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

Chiesi Farmaceutici S.p.A.8 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Chronic Obstructive Pulmonary Disease (COPD)COPD

Interventions

CHF6001DRUG

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

Eligibility

Sex: MALEMin age: 30 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (1)

Covance - Clinical Research Unit

Leeds, United Kingdom

Outcomes

Primary Outcomes

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.

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

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

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

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

Data from ClinicalTrials.gov

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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.

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

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

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

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

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

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

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.

PK Parameter -- Clearance (CL_iv) -- Plasma -- [14^C] CHF6001

Systemic plasma clearance for \[14\^C\] CHF6001.

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.

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

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.

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

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

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

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).

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.

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.

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.

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.

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).

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).