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

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: BC-3781

• Registration Number: NCT03131141
• Lead Sponsor: Nabriva Therapeutics AG

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

Study Timeline

• Study Start: 2017-01-08
• Study First Submitted: 2017-02-16
• Study First Submitted QC: 2017-04-24
• Study First Posted: 2017-04-27
• Primary Completion: 2017-10-09
• Study Completion: 2018-03-30
• Status Verified: 2018-04
• Last Update Submitted: 2018-04-01
• Last Update Posted: 2018-04-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 10

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A	BC-3781	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
Cohort B	BC-3781	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

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Safety - hematology	Day 1 pre-dose to Day 8 post-dose	Safety as assessed by review of changes in hematology
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
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
PK of total radioactivity: Cmax	Day 1 pre-dose to Day 8 post-dose	Peak plasma concentration (Cmax), BC-3781 and major metabolites
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

Trial Locations

Locations (1)

Quotient Clinical; 🇬🇧 Nottingham, United Kingdom