Clinical trial NCT04991181: Absorption, Distribution, Metabolism and Excretion of BIA 5-1058
Official title: An Open-label Study to Assess the Absorption, Distribution, Metabolism and Excretion, Including the Mass Balance, of [14C] Labeled BIA 5-1058 and Metabolites Following a Single Oral Dose Administration in Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: Bial - Portela C S.A.
Sponsor class: INDUSTRY
First posted: 2021-08-05
Enrollment: 15
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: the purpose of this study is:

* to determine the rate and routes of excretion of BIA 5-1058 and the mass balance in urine, feces and exhaled air, after a single oral dose of 400 mg 14C labeled BIA 5 1058 containing 3.7 Megabecquerel (MBq) of radiocarbon;
* to determine the pharmacokinetics (PK) of total radioactivity (TRA) in plasma and whole blood and to assess the blood-to-plasma ratio;
* to determine the PK of BIA 5-1058 and its metabolites in plasma.

Detailed description: This was a Phase 1, single-center, open-label, absorption, distribution, metabolism, and excretion study in 8 healthy adult male subjects. Subjects received a single oral dose of 400 mg BIA 5-1058, containing approximately 3.7 MBq (0.08 milliSievert \[mSv\]) of 14C-BIA 5-1058 as oral capsules. Screening was between Day -21 and Day -2 and confinement period was of one period in the clinic involving drug administration on Day 1, with admission on Day 1 and discharge on Day 15 (336 hours post-dose).

Eligibility criteria: Inclusion Criteria:

1. Gender :male
2. Age :18-65 years, inclusive
3. Body Mass Index (BMI) :18.0-30.0 kg/m2 (BMI \[kg/m2\] = Body weight \[kg\] ÷ Height2 \[m2\]) at screening
4. Subjects, if not surgically sterilized, were willing to use adequate contraception and not donate sperm from admission to the clinical research center until 90 days after discharge on Day 15. Adequate contraception for the male subject (and his female partner) was defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. Also, total abstinence, in accordance with the lifestyle of the volunteer, was acceptable
5. All prescribed medication had to be stopped at least 30 days prior to admission to the clinical research center
6. All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (e.g., St. John's Wort) had to be stopped at least 14 days prior to admission to the clinical research center. An exception was made for paracetamol, which was allowed up to admission to the clinical research center
7. Ability and willingness to abstain from alcohol, methylxanthine-containing beverages or food (coffee, tea, cola, chocolate and "powerdrinks"), commercially available orange juice (because of a potential interaction of radioactivity and vitamin C), grapefruit (juice) and tobacco products from 48 hours prior to admission to in the clinical research center until discharge (Day 15)
8. Normal resting supine blood pressure and pulse showing no clinically relevant deviations as judged by the PI
9. Computerized (12-lead) ECG recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the PI
10. All values for clinical laboratory tests of blood and urine within the normal range or showing no clinically relevant deviations as judged by the PI
11. Willing and able to sign the ICF.

Exclusion Criteria:

1. Employee of PRA or the Sponsor
2. Evidence of clinically relevant pathology or a medical history of a major pathology as judged by the PI
3. Frequent headaches and/or migraine, recurrent nausea, and/or vomiting (more than twice a month)
4. Mental handicap (i.e. a general or specific intellectual disability, resulting directly or indirectly from injury to the brain or from abnormal neurological development)
5. History of relevant drug and/or food allergies
6. Smoking more than 5 cigarettes, 1 cigar or 1 pipe daily; the use of tobacco products in the 48 hours (2 days) prior to admission to the clinical research center on Day 1 was not allowed
7. History of alcohol abuse or drug addiction (including soft drugs like cannabis products)
8. Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines \[including ecstasy\], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants and alcohol)
9. Average intake of more than 24 units of alcohol per week (1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits)
10. Positive screen for hepatitis B surface antigen (HBsAg), anti hepatitis C virus (HCV) antibodies or anti human immunodeficiency virus (HIV) 1 and 2 antibodies
11. Participation in a drug study within 90 days prior to drug administration in the current study. Participation in more than 2 other drug studies in the 12 months prior to drug administration in the current study
12. Donation or loss of more than 100 mL of blood within 90 days prior to drug administration. Donation or loss of more than 1.5 liters of blood in the 10 months prior to drug administration in the current study
13. Subject with irregular bowel habits (more than 3 times a day or less than once every 2 days)
14. Strenuous exercise within 96 hours (4 days) prior to admission to the clinical research center
15. Significant and/or acute illness within 5 days prior to drug administration that may impact the safety of the subject, in the opinion of the PI
16. Participation in another ADME study with a radiation burden \>0.1 mSv in the period of 1 year prior to screening
17. Exposure to radiation for diagnostic reasons (except dental X rays and plain X rays of thorax and bony skeleton \[excluding spinal column\]), during work or during participation in a clinical study in the period of 1 year prior to screening
18. Previous use of BIA 5 1058.

Primary outcomes:
measure: Cmax - Maximum observed plasma concentration
timeFrame: Up to 20 days
measure: Tmax - Time to attain maximum observed plasma concentration
timeFrame: Up to 20 days
measure: AUC0-t Area under the plasma concentration-time curve up to time t, where t is the last point with concentrations above the lower limit of quantitation (LLOQ)
timeFrame: Up to 20 days
measure: AUC0-inf - Area under the plasma concentration-time curve from time 0 extrapolated to infinity
timeFrame: Up to 20 days
measure: t1/2 - Elimination half-life
timeFrame: Up to 20 days
measure: CLR - Renal clearance
timeFrame: Up to 20 days
measure: Aeurine - Cumulative amount excreted in urine
timeFrame: Up to 20 days
measure: Ae feces - Cumulative amount excreted in feces
timeFrame: Up to 20 days
measure: Aeair - Cumulative amount excreted in exhaled air
timeFrame: Up to 20 days
measure: Aetotal - Total amount excreted, calculated as Aeurine + Aefeces + Aeair
timeFrame: Up to 20 days
measure: TRA t1/2 plasma
timeFrame: Up to 20 days
measure: TRA t1/2 urine
timeFrame: Up to 20 days
measure: TRA t1/2 feces
timeFrame: Up to 20 days
Secondary outcomes:
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: PRA Health Sciences (PRA) - Early Development Services (EDS)
Study officials:
References: