1. Novel Nebulized Milrinone Formulation for the Treatment of Acute Heart Failure Requiring Inotropic Therapy: A Phase 1 Study.
- Author
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COX, ZACHARY L., DALIA, TARUN, GOYAL, AMANDEEP, FRITZLEN, JOHN, GUPTA, BHANU, SHAH, ZUBAIR, SAUER, ANDREW J., and HAGLUND, NICHOLAS A.
- Abstract
• Inotrope formulations avoiding the burdens of continuous IV infusion are needed. • We tested a novel, concentrated formulation of milrinone for inhalation. • Nebulized milrinone was well tolerated and without adverse events. • Intermittent inhalation of milrinone produced therapeutic serum concentrations. • Nebulized milrinone improved invasive hemodynamic parameters. Nonintravenous inotropic-delivery options are needed for patients with inotropic-dependent heart failure (HF) to reduce the costs, infections and thrombotic risks associated with chronic central venous catheters and home infusion services. We developed a novel, concentrated formulation of nebulized milrinone for inhalation and evaluated the feasibility, safety and pharmacokinetic profile in a prospective, single-arm, phase I clinical trial. We enrolled 10 patients with stage D HF requiring inotropic therapy during a hospital admission for acute HF. Milrinone 60 mg/4 mL was inhaled via nebulization 3 times daily for 48 hours. The coprimary outcomes were adverse events and pharmacokinetic profiles of inhaled milrinone. Acute changes in hemodynamic parameters were secondary outcomes. A concentrated nebulized milrinone formulation was well tolerated, without hypotensive events, arrhythmias or inhalation-related adverse events requiring discontinuation. Nebulized milrinone produced serum concentrations in the goal therapeutic range with a median plasma milrinone trough concentration of 39 (17–66) ng/mL and a median peak concentration of 207 (134–293) ng/mL. There were no serious adverse events. From baseline to 24 hours, mean pulmonary artery saturation increased (60% ± 7%–65 ± 5%; P = 0.001), and mean cardiac index increased (2.0 ± 0.5 mL/min/1.73m
2 –2.5 ± 0.1 mL/min/1.73m2 ; P = 0.001) with nebulized milrinone. In a proof-of-concept study, a concentrated, nebulized milrinone formulation for inhalation was safe and produced therapeutic serum milrinone concentrations. Nebulized milrinone was associated with improved hemodynamic parameters of cardiac output in a population with advanced HF. These promising results require further investigation in a longer-term trial in patients with inotrope-dependent advanced HF. [ABSTRACT FROM AUTHOR]- Published
- 2024
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