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

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 m...

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Auteurs principaux:	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
Format:	article
Langue:	EN
Publié:	Wiley 2021
Sujets:	Therapeutics. Pharmacology RM1-950
Accès en ligne:	https://doaj.org/article/af2cc48054174339a0403cbbf840ec73
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spelling	oai:doaj.org-article:af2cc48054174339a0403cbbf840ec732021-11-19T15:35:29ZPK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma2163-830610.1002/psp4.12666https://doaj.org/article/af2cc48054174339a0403cbbf840ec732021-08-01T00:00:00Zhttps://doi.org/10.1002/psp4.12666https://doaj.org/toc/2163-8306Abstract 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.Kimiko KoiwaiRaouf El‐CheikhHoai‐Thu ThaiClaire BrillacJean‐Baptiste FauChristine Veyrat‐FolletMarie‐Laure RisseHelgi van deVeldeDorothée SemiondLaurent NguyenWileyarticleTherapeutics. PharmacologyRM1-950ENCPT: Pharmacometrics & Systems Pharmacology, Vol 10, Iss 8, Pp 928-940 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 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 PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma
description	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.
format	article
author	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
author_facet	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
author_sort	Kimiko Koiwai
title	PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma
title_short	PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma
title_full	PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma
title_fullStr	PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma
title_full_unstemmed	PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma
title_sort	pk/pd modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/af2cc48054174339a0403cbbf840ec73
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PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma

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