A Randomized, Single-Dose and Multiple Dose Dose-Ranging Safety and Pharmacokinetics Study of Tacrolimus Powder for Inhalation in Healthy Adult Subjects

INTERVENTION: Part A: This is a double‐blinded, placebo‐controlled, randomized, dose‐ranging study evaluating five different dose levels (0.5, 1.0, 2.5, 5, and 10 mg). On Day 1 of each period, subjects will receive a single dose of either TFF tacrolimus inhalation powder or a matching placebo. Participants will receive only one dose level of TFF tacrolimus. Participants will be required to fast overnight prior to dosing and for 2 hours following dosing, and will be domiciled at the clinical research center. Treatments will be administered by the clinic staff. For the 2.5 mg dose level, subjects will be given two administrations, one fasted and one with a high fat meal (50%‐60% fat), in a fixed sequence fashion separated by one week. Safety and PK will be monitored on both occasions. Part B: This is a double‐blinded, placebo‐controlled, randomized, multi‐dose study evaluating three different dose levels (1.0, 2.5, and 5.0 mg BID). Participants who enrolled in Part A are not eligible to enroll in Part B. Tacrolimus inhalation powder or matching placebo will be administered twice per day for 6.5 days for a total of 13 doses. Participants will receive only one dose level of TFF tacrolimus. Participants will be domiciled at the clinical research center and treatments will be administered by the clinic staff. CONDITION: Inflammatory and Immune System ‐ Other inflammatory or immune system disorders Prophylactic therapy of organ rejection in patients receiving allogeneic lung transplants; ; Prophylactic therapy of organ rejection in patients receiving allogeneic lung transplants Respiratory ‐ Other respiratory disorders / diseases PRIMARY OUTCOME: Part A: ; To evaluate the safety and tolerability of a single inhalation dose of TFF tacrolimus administered in a dose‐ranging sequence; ; Part B: ; To evaluate the safety and tolerability of a multi‐dose regimen of inhaled TFF tacrolimus; ; Safety and tolerability will be assessed using clinical labs, pulmonary function testing, cardiac monitoring, and physical examination for Part A and Part B.[Part A:; Day 3; ; Part B: ; Day 9] Part A:; To evaluate the pharmacokinetics (PK) of a single inhalation dose of TFF tacrolimus administered in a dose‐ranging sequence; ; Part B: ; To evaluate the pharmacokinetics (PK) of multidose inhalation TFF tacrolimus administered in a multiple dose dose‐ranging sequence; ; Pharmacokinetic outcomes will be assessed using Tmax, Cmax, T 1/2, and AUC for both Part A and Part B.; [Part A;; Peak, trough, other pharmacokinetic measures of blood levels of drug; ; Blood draws will be performed at the following timepoints for Part A: pre‐dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 20, 24, 36, 48 hours.; ; Part B: ; Peak, trough, other pharmacokinetic measures of blood levels of drug; ; Blood draws will be performed at the following timepoints for Part B Day 1: pre‐dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 20, 24, 36, 48 hours. ; On Day 7 blood draws will be performed at the following timepoints: pre‐dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 20, 24, 36, 48 hours. ] SECONDARY OUTCOME: Nil[Nil ; ; ] INCLUSION CRITERIA: 1. Healthy, adult, male or female (women of non‐child bearing potential only), 3. Medically healthy with no clinically significant medical history, physical and neurologic examination, laboratory profiles, vital signs or ECGs, as deemed by the PI or designee. 4. A CKD‐EPI Creatinine 2009 estimated creatinine clearance of >=80 mL/min 5. A non vasectomized, male subject must agree to use a highly effective method of birth control with female partners of childbearing potential during the study and for 120 days following dosing. 2. Continuous non smoker who has not used nicotine containing products (including e vaping) for at least 3 months prior to the first dosing and throughout the study, based on subject’s self‐reporting and urine cotinine levels at screening.