CPT: Pharmacometrics & Systems Pharmacology (Aug 2021)

PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma

  • Kimiko Koiwai,
  • Raouf El‐Cheikh,
  • Hoai‐Thu Thai,
  • Claire Brillac,
  • Jean‐Baptiste Fau,
  • Christine Veyrat‐Follet,
  • Marie‐Laure Risse,
  • Helgi van deVelde,
  • Dorothée Semiond,
  • Laurent Nguyen

DOI
https://doi.org/10.1002/psp4.12666
Journal volume & issue
Vol. 10, no. 8
pp. 928 – 940

Abstract

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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.