Chronic Obstructive Pulmonary Disease (COPD), COPD
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, COPD, Healthy subjects, Phase I, CHF6001, Tanimilast, 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.
Interventions
DRUGCHF6001
4 inhalations of CHF6001 800 µg/20 mg NEXThaler® dry-powder inhaler (DPI), (total dose of 3200µg) co-administered with an intravenous microdose (18.5µg (18.5 kBq)) of \[14\^C\]-labelled CHF6001
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
30 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Subject's written informed consent obtained prior to any study-related procedure; 2. 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; 3. Male subjects aged 30 to 55 years inclusive; 4. Body mass index (BMI) within the range of 18 to 35 kg/m\^2 inclusive; 5. Non- or ex-smoker who smoked \< 5 pack years and who stopped smoking \> 1 year prior to screening; 6. Good physical and mental status; 7. Vital signs at screening within limits; 8. 12-lead digitised Electrocardiogram (12-lead ECG) in triplicate considered as normal; 9. Lung function measurements within normal limits at screening; 10. Regular bowel movements at screening; 11. 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
1. 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; 2. Clinically relevant and uncontrolled respiratory, cardiac, hepatic (including Gilbert syndrome), gastrointestinal, renal, endocrine, metabolic, neurologic, or psychiatric disorder; 3. Clinically relevant abnormal laboratory values; 4. Subjects with history of breathing problems; 5. Positive to Human Immunodeficiency Virus 1/Human Immunodeficiency Virus 2 (HIV1/HIV2) serology at screening; 6. Positive results from the Hepatitis serology which indicates acute or chronic Hepatitis B or Hepatitis C at screening; 7. Blood donation or blood loss (equal or more than 450 mL) less than 2 months prior screening or prior to treatment; 8. Positive urine test for cotinine; 9. Documented history of alcohol abuse within 12 months prior to screening or a positive alcohol breath test; 10. Documented history of drug abuse within 12 months prior to screening or a positive urine drug screen; 11. Intake of non-permitted concomitant medications in the predefined period; 12. Presence of any current infection, or previous infection that resolved less than 7 days prior to screening or before treatment; 13. Known intolerance and/or hypersensitivity to any of the excipients contained in the formulation used in the trial; 14. Unsuitable veins for repeated venipuncture; 15. Heavy caffeine drinker; 16. Abnormal haemoglobin level at screening; 17. Subjects using e-cigarettes within 6 months prior to screening; 18. Subjects been involved in a study involving a 14\^C-labeled drug within the 12 months prior to enrollment; 19. 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; 20. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 -- 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 -- 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 -- (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 -- 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 -- 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 -- 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 -- 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 -- 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 -- 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 -- 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 -- 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 -- 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 -- 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 -- 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 -- 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 -- 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. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CHF6001 Single dose of CHF6001 DPI co-administered with an intravenous microdose of \[14\^C\]-labelled CHF6001
CHF6001: 4 inhalations of CHF6001 800µg/20mg NEXThaler® DPI (total dose of 3200µg) co-administered with an intravenous microdose (18.5µg (18.5kBq)) of \[14\^C\]-labelled CHF6001 | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | CHF6001 |
|---|---|
| Age, Continuous | 36.3 years STANDARD_DEVIATION 4.4 |
| Body mass index | 28.09 kg/m^2 STANDARD_DEVIATION 4.73 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United Kingdom | 8 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 1 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
PK Parameter -- Absolute Inhaled Bioavailability (F_inh) -- Plasma -- CHF6001
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).
Time frame: 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
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- Absolute Inhaled Bioavailability (F_inh) -- Plasma -- CHF6001 | 0.4977 Ratio | Geometric Coefficient of Variation 26.8 |
Primary
PK Parameter -- AUC(0-∞_inh) -- Plasma -- CHF6001
AUC(0-∞\_inh) for CHF6001 in plasma. AUC(0-∞\_inh)=Area under curve extrapolated to infinity after inhalation of CHF6001
Time frame: 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
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- AUC(0-∞_inh) -- Plasma -- CHF6001 | 72403 h*pg/mL | Geometric Coefficient of Variation 28.4 |
Primary
PK Parameter -- AUC(0-∞_iv) -- Plasma -- [14^C] CHF6001
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
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- AUC(0-∞_iv) -- Plasma -- [14^C] CHF6001 | 0.8138 h*ng/mL | Geometric Coefficient of Variation 18.6 |
Primary
PK Parameter -- AUC(0-∞_iv) -- Plasma -- [14^C] Total
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
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- AUC(0-∞_iv) -- Plasma -- [14^C] Total | 6.0825 h*ngEq/mL | Geometric Coefficient of Variation 19.6 |
Primary
PK Parameter -- AUC(0-t)_inh -- Plasma -- CHF6001
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
Time frame: 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
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- AUC(0-t)_inh -- Plasma -- CHF6001 | 71088 h*pg/mL | Standard Deviation 28.2 |
Primary
PK Parameter -- AUC(0-t_iv) -- Plasma -- [14^C] CHF6001
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
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- AUC(0-t_iv) -- Plasma -- [14^C] CHF6001 | 0.7825 h*ng/mL | Geometric Coefficient of Variation 18.2 |
Primary
PK Parameter -- AUC(0-t_iv) -- Plasma -- [14^C] Total
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.
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- AUC(0-t_iv) -- Plasma -- [14^C] Total | 5.4025 h*ngEq/mL | Geometric Coefficient of Variation 16.7 |
Primary
PK Parameter -- Blood to Plasma Ratio -- Blood, Plasma -- [14^C] CHF6001
Blood to plasma ratio for \[14\^C\] CHF6001.
Time frame: Pre-dose (within 60 min from inhaled dosing) and at 20 min after the start of IV infusion.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- Blood to Plasma Ratio -- Blood, Plasma -- [14^C] CHF6001 | 0.5166 Ratio | Geometric Coefficient of Variation 54.9 |
Primary
PK Parameter -- (Blood to Plasma Ratio) -- Blood, Plasma -- [14^C] Total
Blood to plasma ratio for \[14\^C\] total.
Time frame: Pre-dose (within 60 min from inhaled dosing) and at 20 min after the start of IV infusion.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- (Blood to Plasma Ratio) -- Blood, Plasma -- [14^C] Total | 0.6490 Ratio | Geometric Coefficient of Variation 23.9 |
Primary
PK Parameter -- Clearance (CL_iv) -- Plasma -- [14^C] CHF6001
Systemic plasma clearance for \[14\^C\] CHF6001.
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- Clearance (CL_iv) -- Plasma -- [14^C] CHF6001 | 21.9951 Litres/h | Geometric Coefficient of Variation 18.6 |
Primary
PK Parameter -- C(max_inh) -- Plasma -- CHF6001
C(max\_inh) for CHF6001 in plasma. C(max\_inh)=Peak plasma concentration after inhalation of CHF6001
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- C(max_inh) -- Plasma -- CHF6001 | 1979 pg/mL | Geometric Coefficient of Variation 22.5 |
Primary
PK Parameter -- C(max_iv) -- Plasma -- [14^C] CHF6001
C(max\_iv) for \[14\^C\] CHF6001 in plasma. C(max\_iv)=Peak plasma concentration, after intravenous (iv) infusion administration
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- C(max_iv) -- Plasma -- [14^C] CHF6001 | 0.6312 ng/mL | Geometric Coefficient of Variation 19.1 |
Primary
PK Parameter -- C(max_iv) -- Plasma -- [14^C] Total
C(max\_iv) for \[14\^C\] total in plasma. C(max\_iv)=Peak plasma concentration after intravenous (iv) infusion administration
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- C(max_iv) -- Plasma -- [14^C] Total | 0.7072 ngEq/mL | Geometric Coefficient of Variation 21.6 |
Primary
PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001
Fecal excreted fraction for cumulative \[14\^C\]-CHF6001.
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-24 h | 0.0435 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0676 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-48 h | 0.1748 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0895 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-72 h | 0.2507 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0855 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-96 h | 0.2816 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0685 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-120 h | 0.3048 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.066 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-144 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-168 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-192 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-216 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C]-CHF6001 | 0-240 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
Primary
PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total
Fecal excreted fraction for cumulative \[14\^C\] total.
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 0-24 h | 7.64 Cumulative % of dose excreted in feces | Standard Deviation 12 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 24-48 h | 38.9 Cumulative % of dose excreted in feces | Standard Deviation 20.6 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 48-72 h | 57.7 Cumulative % of dose excreted in feces | Standard Deviation 8.53 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 72-96 h | 64.9 Cumulative % of dose excreted in feces | Standard Deviation 4.26 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 96-120 h | 68.6 Cumulative % of dose excreted in feces | Standard Deviation 2.35 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 120-144 h | 69.6 Cumulative % of dose excreted in feces | Standard Deviation 2.08 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 144-168 h | 70.0 Cumulative % of dose excreted in feces | Standard Deviation 2.09 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 168-192 h | 70.5 Cumulative % of dose excreted in feces | Standard Deviation 2.19 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 192-216 h | 70.7 Cumulative % of dose excreted in feces | Standard Deviation 2.22 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Fecal -- [14^C] Total | 216-240 h | 70.8 Cumulative % of dose excreted in feces | Standard Deviation 2.26 |
Primary
PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001
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.
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.~Measurements in urine were performed and no substance was detected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-4 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-8 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-12 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-24 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-48 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-72 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-96 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-120 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-144 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-168 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-192 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-216 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C]-CHF6001 | 0-240 h | 0.00 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0 |
Primary
PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total
Urine excreted fraction for cumulative \[14\^C\] total.
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 0-4 h | 1.99 Cumulative % of dose excreted in urine | Standard Deviation 0.523 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 4-8 h | 3.26 Cumulative % of dose excreted in urine | Standard Deviation 0.552 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 8-12 h | 3.93 Cumulative % of dose excreted in urine | Standard Deviation 0.549 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 12-24 h | 5.24 Cumulative % of dose excreted in urine | Standard Deviation 0.554 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 24-48 h | 6.77 Cumulative % of dose excreted in urine | Standard Deviation 0.519 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 48-72 h | 7.35 Cumulative % of dose excreted in urine | Standard Deviation 0.553 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 72-96 h | 7.64 Cumulative % of dose excreted in urine | Standard Deviation 0.622 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 96-120 h | 7.80 Cumulative % of dose excreted in urine | Standard Deviation 0.673 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 120-144 h | 7.89 Cumulative % of dose excreted in urine | Standard Deviation 0.703 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 144-168 h | 7.96 Cumulative % of dose excreted in urine | Standard Deviation 0.72 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 168-192 h | 8.01 Cumulative % of dose excreted in urine | Standard Deviation 0.729 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 192-216 h | 8.06 Cumulative % of dose excreted in urine | Standard Deviation 0.763 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine -- [14^C] Total | 216-240 h | 8.10 Cumulative % of dose excreted in urine | Standard Deviation 0.771 |
Primary
PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001
Urine and Fecal excreted fraction for cumulative \[14\^C\]-CHF6001.
Time frame: Over 240 h after administration; please see timepoints for outcome #22 (urine) and #24 (fecal).
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-24 h | 0.0435 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0676 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-48 h | 0.1748 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0895 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-72 h | 0.2507 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0855 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-96 h | 0.2816 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0685 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-120 h | 0.3048 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.066 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-144 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-168 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-192 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-216 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C]-CHF6001 | 0-240 h | 0.3060 (%) percent of injected [14C]-CHF6001 | Standard Deviation 0.0642 |
Primary
PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total
Urine and fecal excreted fraction for cumulative \[14\^C\] total.
Time frame: Over 240 h after administration; please see timepoints for outcome #22 (urine) and #24 (fecal).
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 0-4 h | 1.99 Cumulative % of dose excreted | Standard Deviation 0.523 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 4-8 h | 3.26 Cumulative % of dose excreted | Standard Deviation 0.552 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 8-12 h | 3.93 Cumulative % of dose excreted | Standard Deviation 0.549 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 12-24 h | 12.9 Cumulative % of dose excreted | Standard Deviation 12.3 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 24-48 h | 45.6 Cumulative % of dose excreted | Standard Deviation 20.8 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 48-72 h | 65.1 Cumulative % of dose excreted | Standard Deviation 8.67 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 72-96 h | 72.5 Cumulative % of dose excreted | Standard Deviation 4.12 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 96-120 h | 76.4 Cumulative % of dose excreted | Standard Deviation 2.46 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 120-144 h | 77.5 Cumulative % of dose excreted | Standard Deviation 2.23 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 144-168 h | 77.9 Cumulative % of dose excreted | Standard Deviation 2.32 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 168-192 h | 78.5 Cumulative % of dose excreted | Standard Deviation 2.46 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 192-216 h | 78.7 Cumulative % of dose excreted | Standard Deviation 2.51 |
| CHF6001 | PK Parameter -- Cumulative Excreted Fraction (in %) -- Urine and Fecal -- [14^C] Total | 216-240 h | 78.9 Cumulative % of dose excreted | Standard Deviation 2.58 |
Primary
PK Parameter -- t(1/2_inh) -- Plasma -- CHF6001
t(1/2\_inh) for CHF6001 in plasma. t(1/2\_inh)=Terminal half-life, after inhalation of CHF6001
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CHF6001 | PK Parameter -- t(1/2_inh) -- Plasma -- CHF6001 | 41.5691 h |
Primary
PK Parameter -- t(1/2_iv) -- Plasma -- [14^C] CHF6001
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
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CHF6001 | PK Parameter -- t(1/2_iv) -- Plasma -- [14^C] CHF6001 | 13.5816 h |
Primary
PK Parameter -- t(1/2_iv) -- Plasma -- [14^C] Total
Terminal half-life t(1/2\_iv) for \[14\^C\] total and CHF6001. t1/2\_iv=Terminal half-life, after intravenous (iv) infusion administration
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CHF6001 | PK Parameter -- t(1/2_iv) -- Plasma -- [14^C] Total | 72.4057 h |
Primary
PK Parameter -- t(max_inh) -- Plasma -- CHF6001
t(max\_inh) for CHF6001 in plasma. t(max\_inh)=Time to reach the Cmax after inhalation of CHF6001
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CHF6001 | PK Parameter -- t(max_inh) -- Plasma -- CHF6001 | 2.008 h |
Primary
PK Parameter -- t(max_iv) -- Plasma -- [14^C] CHF6001
t(max\_iv) for \[14\^C\] CHF6001. t(max\_iv)=Time to reach the Cmax, after intravenous (iv) infusion administration
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CHF6001 | PK Parameter -- t(max_iv) -- Plasma -- [14^C] CHF6001 | 0.217 h |
Primary
PK Parameter -- t(max_iv) -- Plasma -- [14^C] Total
t(max\_iv) for \[14\^C\] total. t(max\_iv)=Time to reach the Cmax, after intravenous (iv) infusion administration
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CHF6001 | PK Parameter -- t(max_iv) -- Plasma -- [14^C] Total | 0.217 h |
Primary
PK Parameter -- Vdss_iv -- Plasma -- [14^C] CHF6001
Vdss\_iv=Volume of distribution is calculated at steady-state for \[14\^C\] CHF6001 in plasma, after intravenous (iv) infusion administration.
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- Vdss_iv -- Plasma -- [14^C] CHF6001 | 201.2514 Litres | Geometric Coefficient of Variation 36.2 |
Primary
PK Parameter -- Volume of Distribution During the Terminal Phase (Vz_iv) -- Plasma -- [14^C] CHF6001
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
Time frame: 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.
Population: Pharmacokinetic Population: all subjects from the safety population excluding subjects without any valid pharmacokinetic (PK) measurement or with major protocol deviations significantly affecting PK, for example: incorrect inhalation, change in subject condition (cold), failure in delivery of the device, use of non-permitted medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CHF6001 | PK Parameter -- Volume of Distribution During the Terminal Phase (Vz_iv) -- Plasma -- [14^C] CHF6001 | 436.1078 Litres | Geometric Coefficient of Variation 38.6 |