Abstract 10372: A Clinical Drug-Drug Interaction Study of Imb-1018972, a Novel Investigational Cardiac Mitotrope in Phase 2 Development for the Treatment of Myocardial Ischemia and Hypertrophic Cardiomyopathy

• Published in: Circulation (New York, N.Y.) N.Y.), 2021-11, Vol.144 (Suppl_1), p.A10372-A10372
• Main Authors: Tremaine, Larry, Al-Fayoumi, Suliman, van de Wetering, Jeroen, van Iersel, Thjis, Patel, Jaikrishna, Chamberlin, Paul
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.144.suppl_1.10372

BackgroundIMB-1018972 (IMB-101) is a novel mitotropic agent designed to increase myocardial metabolic efficiency by shifting substrate utilization towards glucose through reducing fatty acid oxidation (inhibiting 3-ketoacyl CoA thiolase), thereby generating more ATP per unit of oxygen consumed. IMB-101 is hydrolyzed to IMB-1028814 (IMB-102, the active moiety) which is further metabolized with ~60% forming trimetazidine (TMZ). In vitro cytochrome P450 (CYP) studies reveal IMB-102 to be metabolized by multiple CYPs with CYP2C19 and CYP2D6 potentially comprising a major portion of its clearance and formation of TMZ. IMB-101 is under evaluation in Phase 2 studies in stable CAD, non-obstructive HCM & T2DM, indications for which patients often take multiple medications concurrently. AimTo evaluate the drug-drug interaction (DDI) potential of IMB-101 in healthy subjects. MethodsA fixed sequence crossover study conducted in 3 parts evaluating the effect of1) multiple dose oral (PO) IMB-101 on the single dose PK of PO CYP3A4 (midazolam) and CYP2C8 (repaglinide) substrates (n=23); multiple doses of strong inhibitors of 2) CYP2D6 (paroxetine) or 3) CYP2C19 (fluvoxamine) on the single dose PK of PO IMB-101 (n=14 each). Results1) Weak inhibition of CYP2C8 by IMB-101 based on AUC of repaglinide but none based on its Cmax. Weak inhibition of CYP3A4 by IMB-101 based on AUC and Cmax of midazolam. 2) Limited involvement of CYP2D6 in the metabolism of IMB-102 to metabolites other than TMZ based on IMB-102 AUC and Cmax when given with paroxetine. 3) A major role for CYP2C19 in the metabolism of IMB-102 to TMZ in vivo evidenced by increased IMB-102 exposure and reduced TMZ exposure when given with fluvoxamine. Based on the summation of AUCs for the active entities (IMB-102 and TMZ), exposure is unchanged with co-administration of fluvoxamine suggesting no IMB-101 dose adjustment is needed with concurrent strong CYP2C19 inhibition. ConclusionsIMB-101 does not result in clinically significant inhibition of CYP3A4 or 2C8 isoenzymes and its metabolites are not clinically relevant CYP2D6 substrates. These findings support the administration of IMB-101 with commonly used cardiovascular medications without a significant risk of DDI or requirement for dose alterations.