Ascending multiple dose administration (every 8 hours, [Q8H]) of AIR001 or placebo for 16 consecutive doses

Single escalating doses of AIR001 or placebo (Q8H, Day 4-6) administered in combination with steady-state sildenafil administration (Q8H, Days 1-6)

Four doses of AIR001 will be administered via nebulization to patients with PAH.

PK, safety and tolerability of single doses of AIR001 administered in a randomized order with three different nebulizers.

Pulmonary Hypertension

Pulmonary Arterial Hypertension

15 mg sodium nitrite inhalation solution Q8H

15 mg sodium nitrite inhalation solution

90 mg sodium nitrite inhalation solution Q8H

90 mg sodium nitrite inhalation solution

45 mg sodium nitrite inhalation solution Q8H

45 mg sodium nitrite inhalation solution

120 mg sodium nitrite inhalation solution or placebo Q8H

120 mg sodium nitrite inhalation solution

Multiple oral doses of 20 mg sildenafil will be administered open-label Q8H to a single cohort of eight subjects on Days 1 to 6. A single dose of sodium nitrite inhalation solution equal to 25% of the maximum tolerated dose (MTD) identified in Part A (or placebo) will be administered on Day 4, a single dose equal to 50% of the MTD (or placebo) will be administered on Day 5, and a single dose equal to 100% of the MTD (or placebo) will be administered on Day 6.

25% MTD sodium nitrite inhalation solution

PAREXEL International Early Phase Clinical Unit - Baltimore

Safety, Tolerability, and PK Parameters of Sodium Nitrite Inhalation Solution in Healthy Subjects

A Phase 1, Placebo Controlled, Blinded, Multiple Dose Escalation Study of AIR001 (Sodium Nitrite Inhalation Solution) in Healthy Subjects, an Assessment of the Tolerability in Combination With Oral Sildenafil, and an Open-Label Study of Multiple Dose AIR001 in Patients With Pulmonary Arterial Hypertension

To evaluate the safety and tolerability of ascending multiple dose administration (every 8 hours, [Q8H]) of AIR001 for 16 consecutive doses
Adverse Events
12 lead ECG
Vital Signs (change in supine BP, Pulse Rate and change in orthostatic BP)
Venous Methemoglobin
Spirometry
Percutaneous Saturation of Oxygen and Methemoglobin concentrations
Plasma cGMP

To evaluate the safety and tolerability of single escalating doses of AIR001 when administered in combination with steady-state sildenafil administration.
Adverse Events
12 lead ECG
Vital Signs (change in supine BP, Pulse Rate and change in orthostatic BP)
Venous Methemoglobin
Spirometry
Percutaneous Saturation of Oxygen and Methemoglobin concentrations
Plasma cGMP

Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½, CL/F, and Vz/F.

: Cmax, tmax, AUC0-T, AUC0-inf, AUC%extrap, t½,CL/F, and Vz/F.

To evaluate the safety and tolerability of multiple doses of AIR001 when administered in combination with steady-state background PAH medications in patients with PAH.
Adverse Events
12 lead ECG
Vital Signs (change in supine BP, Pulse Rate and change in orthostatic BP)
Venous Methemoglobin
Spirometry
Percutaneous Saturation of Oxygen and Methemoglobin concentrations

To evaluate the safety and tolerability of single doses of AIR001 when administered in a randomized fashion with each of three different nebulizers in healthy volunteers.
Adverse Events
12 lead ECG
Vital Signs (change in supine BP, Pulse Rate and change in orthostatic BP)
Venous Methemoglobin
Spirometry
Percutaneous Saturation of Oxygen and Methemoglobin concentrations

monocrotaline/hypoxia

Safety, Tolerability, and PK Parameters of Sodium Nitrite Inhalation Solution in Healthy Subjects

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