PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma. (8th July 2021)

• Record Type: Journal Article
• Authors: Koiwai, Kimiko; El‐Cheikh, Raouf; Thai, Hoai‐Thu; Brillac, Claire; Fau, Jean‐Baptiste; Veyrat‐Follet, Christine; Risse, Marie‐Laure; van de Velde, Helgi; Semiond, Dorothée; Nguyen, Laurent
• Is Part Of: CPT: pharmacometrics & systems pharmacology. Volume 10:Number 8(2021)
• Page Start: 928
• Page End: 940
• Publication Date: 2021-07-08
• Subjects: Pharmacokinetics -- Periodicals; Pharmacology -- Periodicals; Pharmacokinetics; Periodicals; 615.05
• DOI: 10.1002/psp4.12666
• Languages: English
• ISSNs: 2163-8306

Abstract

Abstract: This analysis describes the pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that supported selection of the isatuximab (anti‐CD38 monoclonal antibody) dosing regimen alongside its early clinical development in patients with relapsed/refractory multiple myeloma (RRMM). The PK/PD mathematical model characterized the variations of patient serum M‐protein concentrations, the primary marker of tumor burden in multiple myeloma (MM). Three separate PK/PD models were built sequentially as data became available from phase I clinical trials. The primary PK/PD analysis was initiated using monotherapy phase I study data ( n = 122), followed by analysis of data collected from phase Ib combination studies with lenalidomide and dexamethasone (Rd, n = 40) and then with pomalidomide and dexamethasone (Pd, n = 31). Using the PK/PD model, abnormal "myeloma" protein (M‐protein) profiles under different isatuximab dosing regimens were simulated. Overall, simulations revealed that regimens which included a loading period of four weekly administrations followed by administration every 2 weeks thereafter (QW4‐Q2W), reduced M‐protein levels more than a Q2W regimen without a loading period. For isatuximab monotherapy, a 20 mg/kg dose induced greater reduction in serum M‐protein levels compared with doses equal or lower than 10 mg/kg. For isatuximab in combination with either Rd or Pd, simulations yielded no substantial benefit in terms of M‐protein reduction between isatuximab 10 mg/kg and 20 mg/kg. These PK/PD analyses supported the use of isatuximab 10 mg/kg QW4‐Q2W in combination with Pd in the phase III trial.