Translational PK/PD Modeling of Tumor Growth Inhibition and Target Inhibition to Support Dose Range Selection of the LMP7 Inhibitor M3258 in Relapsed/Refractory Multiple Myeloma.
Autor: | Lignet F; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.) floriane.lignet@merckgroup.com., Esdar C; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.)., Walter-Bausch G; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.)., Friese-Hamim M; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.)., Stinchi S; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.)., Drouin E; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.)., El Bawab S; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.)., Becker AD; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.)., Gimmi C; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.)., Sanderson MP; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.)., Rohdich F; The Healthcare Business of Merck KGaA, Darmstadt, Germany (F.L., C.E., G.W.-B., M.F.-H., S.S., S.E.B., A.D.B., C.G., M.P.S., F.R.) and EMD Serono, Billerica, Massachusetts (E.D.). |
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Jazyk: | angličtina |
Zdroj: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2023 Jan; Vol. 384 (1), pp. 163-172. Date of Electronic Publication: 2022 Oct 23. |
DOI: | 10.1124/jpet.122.001355 |
Abstrakt: | M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β 5i, PSMB8) proteolytic subunit of the immunoproteasome, a component of the cellular protein degradation machinery, highly expressed in malignant hematopoietic cells including multiple myeloma. Here we describe the fit-for-purpose pharmacokinetic (PK)/pharmacodynamic (PD)/efficacy modeling of M3258 based on preclinical data from several species. The inhibition of LMP7 activity (PD) and tumor growth (efficacy) were tested in human multiple myeloma xenografts in mice. PK and efficacy data were correlated yielding a free M3258 concentration of 45 nM for half-maximal tumor growth inhibition (KC Competing Interests: C.E., G.W.-B, M.F.-H., and M.P.S. are inventors of the patent WO2022073994. C.E. is inventor of the patent WO2019038250. (Copyright © 2022 by The Author(s).) |
Databáze: | MEDLINE |
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