Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma

  • Leonid Gibiansky
  • Chaitali Passey
  • Amit Roy
  • Akintunde Bello
  • Manish Gupta
Original Paper

Abstract

Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody in development for the treatment of patients with multiple myeloma who have received one or more prior therapies. In this work, 6958 elotuzumab serum concentrations from 375 patients enrolled in four Phase 1 to 3 clinical trials were used to analyze the pharmacokinetics (PK) of elotuzumab. A population PK model with parallel linear and Michaelis–Menten elimination from the central compartment and limited-capacity target-mediated elimination from the peripheral compartment described the elotuzumab concentration–time course. Clearance of elotuzumab increased with increasing body weight and weight-based dosing generated uniform exposures across a range of body weights. Coadministration of lenalidomide/dexamethasone background therapy decreased elotuzumab nonspecific clearance by 35 %. Target-mediated elimination of elotuzumab increased with increasing baseline serum M-protein, resulting in lower exposure in patients with high baseline serum M-protein concentration. Age, race, sex, renal and hepatic function, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, albumin and β2-microglobulin had less than 20 % effect on model parameters and are unlikely to have clinically meaningful effects. Impact of anti-drug antibodies (ADAs) on the PK of elotuzumab was assessed as an ad hoc analysis. In the majority of ADA-positive patients, immunogenicity started early, was transient and resolved by 2–4 months. Since the majority of patients had ADAs detected early, this resulted in a corresponding transient increase in nonspecific clearance at these time points. Nonspecific clearance appeared to return to baseline at later time points when ADAs were no longer detected.

Keywords

Immunotherapy Monoclonal antibody Multiple myeloma Target-mediated drug disposition (TMDD) Population pharmacokinetics Elotuzumab 

Supplementary material

10928_2016_9469_MOESM1_ESM.doc (1 mb)
Supplementary material 1 (DOC 1032 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Leonid Gibiansky
    • 1
  • Chaitali Passey
    • 2
  • Amit Roy
    • 2
  • Akintunde Bello
    • 2
  • Manish Gupta
    • 2
  1. 1.QuantPharm LLCNorth PotomacUSA
  2. 2.Clinical Pharmacology and PharmacometricsBristol-Myers SquibbPrincetonUSA

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