P66: Nebulized inhaled nitrite (AIR001) for pulmonary arterial hypertension: Studies to determine safety, pharmacokinetics, and maximum tolerated dose, lack of pharmacodynamic interaction with sildenafil and optimal nebulizer device

Abstract

Background Prior work by Bradley et al. [ 1 ] demonstrated single doses of inhaled sodium nitrite up to 125 mg (dose loaded into the nebulizer) were well tolerated and resulted in increased plasma nitrite concentrations, increased exhaled NO, and minimal methemoglobin increases. Thus further clinical development of nebulized sodium nitrite (AIR001) for treatment of pulmonary arterial hypertension (PAH) was planned. Nitrite-generated NO, by acting upon guanylate cyclase is likely to be synergistic with phosphodiesterase type 5 inhibitors (PDE-5i’s), as both increase cGMP and likely would be used concomitantly in PAH patients, thus an interaction study was performed. Clinical trials utilizing AIR001 require a portable, highly efficient nebulizer capable of precise dosing as well as monitoring adherence and compliance which necessitated careful device characterization and tolerance studies. Methods This placebo controlled study of AIR001 was conducted in parts; Parts A, B, and D are reported here. In Part A, ascending doses of AIR001 or placebo from 15 mg to 120 mg (dose loaded into nebulizer) nebulized over 8–10 min every 8 h to cohorts of 8 subjects on days 1–6 to determine maximum tolerated dose (MTD). In Part B, ascending doses of AIR001 were administered at steady state sildenafil (dosed at 20 mg every 8 h), while AIR001 was administered every 6 h (QID). Part D was a randomized, cross-over, open label study to evaluate the pharmacokinetics (PK), safety, and tolerability of AIR001 comparing the Philips I-neb AAD System (Philips Respironics) with the Solo-Idehaler (nebulization head, Aeroneb® Solo (Aerogen, Ltd.), aerosol–reservoir attachment, Idehaler™ (Diffusion Technique Francais)), and the Aeroneb-Go (Aerogen, Ltd). Results In Part A, the MTD was defined at 90 mg (dose loaded into the nebulizer) by expected hemodynamic changes with minimal cough or throat irritation and no significant change in laboratory, spirometric, or electrocardiographic parameters. Plasma nitrite levels were dose dependent with no evidence of accumulation from day 1 to day 6. At the MTD, 90 mg, Cmax was approximately 600 ng/ml (13 μM). Bioconversion to NO resulted in an increase in exhaled NO from 8 ppb predose to 192 ppb. The maximum venous methemoglobin concentration was 2.5%. In Part B, the MTD of 90 mg was well tolerated with no significant effects on systemic blood pressures, or effects on sildenafil PK. In Part D, nitrite PK differences were not statistically significant (p Conclusions Inhaled AIR001 is well tolerated up to doses of 90 mg (loaded dose), and early dose effects are ameliorated upon repeat dosing, both in the absence and presence of sildenafil. Efficacious delivery of AIR001 was demonstrated by the inhalation route and no accumulation of AIR001 was observed. Plasma PK parameters (Cmax at MTD of 10 uM, and half-life of approximately 42 min) lend themselves to application in PAH. Because of precise dosing, adaptive capacity, and its ability to monitor adherence and compliance, the I-neb AAD System is optimal for further study of AIR001 in patients with PAH. Disclosure Dr. Lewis J. Rubin and Dr. Mark T. Gladwin have received support by Aires Pharmaceuticals, Inc.