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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 13
- 试验地点
- 6
- 主要终点
- The Key Geometric Mean for Lefamulin and Its Main Metabolite BC-8041 for PK Plasma Parameter Cmax in CF Patients.
研究概览
简要总结
This study is intended to assess the pharmacokinetic (PK) and safety of a single dose of IV and oral formulations of lefamulin in adults with cystic fibrosis (CF).
详细描述
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 Methicillin-resistant Staphylococcus aureus (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 Cystic fibrosis transmembrane conductance regulator (protein) (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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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
- •Use of cytochrome P450 (CYP)3A substrates that prolong the QT interval within 24 hours prior to Day
- •Use of strong and moderate Cytochrome P450 (CYP3A) inducers or P-glycoprotein (P-gp) inducers within 28 days prior to Day
- •Use of strong inhibitors of CYP3A4 within 24 hours prior to Day
- •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
- •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
- •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.
研究组 & 干预措施
Group B
Group B will receive one dose of 600 mg lefamulin oral followed by one dose of 150 mg lefamulin IV
干预措施: Lefamulin (Drug)
Group A
Group A will receive one dose of 150 mg lefamulin IV followed by one dose of 600 mg lefamulin oral
干预措施: Lefamulin (Drug)
结局指标
主要结局
The Key Geometric Mean for Lefamulin and Its Main Metabolite BC-8041 for PK Plasma Parameter Cmax in CF Patients.
时间窗: Pre-dose, 0.5 hr, 1 hr, 1.5 hrs, 2 hrs, 4 hrs, 8 hrs, 12 hrs & 24 hrs Post-dose
Appropriate non-compartmental techniques will be used to obtain estimates for the PK parameter Cmax in plasma for lefamulin and its metabolite BC-8041. Maximum observed plasma concentration (Cmax) Cmax was determined by direct inspection of the concentration versus time data by WinNonlin.
The Median for Lefamulin and Its Main Metabolite BC-8041 for PK Plasma Parameter Tmax in Cystic Fibrosis (CF) Patients.
时间窗: Pre-dose, 0.5 hr, 1 hr, 1.5 hrs, 2 hrs, 4 hrs, 8 hrs, 12 hrs & 24 hrs Post-dose
Appropriate non-compartmental techniques were used to obtain estimates for the PK parameter Tmax in plasma for lefamulin and its metabolite BC-8041. Time to reach maximum plasma concentration of lefamulin following drug administration (Tmax) Tmax will be determined by direct inspection of the concentration versus time data by WinNonlin.
The Key Geometric Mean for Lefamulin and Its Main Metabolite BC-8041 for PK Plasma Parameter AUC(0-last) in CF Patients.
时间窗: Pre-dose, 0.5 hr, 1 hr, 1.5 hrs, 2 hrs, 4 hrs, 8 hrs, 12 hrs & 24 hrs Post-dose
Appropriate non-compartmental techniques will be used to obtain estimates for the PK parameter (AUC0-last) in plasma for lefamulin and its metabolite BC-8041. AUC calculations will be performed using the linear/log trapezoidal rule. AUC0-last will be calculated between t0hr and the last measurable concentration. Area under the drug concentration curve from time zero (0 h) to 24 h (AUC0-last)
The Key Geometric Mean for Lefamulin and Its Main Metabolite BC-8041 for PK Plasma Parameter AUC(0-inf) in CF Patients.
时间窗: Pre-dose, 0.5 hr, 1 hr, 1.5 hrs, 2 hrs, 4 hrs, 8 hrs, 12 hrs & 24 hrs Post-dose
Appropriate non-compartmental techniques will be used to obtain estimates for PK parameter AUC(0-inf) in plasma for lefamulin and its metabolite BC-8041. AUC calculations will be performed using the linear/log trapezoidal rule. AUC(0-inf) will be will be calculated between t0hr and infinity. Area under the drug concentration curve from time zero (0 h) to infinity (AUC(0-inf)
The Key Geometric Mean for Lefamulin and Its Main Metabolite BC-8041 for PK Plasma Parameter t1/2 in CF Patients.
时间窗: Pre-dose, 0.5 hr, 1 hr, 1.5 hrs, 2 hrs, 4 hrs, 8 hrs, 12 hrs & 24 hrs Post-dose
Appropriate non-compartmental techniques will be used to obtain estimates for thr PK parameter t1/2 in plasma for lefamulin and its metabolite BC-8041. Apparent elimination half-life calculated as ln(2)/ke (t½)
次要结局
未报告次要终点