Evaluation of the Absolute Bioavailability and Mass Balance of CHF6001 (Tanimilast) in Healthy Subjects

Phase 1

Completed

Conditions: Chronic Obstructive Pulmonary Disease (COPD)
COPD

Interventions: Drug: CHF6001

Registration Number: NCT04756960

Lead Sponsor: Chiesi Farmaceutici S.p.A.

Brief Summary: The objective of the study is to evaluate the bioavailability of CHF6001 after inhaled administration, to characterize the mass balance and route of elimination of CHF6001 along with its relevant metabolites, in healthy male subjects.

Detailed Description: This clinical trial is a single centre Phase I study, with a single dose, non-randomized, open-label, uncontrolled design. A total of 8 healthy male subjects were included in the study.

The aim was to assess the absolute bioavailability, the mass balance, and routes of elimination of CHF6001 (Tanimilast) in healthy male subjects, using \[14\^C\]-radiolabelled drug substance, administered as an intravenous (iv) infusion concomitantly with an inhaled (inh) non-radiolabelled dose of CHF6001.

Standard safety assessments were conducted during the study, including safety blood and urine laboratory tests, vital signs, physical examinations, ECGs, and assessment of any adverse events (AE). Blood, urine, and feces samples were collected for pharmacokinetic (PK) analyses.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 8

Inclusion Criteria

Subject's written informed consent obtained prior to any study-related procedure;
Able to understand the study procedures, the risks involved and ability to be trained to use correctly the inhalers and to generate sufficient Peak Inspiratory Flow (PIF), using the In-Check device and Placebo inhaler;
Male subjects aged 30 to 55 years inclusive;
Body mass index (BMI) within the range of 18 to 35 kg/m^2 inclusive;
Non- or ex-smoker who smoked < 5 pack years and who stopped smoking > 1 year prior to screening;
Good physical and mental status;
Vital signs at screening within limits;
12-lead digitised Electrocardiogram (12-lead ECG) in triplicate considered as normal;
Lung function measurements within normal limits at screening;
Regular bowel movements at screening;
Males with non-pregnant Women of Childbearing Potential (WOCBP) partners: they and/or their partner of childbearing potential must be willing to use a highly effective birth control method in addition to the male condom from the signature of the informed consent and until 90 days after the follow-up visit. Males with pregnant WOCBP partner: they must be willing to use male contraception (condom) from the signature of the informed consent and until 90 days after the follow-up visit.

Exclusion Criteria

Participation in another clinical trial with an investigational drug in the 3 months or 5 half-lives of that investigational drug (whichever is longer) preceding the administration of the study drug;
Clinically relevant and uncontrolled respiratory, cardiac, hepatic (including Gilbert syndrome), gastrointestinal, renal, endocrine, metabolic, neurologic, or psychiatric disorder;
Clinically relevant abnormal laboratory values;
Subjects with history of breathing problems;
Positive to Human Immunodeficiency Virus 1/Human Immunodeficiency Virus 2 (HIV1/HIV2) serology at screening;
Positive results from the Hepatitis serology which indicates acute or chronic Hepatitis B or Hepatitis C at screening;
Blood donation or blood loss (equal or more than 450 mL) less than 2 months prior screening or prior to treatment;
Positive urine test for cotinine;
Documented history of alcohol abuse within 12 months prior to screening or a positive alcohol breath test;
Documented history of drug abuse within 12 months prior to screening or a positive urine drug screen;
Intake of non-permitted concomitant medications in the predefined period;
Presence of any current infection, or previous infection that resolved less than 7 days prior to screening or before treatment;
Known intolerance and/or hypersensitivity to any of the excipients contained in the formulation used in the trial;
Unsuitable veins for repeated venipuncture;
Heavy caffeine drinker;
Abnormal haemoglobin level at screening;
Subjects using e-cigarettes within 6 months prior to screening;
Subjects been involved in a study involving a 14^C-labeled drug within the 12 months prior to enrollment;
Subjects with exposure to significant diagnostic or therapeutic radiation or current employment in a job requiring radiation exposure monitoring within 12 months prior to Day-1;
Documented coronavirus disease 2019 (COVID-19) diagnosis within the last 8 weeks or which has not resolved within 14 days prior to screening and before treatment.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CHF6001	CHF6001	single dose of CHF6001 dry-powder inhaler (DPI) co-administered with an intravenous microdose of \[14\^C\]-labelled CHF6001

Primary Outcome Measures

Name	Time	Method
PK Parameter -- t(1/2_iv) -- Plasma -- [14^C] Total	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	Terminal half-life t(1/2_iv) for \[14\^C\] total and CHF6001. t1/2_iv=Terminal half-life, after intravenous (iv) infusion administration
PK Parameter -- Clearance (CL_iv) -- Plasma -- [14^C] CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	Systemic plasma clearance for \[14\^C\] CHF6001.
PK Parameter -- C(max_inh) -- Plasma -- CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints post inhaled dose: 15, 30, 60, 90 min, 2, 3.75, 5.75, 7.75, 9.75, 11.75, 13.75, 25.75, 49.75, 73.75, 97.75, 121.75, 145.75, 169.75, 193.75, 217.75, and 241.75 hours.	C(max_inh) for CHF6001 in plasma. C(max_inh)=Peak plasma concentration after inhalation of CHF6001
PK Parameter -- AUC(0-t)_inh -- Plasma -- CHF6001	At baseline (pre-dose) (within 60 min from inhaled dosing) and at the following timepoints post inhaled dose: 15, 30, 60, 90 min, 2, 3.75, 5.75, 7.75, 9.75, 11.75, 13.75, 25.75, 49.75, 73.75, 97.75, 121.75, 145.75, 169.75, 193.75, 217.75, and 241.75 hours	AUC(0-t)_inh for CHF6001 in plasma. AUC(0-t)_inh=Area Under the curve, from 0 to the last quantifiable concentration after inhalation of CHF6001
PK Parameter -- t(max_inh) -- Plasma -- CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints post inhaled dose: 15, 30, 60, 90 min, 2, 3.75, 5.75, 7.75, 9.75, 11.75, 13.75, 25.75, 49.75, 73.75, 97.75, 121.75, 145.75, 169.75, 193.75, 217.75, and 241.75 hours.	t(max_inh) for CHF6001 in plasma. t(max_inh)=Time to reach the Cmax after inhalation of CHF6001
PK Parameter -- AUC(0-∞_inh) -- Plasma -- CHF6001	At baseline (pre-dose) (within 60 min from inhaled dosing) and at the following timepoints post inhaled dose: 15, 30, 60, 90 min, 2, 3.75, 5.75, 7.75, 9.75, 11.75, 13.75, 25.75, 49.75, 73.75, 97.75, 121.75, 145.75, 169.75, 193.75, 217.75, and 241.75 hours	AUC(0-∞_inh) for CHF6001 in plasma. AUC(0-∞_inh)=Area under curve extrapolated to infinity after inhalation of CHF6001
PK Parameter -- t(1/2_inh) -- Plasma -- CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints post inhaled dose: 15, 30, 60, 90 min, 2, 3.75, 5.75, 7.75, 9.75, 11.75, 13.75, 25.75, 49.75, 73.75, 97.75, 121.75, 145.75, 169.75, 193.75, 217.75, and 241.75 hours.	t(1/2_inh) for CHF6001 in plasma. t(1/2_inh)=Terminal half-life, after inhalation of CHF6001
PK Parameter -- Absolute Inhaled Bioavailability (F_inh) -- Plasma -- CHF6001	At baseline (pre-dose) (within 60 min from inhaled dosing) and at the following timepoints post inhaled dose: 15, 30, 60, 90 min, 2, 3.75, 5.75, 7.75, 9.75, 11.75, 13.75, 25.75, 49.75, 73.75, 97.75, 121.75, 145.75, 169.75, 193.75, 217.75, and 241.75 hours	Absolute inhaled bioavailability for CHF6001. F_inh=Inhaled absolute bioavailability based on AUC(0-∞) after inhalation of CHF6001 F_inh=(AUC(0-∞)_inh x Dose_iv)/ (AUC(0-∞)_iv x Dose_inh).
PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total	Baseline (pre dose, -12-0h) and relative to the start of the IV infusion at: 0-4h, 4-8h, 8-12h, 12-24h, 24-48h, 48-72h, 72-96h, 96-120h, 120-144h, 144-168h, 168-192h, 192-216h, and 216-240h.	Urine excreted fraction for cumulative \[14\^C\] total.
PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001	Baseline (pre dose, -12-0h) and relative to the start of the IV infusion at: 0-4h, 4-8h, 8-12h, 12-24h, 24-48h, 48-72h, 72-96h, 96-120h, 120-144h, 144-168h, 168-192h, 192-216h, and 216-240h.	Urine excreted fraction for cumulative \[14\^C\]-CHF6001. Measurements in urine were performed. All measured values were below the limit of quantification of the bioanalytical method.
PK Parameter -- AUC(0-t_iv) -- Plasma -- [14^C] Total	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	AUC(0-t_iv) for \[14\^C\] total in plasma. AUC(0-t_iv)=Area Under the curve, from 0 to the last quantifiable concentration, after intravenous (iv) infusion administration.
PK Parameter -- C(max_iv) -- Plasma -- [14^C] Total	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	C(max_iv) for \[14\^C\] total in plasma. C(max_iv)=Peak plasma concentration after intravenous (iv) infusion administration
PK Parameter -- AUC(0-t_iv) -- Plasma -- [14^C] CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	AUC(0-t_iv) for \[14\^C\] CHF6001 in plasma. AUC(0-t_iv)=Area Under the curve, from 0 to the last quantifiable concentration, after intravenous (iv) infusion administration
PK Parameter -- AUC(0-∞_iv) -- Plasma -- [14^C] CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	Area under curve extrapolated to infinity (AUC0-∞_iv) for \[14\^C\] CHF6001 in plasma. AUC(0-∞_iv)=Area under curve extrapolated to infinity, after intravenous (iv) infusion administration
PK Parameter -- Volume of Distribution During the Terminal Phase (Vz_iv) -- Plasma -- [14^C] CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	Volume of distribution during the terminal phase (Vz_iv) of \[14\^C\] CHF6001 in plasma. Vz_iv=Volume of distribution during the terminal phase, after intravenous (iv) infusion administration
PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total	Baseline (pre dose, Day -1) and relative to the start of the IV infusion at: 0-24h, 24-48h, 48-72h, 72-96h, 96-120h, 120-144h, 144-168h, 168-192h, 192-216h, and 216 -240h.	Fecal excreted fraction for cumulative \[14\^C\] total.
PK Parameter -- t(max_iv) -- Plasma -- [14^C] Total	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	t(max_iv) for \[14\^C\] total. t(max_iv)=Time to reach the Cmax, after intravenous (iv) infusion administration
PK Parameter -- AUC(0-∞_iv) -- Plasma -- [14^C] Total	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	Area under curve extrapolated to infinity (AUC(0-∞_iv) for \[14\^C\] total in plasma. AUC(0-∞_iv)=Area under curve extrapolated to infinity, after intravenous (iv) infusion administration
PK Parameter -- (Blood to Plasma Ratio) -- Blood, Plasma -- [14^C] Total	Pre-dose (within 60 min from inhaled dosing) and at 20 min after the start of IV infusion.	Blood to plasma ratio for \[14\^C\] total.
PK Parameter -- C(max_iv) -- Plasma -- [14^C] CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	C(max_iv) for \[14\^C\] CHF6001 in plasma. C(max_iv)=Peak plasma concentration, after intravenous (iv) infusion administration
PK Parameter -- t(max_iv) -- Plasma -- [14^C] CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	t(max_iv) for \[14\^C\] CHF6001. t(max_iv)=Time to reach the Cmax, after intravenous (iv) infusion administration
PK Parameter -- t(1/2_iv) -- Plasma -- [14^C] CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	Terminal half-life t(1/2_iv) for \[14\^C\] CHF6001 in plasma. t(1/2_iv)=Terminal half-life, after intravenous (iv) infusion administration
PK Parameter -- Vdss_iv -- Plasma -- [14^C] CHF6001	Pre-dose (within 60 min from inhaled dosing) and at the following timepoints relative to the start of the IV infusion: 5, 10, 15 [end of infusion], 20, 25, 30, 45, 60 min, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours.	Vdss_iv=Volume of distribution is calculated at steady-state for \[14\^C\] CHF6001 in plasma, after intravenous (iv) infusion administration.
PK Parameter -- Blood to Plasma Ratio -- Blood, Plasma -- [14^C] CHF6001	Pre-dose (within 60 min from inhaled dosing) and at 20 min after the start of IV infusion.	Blood to plasma ratio for \[14\^C\] CHF6001.
PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001	Baseline (pre dose, Day -1) and relative to the start of the IV infusion at: 0-24h, 24-48h, 48-72h, 72-96h, 96-120h, 120-144h, 144-168h, 168-192h, 192-216h, and 216 -240h.	Fecal excreted fraction for cumulative \[14\^C\]-CHF6001.
PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total	Over 240 h after administration; please see timepoints for outcome #22 (urine) and #24 (fecal).	Urine and fecal excreted fraction for cumulative \[14\^C\] total.
PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001	Over 240 h after administration; please see timepoints for outcome #22 (urine) and #24 (fecal).	Urine and Fecal excreted fraction for cumulative \[14\^C\]-CHF6001.