Preclinical Pharmacokinetics and Translational Pharmacokinetic/Pharmacodynamic Modeling of M8891, a Potent and Reversible Inhibitor of Methionine Aminopeptidase 2

• DOI: 10.1007/s11095-023-03611-z
• Publication Date: 2023-10-05T21:01:40Z
• Authors: Floriane Lignet; Manja Friese-Hamim; Frank Jaehrling; Samer El Bawab; Felix Rohdich
• Keywords: Pharmacodynamics

Abstract Introduction M8891 is a selective and reversible inhibitor of methionine aminopeptidase 2 (MetAP2). We describe translational research to define the target pharmacokinetics (PK) associated pharmacodynamic (PD) levels, which were used support efficacious dose selection in humans. Methods In vitro vivo PK characteristics investigated animal species, data integrated using vitro–in correlation allometric methods predict clearance, volume distribution, absorption parameters parallel, inhibition MetAP2 activity by was studied renal cancer xenografts mice measuring accumulation Met-EF1α, substrate MetAP2. The corresponding PD effect described turnover compartment model. This model simulate at showing efficacy, i.e. significant tumor growth inhibition. Simulations humans conducted integrating predicted human into preclinical PK/PD Results minimum level with efficacy determined be 125 µg Met-EF1α per mg protein. Integrating defined minimal concentration steady-state (C trough ) 1500 ng/mL (3.9 µM) as being required produce Met-EF1a (125 protein). Conclusion levels supported design clinical Phase Ia escalation study (NCT03138538) recommended II dose.