloma Patients
M. Marchand (1), L. Claret (1), N. Losic (2), TA Puchalski (3), R. Bruno (1)
(1) Pharsight Consulting Services, Pharsight, a CertaraTM Company, 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 explore the pharmacokinetics (PK), pharmacodynamic (PD) response and the exposure-response relationship of daratumumab from a Phase I/II study in patients with advanced multiple myeloma (MM). This information was an integral aspect of dose selection.
Methods: Data were available from 25 MM patients with measurable PK who received daratumumab 0.1 to 16 mg/kg weekly by intravenous infusion (data cut 31 July 2012). A population PK model was developed to derive systemic exposure to daratumumab in patients. A simplified tumor growth inhibition (TGI) model [1] was used to estimate response metrics based on time profiles of M-protein and involved free light chain (FLC) after daratumumab administration. Relationship between these TGI metrics and progression free survival (PFS) were assessed.
Results: A 2-compartment population PK model with parallel linear and Michaelis-Menten eliminations best described daratumumab pharmacokinetics, as often described for monoclonal antibodies targeting receptors [2]. Estimated response metrics, i.e. M-protein and involved FLC time to nadir were correlated with daratumumab exposure (p<0.05). Involved FLC and M-protein time to nadir were predictors of PFS (p<0.01).
Conclusions: Daratumumab was shown to inhibit tumor growth and to prolong PFS in an exposure-dependent manner. M-protein and involved FLC TGI responses metrics are biomarkers of response to daratumumab. The PK/PD model together with drug independent clinical endpoint models [3] may be used to optimize dose and schedule for daratumumab and support the Phase II study design.
References:
[1] Claret L., Gupta M., Joshi A., Sarapa N., He J., Powell B., Bruno R., Evaluation of Tumor-Size Response Metrics to Predict Survival and Progression Free Survival in First-Line Metastatic Colorectal Cancer, PAGE 21 (2012) Abstr 2328, J Clin Oncol, accepted for publication.
[2] Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010 Oct;49 (10):633-59.
[3] 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.
