A Study to Assess Mass Balance Recovery, Metabolite Profile and Identification of IV and Oral 14C-BC-3781

Study Overview
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Brief Summary
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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
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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

Official Title
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An Open Label, Single-dose, Single-period Study Designed to Assess the Mass Balance Recovery, Metabolite Profile and Metabolite Identification of 14C-BC-3781 Administered Via the Intravenous or Oral Routes to Healthy Male Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: BC-3781


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Cohort A will receive a single IV administration of 14C-BC-3781 containing 150 mg BC-3781 and NMT 4.3 MBq (117 µCi) 14C, administered as an infusion over 60 min after a light breakfast | Drug: BC-3781<br>* Lefamulin (BC-3781) is a potent, semi-synthetic antibacterial belonging to a novel class for systemic human use known as the pleuromutilins<br>* Other names: Lefamulin;|
| Experimental: Cohort B<br>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 | Drug: BC-3781<br>* Lefamulin (BC-3781) is a potent, semi-synthetic antibacterial belonging to a novel class for systemic human use known as the pleuromutilins<br>* Other names: Lefamulin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of radioactivity eliminated in urine | Amount excreted (Ae) and AE as a percentage of administered dose (%Ae) | Day 1 pre-dose to Day 8 post-dose | 
| Amount of radioactivity eliminated in feces | Amount excreted (Ae) and AE as a percentage of administered dose (%Ae) | Day 1 pre-dose to Day 8 post-dose | 
| Amount of radioactivity eliminated in urine and feces | Amount excreted (Ae) and AE as a percentage of administered dose (%Ae) | Day 1 pre-dose to Day 8 post-dose | 
| Cumulative amount of radioactivity eliminated in urine | Cumulative recovery (CumAe)and CumAe as a percentage of the dose (Cum%Ae) | Day 1 pre-dose to Day 8 post-dose | 
| Cumulative amount of radioactivity eliminated in feces | Cumulative recovery (CumAe)and CumAe as a percentage of the dose (Cum%Ae) | Day 1 pre-dose to Day 8 post-dose | 
| Cumulative amount of radioactivity eliminated in urine and feces | Cumulative recovery (CumAe)and CumAe as a percentage of the dose (Cum%Ae) | Day 1 pre-dose to Day 8 post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - hematology | Safety as assessed by review of changes in hematology | Day 1 pre-dose to Day 8 post-dose | 
| Safety - clinical chemistry | Safety as assessed by review of changes in clinical chemistry | Day 1 pre-dose to Day 8 post-dose | 
| Safety - urinalysis | Safety as assessed by review of changes in urinalysis | Day 1 pre-dose to Day 8 post-dose | 
| Safety - electrocardiograms | Safety as assessed by review of changes in electrocardiograms | Day 1 pre-dose to Day 8 post-dose | 
| Safety - vital signs | Safety as assessed by review of changes in vital signs | Day 1 pre-dose to Day 8 post-dose | 
| Safety - adverse events | Safety as assessed by review of adverse events | Day 1 pre-dose to Day 8 post-dose | 
| Metabolic profiling and structural identification in plasma | Number of metabolites >10% of circulating radioactivity in plasma | Day 1 pre-dose to Day 8 post-dose | 
| Metabolic profiling and structural identification in urine | Number of metabolites >10% of the dose in urine | Day 1 pre-dose to Day 8 post-dose | 
| Metabolic profiling and structural identification in feces | Number of metabolites >10% of the dose in feces | Day 1 pre-dose to Day 8 post-dose | 
| PK of total radioactivity: lag time (tlag), BC-3781 and major metabolites | Assessment of pharmacokinetics of lefamulin as assessed by radioactivity lag time | Day 1 pre-dose to Day 8 post-dose | 
| PK of total radioactivity: Cmax | Peak plasma concentration (Cmax), BC-3781 and major metabolites | Day 1 pre-dose to Day 8 post-dose | 
| PK of total radioactivity: AUC | area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUC last) of BC-3781 and major metabolites | Day 1 pre-dose to Day 8 post-dose | 
| PK of total radioactivity: AUC (0-infinity) | area under the plasma concentration-time curve from time zero to infinity (AUCinf), BC-3781 and major metabolites | Day 1 pre-dose to Day 8 post-dose | 
| PK of total radioactivity: Time to Cmax | Time to reach total maximum observed concentration (tmax), BC-3781 and major metabolites | Day 1 pre-dose to Day 8 post-dose | 
| PK of total radioactivity: elimination half-life | elimination half-life (t1/2), BC-3781 and major metabolites | Day 1 pre-dose to Day 8 post-dose |