title: Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma.
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.
authors.affiliation: QuantPharm LLC, 49 Flints Grove Drive, North Potomac, MD, 20878, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Gibiansky
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543, USA.
authors.forename: Chaitali
authors.initials: C
authors.lastname: Passey
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Roy
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543, USA.
authors.forename: Akintunde
authors.initials: A
authors.lastname: Bello
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543, USA. Manish.Gupta-LVL@bms.com.
authors.forename: Manish
authors.initials: M
authors.lastname: Gupta
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D012008:Recurrence; D014018:Tissue Distribution
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C546027:elotuzumab
keywords: Elotuzumab; Immunotherapy; Monoclonal antibody; Multiple myeloma; Population pharmacokinetics; Target-mediated drug disposition (TMDD)