A Randomized, Placebo-Controlled, Dose-Escalation, Phase 1 Study of the Safety and Pharmacokinetics of Amphotericin B Inhalation Powder in Healthy Subjects.

Nektar is developing Amphotericin B Inhalation Powder (ABIP; NKTR-024) to prevent invasive pulmonary fungal infections in immunocompromised patients. NKTR-024 is a proprietary dry-powder amphotericin B (AmB) formulation that is delivered to the patient’s respiratory tract with a proprietary breath-actuated inhalation device (T-326). This study assessed 1) the safety and tolerability and 2) the pharmacokinetics (PK) of AmB in epithelial lining fluid (ELF) and plasma after a loading dose (LD) and 4 weekly maintenance doses (MD) of NKTR-024 in healthy subjects. Thirty-six (36) subjects enrolled in a single center in the US into 2 cohorts 2:1 to receive either NKTR-024 (n=12) or a matching (powder load) placebo inhalation powder (n=6), respectively. Subjects in Cohort 1 (Coh1) received a 25-mg LD and 4 weekly 5-mg MD (25/5) and subjects in Cohort 2 (Coh2) received a 50-mg LD and 4 weekly 10-mg MD (50/10) of NKTR-024 or placebo, respectively. PK assessments used blood [plasma] and bronchoalveolar lavage (BAL) [ELF] samples. Concomitant medications, adverse events (AEs) and other safety parameters were monitored for 17 wk (screening period of up to 28 d, a 4-wk treatment period, and a 9-wk post-treatment period). All 36 subjects received 1 LD and 4 MDs. Subjects were mostly male (n=24, 66.7%) and Caucasian (n=27, 75%). Mean age=28.1 yr, median height=175.3 cm and median weight=77.4 kg. PK data have been previously presented and will not serve as the focus of this abstract. Maximal plasma AmB concentrations occurred at ∼8–12 hr postdose following a ∼1 hr postdose lag. Plasma AmB concentrations (<54.6 ng/mL after the 50-mg NKTR-024 LD) remained well below those typically associated with renal toxicity (plasma AmB concentrations of ≥1000 ng/mL). Mean lung ELF AmB concentrations from the first BAL samples (∼4 hr) were 70.7 and 189 μg/mL for Coh1 and Coh2, respectively. These high lung ELF AmB concentrations show that a large fraction of the nominal NKTR-024 doses were delivered to the lung. Both the NKTR-024 regimens (25/5 and 50/10) were well-tolerated. AEs were mild or moderate. No serious AEs occurred. Most of the AEs across treatment groups were related to bronchoscopy or “other” reasons. Respiratory AEs were most common across treatment groups. Slightly more respiratory AEs (cough, productive cough, increased bronchial secretions, wheezing, dyspnea, and exertional dyspnea) occurred in the NKTR-024 groups versus the placebo groups. AEs were greatest on the day of dosing and for the first 2 days after dosing. Hematology, chemistry, and urinalysis showed no clinically concerning treatment-induced toxicity. No clinically significant abnormalities were noted on physical examination, vital signs, chest x-ray, or electrocardiogram. Spirometry (FVC and FEV1) remained virtually unchanged from predose to postdose at all scheduled visits except for 4 subjects who had transient declines in FVC or FEV1 >20% temporally related to bronchoscopy. Repeated administration of NKTR-024 resulted in high pulmonary and low systemic AmB exposure. Plasma AmB concentrations were well below those associated with renal toxicity; this observation supports an important potential benefit of the NKTR-024 investigational product. Constitutional symptoms and electrolyte abnormalities traditionally seen with systemic administration of AmB were essentially spared.