Healthy
Conditions
Brief summary
This is a single-centre, open-label, non-randomized, single dose study in healthy male subjects designed to assess mass balance recovery, metabolite profile and metabolite identification of radio-labeled BC-3781 administered via the intravenous or oral routes.
Detailed description
This is a single-centre, open-label, non-randomised, single dose study to assess the pharmacokinetics, mass balance recovery, and metabolite profiling and identification following administration of iv or oral 14C-BC-3781 to healthy male subjects It is planned to enrol 2 cohorts of 5 subjects or 10 subjects in total. The active substance being investigated in this study is radiolabeled lefamulin (\[14C\] BC 3781), present in the investigational medicinal products (IMPs) as the acetate salt (\[14C\]-BC-3781.Ac). Subjects assigned to Cohort A will receive a single IV administration of 14C-BC-3781 containing 150 mg BC-3781 and not more than (NMT) 4.3 MBq (117 µCi) 14C, administered as an infusion over 60 min after a light breakfast. Subjects assigned to Cohort B will receive a single oral administration of 14C-BC-3781 containing 600 mg BC-3781 and NMT 4.1 MBq (112 µCi) 14C, in the fasted state
Interventions
DRUGBC-3781
Lefamulin (BC-3781) is a potent, semi-synthetic antibacterial belonging to a novel class for systemic human use known as the pleuromutilins
Sponsors
Quotient Clinical
Nabriva Therapeutics AG
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
open label
Eligibility
Sex/Gender
MALE
Age
30 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy males * Aged 30 to 65 years * Body mass index of 18.0 to 35.0 kg/m2, inclusive * Must have regular bowel movements * Must provide written informed consent * Must agree to use an adequate method of contraception
Exclusion criteria
* Subjects who have received any IMP in a clinical research study within the previous 3 months * History of any drug or alcohol abuse in the past 2 years * Regular alcohol consumption in males \>21 units per week and females \>14 units per week * Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 1999, shall participate in the study * Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening * Subjects who have been dosed in an ADME study in the last 12 months * Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator * Positive drugs of abuse test result at screening and admission * Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results * Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of \<90 mL/min using the Cockcroft-Gault equation * Significant history of cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, or psychiatric disorders as judged by the investigator * A familial history or presence of Long QT syndrome * Subjects with QT interval corrected according to Fridericia's formula (QTcF) \>480 ms * A serum potassium level of less than 3.5 mmol/L at screening * Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients * Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. * Donation or loss of greater than 400 mL of blood within the previous 3 months * Have taken medications known to be strong P-gp inhibitors, or strong CYP3A4 inducers or inhibitors, within 28 days before IMP administration * Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than 4 g per day paracetamol or herbal remedies) in the 14 days before IMP administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Amount of radioactivity eliminated in urine | Day 1 pre-dose to Day 8 post-dose | Amount excreted (Ae) and AE as a percentage of administered dose (%Ae) |
| Amount of radioactivity eliminated in feces | Day 1 pre-dose to Day 8 post-dose | Amount excreted (Ae) and AE as a percentage of administered dose (%Ae) |
| Amount of radioactivity eliminated in urine and feces | Day 1 pre-dose to Day 8 post-dose | Amount excreted (Ae) and AE as a percentage of administered dose (%Ae) |
| Cumulative amount of radioactivity eliminated in urine | Day 1 pre-dose to Day 8 post-dose | Cumulative recovery (CumAe)and CumAe as a percentage of the dose (Cum%Ae) |
| Cumulative amount of radioactivity eliminated in feces | Day 1 pre-dose to Day 8 post-dose | Cumulative recovery (CumAe)and CumAe as a percentage of the dose (Cum%Ae) |
| Cumulative amount of radioactivity eliminated in urine and feces | Day 1 pre-dose to Day 8 post-dose | Cumulative recovery (CumAe)and CumAe as a percentage of the dose (Cum%Ae) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Metabolic profiling and structural identification in plasma | Day 1 pre-dose to Day 8 post-dose | Number of metabolites \>10% of circulating radioactivity in plasma |
| Metabolic profiling and structural identification in urine | Day 1 pre-dose to Day 8 post-dose | Number of metabolites \>10% of the dose in urine |
| Metabolic profiling and structural identification in feces | Day 1 pre-dose to Day 8 post-dose | Number of metabolites \>10% of the dose in feces |
| PK of total radioactivity: lag time (tlag), BC-3781 and major metabolites | Day 1 pre-dose to Day 8 post-dose | Assessment of pharmacokinetics of lefamulin as assessed by radioactivity lag time |
| Safety - hematology | Day 1 pre-dose to Day 8 post-dose | Safety as assessed by review of changes in hematology |
| PK of total radioactivity: AUC | Day 1 pre-dose to Day 8 post-dose | area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUC last) of BC-3781 and major metabolites |
| PK of total radioactivity: AUC (0-infinity) | Day 1 pre-dose to Day 8 post-dose | area under the plasma concentration-time curve from time zero to infinity (AUCinf), BC-3781 and major metabolites |
| PK of total radioactivity: Time to Cmax | Day 1 pre-dose to Day 8 post-dose | Time to reach total maximum observed concentration (tmax), BC-3781 and major metabolites |
| PK of total radioactivity: elimination half-life | Day 1 pre-dose to Day 8 post-dose | elimination half-life (t1/2), BC-3781 and major metabolites |
| PK of total radioactivity: Cmax | Day 1 pre-dose to Day 8 post-dose | Peak plasma concentration (Cmax), BC-3781 and major metabolites |
| Safety - clinical chemistry | Day 1 pre-dose to Day 8 post-dose | Safety as assessed by review of changes in clinical chemistry |
| Safety - urinalysis | Day 1 pre-dose to Day 8 post-dose | Safety as assessed by review of changes in urinalysis |
| Safety - electrocardiograms | Day 1 pre-dose to Day 8 post-dose | Safety as assessed by review of changes in electrocardiograms |
| Safety - vital signs | Day 1 pre-dose to Day 8 post-dose | Safety as assessed by review of changes in vital signs |
| Safety - adverse events | Day 1 pre-dose to Day 8 post-dose | Safety as assessed by review of adverse events |
Countries
United Kingdom
Outcome results
None listed