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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: BC-3781

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 Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom, NG11 6JS
    • Quotient Clinical

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A; 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; Lefamulin (BC-3781) is a potent, semi-synthetic antibacterial belonging to a novel class for systemic human use known as the pleuromutilins; Other Names: Lefamulin
Experimental: Cohort B; 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; Lefamulin (BC-3781) is a potent, semi-synthetic antibacterial belonging to a novel class for systemic human use known as the pleuromutilins; Other Names: Lefamulin

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Nabriva Therapeutics AG
• Collaborators: Quotient Clinical
• Investigators: Study Director: Elyse Seltzer, MD, Nabriva Therapeutics AG

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2017
• Primary Completion (Actual): October 9, 2017
• Study Completion (Actual): March 30, 2018

Study Registration Dates

• First Submitted: February 16, 2017
• First Submitted That Met QC Criteria: April 24, 2017
• First Posted (Actual): April 27, 2017

Study Record Updates

• Last Update Posted (Actual): April 3, 2018
• Last Update Submitted That Met QC Criteria: April 1, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Lefamulin
• Other Study ID Numbers: NAB-BC-3781-1013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No