Study to Assess the Safety and PK of Oral and IV Xenleta in Adults With Cystic Fibrosis

Study Overview
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Brief Summary
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This study is intended to assess the PK and safety of a single dose of IV and oral formulations of lefamulin in adults with CF.

Detailed Description
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Staphylococcus aureus is one of the most common causative pathogens associated with exacerbations of CF. Current treatment guidelines for the management of exacerbations of CF caused by S. aureus recommend the use of unapproved antibacterial agents. Further, many of the recommended treatments can only be administered via the IV route and/or have limitations due to safety and tolerability. Lefamulin is a novel, first-in-class, IV and oral pleuromutilin antimicrobial agent that has been demonstrated to be highly potent against S. aureus, including MRSA and strains obtained from patients with CF. Cystic fibrosis patients have altered drug distribution and elimination kinetics for many antimicrobials relative to patients without CF. While the advent of CFTR modulators has resulted in improved lung function and had a positive impact on the quality of life of CF patients, limited data have been published describing the impact of the concomitant use of CFTR modulators and commonly used antibacterial agents.

Official Title
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A Phase 1, Open-Label, Randomized, Crossover Study to Assess the Safety and Pharmacokinetics Following Single Doses of Oral and Intravenous Xenleta (Lefamulin) in Adult Patients With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Lefamulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent. Adult patients, ≥ 18 years of age. Genetic confirmation of CF diagnosis by a report from a genetic test, such as F508 deletion detected. Weight > 40 kgs. Forced expiration volume (FEV)1 > 40% predicted, as measured during the most recent evaluation. Mentally and physically able to participate in the study as determined by the Investigator, ie, clinically stable with no significant changes in health status within 28 days prior to, and including, Day 1. Vital signs within the following ranges: Tympanic temperature, < 38°C Systolic blood pressure, 90 to 160 mmHg Diastolic blood pressure, 50 to 90 mmHg Heart rate < 100 beats per minute at rest Respiration rate 12 to 20 breaths per minute Oxygen saturation to be documented. No selection criteria; supplemental oxygen use is acceptable. Negative beta-human chorionic gonadotropin (β-hCG) urine or serum pregnancy test for females of childbearing potential. Willing to commit to acceptable methods of contraception as defined in the protocol. Exclusion Criteria: Known history of chronic liver or biliary disease, Gilbert's syndrome, or any of the following at Screening: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 x upper limit of normal (ULN), total bilirubin > 1.5 x ULN. Prolonged baseline corrected QT interval corrected according to Fridericia (QTcF) defined as > 440 ms (females) and > 430 ms (males). Family history or presence of prolonged QTc syndrome, Torsades de Pointes, or known conduction defects (eg, bundle branch block, atrioventricular block). Use of Orkambi® (lumacaftor/ivacaftor) within 28 days prior to Day 1. Use of cytochrome P450 (CYP)3A substrates that prolong the QT interval within 24 hours prior to Day 1. Use of strong and moderate CYP3A inducers or P-glycoprotein (P-gp) inducers within 28 days prior to Day 1. Use of strong inhibitors of CYP3A4 within 24 hours prior to Day 1. Serum potassium level below the normal reference range at Screening. Known allergy to pleuromutilin class of antibiotic or any of the excipients of the lefamulin formulations. Consumption of grapefruit, grapefruit juice, grapefruit products, pomelo, or Seville oranges within 24 hours before Day 1. Use of vaporized nicotine or cannabidiol products, smoking (regularly or intermittently) more than 5 cigarettes (or equivalent) per day, or any use of tobacco other than in cigarettes or cigars within 28 days of Day 1. Positive blood test for hepatitis C, human immunodeficiency virus (HIV), or hepatitis B antigen or core antibody (indicating active infection). Positive test for drugs of abuse or alcohol at Screening or Day 1 that cannot be satisfactorily supported by medical history. Use of an investigational product within the 30 days prior to Day 1 (3 months prior to Day 1 if the study drug was a new chemical entity). Difficulty swallowing tablets. Females who are pregnant or breastfeeding. Does not have suitable venous access for multiple venipuncture or cannulation. Any medical, psychological, cognitive, social, or legal conditions that, in the opinion of the Investigator, would interfere with the patient's ability to give an informed consent and/or participate fully in the study. Any other reason, in the opinion of the Investigator, the patient is unsuitable to participate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Open-label, Crossover Study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Group A will receive one dose of 150 mg lefamulin IV followed by one dose of 600 mg lefamulin oral | Drug: Lefamulin<br>* Antibiotic<br>* Other names: BC-3781;|
| Experimental: Group B<br>Group B will receive one dose of 600 mg lefamulin oral followed by one dose of 150 mg lefamulin IV | Drug: Lefamulin<br>* Antibiotic<br>* Other names: BC-3781;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: Cmax: maximum observed plasma concentration | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: tmax: time to reach maximum plasma concentration of lefamulin following drug administration | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: AUC0-12h: area under the drug concentration curve from time zero (0 hour [h]) to 12 h | 12 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: AUC0-24h: area under the drug concentration curve from time zero (0 h) to 24 h | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: AUC0-last: area under the drug concentration curve from time zero (0 h) to 24 h | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: AUC∞ area under the drug concentration curve from time zero (0 h) to infinity | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: t½: apparent elimination half-life calculated as ln(2)/ ke | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: CL: clearance (IV dose only) | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: CL/F: total body clearance (oral dose only) | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: Tlag (oral dose only): the finite time taken for a drug to appear in systemic circulation following extravascular administration | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: AUC%extrap: percentage of AUC d | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: lambda-z: Individual estimate of the terminal elimination rate constant, calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: Vd (IV dose only): volume of distribution | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: Vd/F (oral dose only): volume of distribution corrected for bioavailability | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: Vss (IV dose only): volume of distribution at steady state | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: MRT: mean residence time | 24 hours | 
| To determine the plasma PK parameters of lefamulin and its main metabolite BC-8041 following 150 mg IV infusion and 500 mg IR tablet in adult patients with Cystic Fibrosis. | Appropriate non-compartmental techniques will be used to obtain estimates, including but not limited to, the following PK parameters in plasma for lefamulin and its metabolite BC-8041 when possible and appropriate: F: oral bioavailability | 24 hours |