Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis

Study Overview
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Brief Summary
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The purpose of this study is to determine antimycobacterial drug pharmacokinetics (PK) and pharmacodynamics (PD) in patients with cystic fibrosis (CF) to improve treatment of nontuberculous mycobacterial (NTM) lung disease.

Detailed Description
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The purpose of this study is to determine antimycobacterial drug pharmacokinetics (PK) and pharmacodynamics (PD) in patients with cystic fibrosis (CF) to improve treatment of nontuberculous mycobacterial (NTM) lung disease. Aim 1: Determine the PK profile of oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient, compared to healthy controls. Aim 2: Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs. Aim 3: Estimate an optimized dosing regimen for the antimycobacterial drugs against Mycobacterium avium complex (MAC) using historic minimum inhibitory concentration (MIC) data and models of Mycobacterium tuberculosis or MAC infection. The central goal of this study is to improve treatment of NTM infection in CF. Upon completion of this study the investigators will determine if and why PK of the antimycobacterial drugs are altered in CF. More importantly, the investigators will develop CF-specific guidelines to achieve therapeutic goals with recommendations for drug dosing (including dose, dose frequency and timing in relation to meals and supplemental pancreatic enzymes) and timing of therapeutic monitoring to be used for future treatment of NTM lung disease in CF.

Official Title
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Pharmacokinetic Evaluation of Nontuberculous Mycobacterial Antibiotics in Cystic Fibrosis Versus Controls

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Ethambutol
* Drug: Rifampin
* Drug: Azithromycin
* Drug: Pancrelipase


Participation Criteria
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Eligibility Criteria
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CF Subject Inclusion Criteria: CF diagnosis defined as a sweat chloride >60mEq/L and/or the presence of two disease-causing CFTR mutations. Ages 16 years and above. Pancreatic insufficient status defined as previous fecal pancreatic elastase <100mcg/g stool and/or having 2 disease-causing CFTR mutations known to be associated with pancreatic insufficiency, and taking supplemental pancreatic enzymes between 1000-2500 lipase units/kg/meal. No positive NTM cultures in the last 2 years. Pulmonary function: Most recent FEV1 > 40% predicted. Willing to participate in and comply with the study procedures, and willingness of a parent or legally authorized representative to provide written informed consent for those subjects less than 18 years of age. Healthy Control Inclusion Criteria: Ages 18 years and above. BMI below 30 to best match CF body type. Willing to participate in and comply with the study procedures, and willingness of a parent or legally authorized representative to provide written informed consent for those subjects less than 18 years of age. CF Subject Exclusion Criteria: Allergy or intolerance to rifampin, ethambutol, or azithromycin. Hepatic insufficiency defined as having an AST or ALT greater than three times the upper limit of normal at the screening appointment. Previous surgical bowel resection. Previous lung transplant. Use of medications known to interact with the antimycobacterial drug levels; of note, the most common interactions in CF patients are the use of itraconazole, voriconazole, and ivacaftor. We will have subjects hold H2 blockers and proton pump inhibitors for 3 days prior to each PK study day. Inability to hold azithromycin: Subjects will not be excluded if they are on chronic azithromycin for immunomodulatory purposes; however, we will ask that the subjects hold the azithromycin starting at the screening visit, through a 2 week wash-out period prior to Visit 2, and remain off through the end of Visit 3 (about 4 weeks total). Acute exacerbations: exclusion if any addition of oral, IV, or inhaled antibiotics, or an acute gastrointestinal illness with vomiting or diarrhea in the 2 weeks prior to each visit. No exclusion for previously prescribed alternating chronic inhaled or oral antibiotics. We will also exclude pregnant women (urine pregnancy test will be performed for females on the day of each PK study) and decisionally challenged subjects. Healthy Control Exclusion Criteria: Allergy or intolerance to rifampin, ethambutol, or azithromycin. Hepatic insufficiency defined as having an AST or ALT greater than three times the upper limit of normal at the screening appointment. Previous chronic GI disease or surgical bowel resection. Use of medications known to interact with the antimycobacterial drug levels. We will have subjects hold H2 blockers and proton pump inhibitors for 3 days prior to the PK study day. Acute illness: exclusion if respiratory illness requiring antibiotics or gastrointestinal illness with vomiting or diarrhea in the 2 weeks prior to the PK visit. We will also exclude pregnant women (urine pregnancy test will be performed on the day of PK study) and decisionally challenged subjects.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fasting<br>Subjects with CF will be given the antimycobacterial drugs in the fasting state, without supplemental pancreatic enzymes Rifampin 10mg/kg oral once daily (max 600mg, round to closest 150mg) Ethambutol 15mg/kg oral once daily (max 2500mg, round to nearest 100mg) Azithromycin 10mg/kg oral once daily (max 500mg, rounded to the nearest 250mg) Blood will be drawn at time points 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | Drug: Ethambutol<br>* Anti-mycobacterial oral drug<br>* Other names: Myambutol;Drug: Rifampin<br>* Anti-mycobacterial oral drug<br>* Other names: Rifadin;Drug: Azithromycin<br>* Anti-mycobacterial oral drug<br>* Other names: Zithromax;|
| Experimental: Food/Enzymes<br>Subjects with CF will be given the antimycobacterial drugs with a standardized meal plus a typical meal-dose of pancreatic enzymes (Pancrelipase). Rifampin 10mg/kg oral once daily (max 600mg, round to closest 150mg) Ethambutol 15mg/kg oral once daily (max 2500mg, round to nearest 100mg) Azithromycin 10mg/kg oral once daily (max 500mg, rounded to the nearest 250mg) Blood will be drawn at time points 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | Drug: Ethambutol<br>* Anti-mycobacterial oral drug<br>* Other names: Myambutol;Drug: Rifampin<br>* Anti-mycobacterial oral drug<br>* Other names: Rifadin;Drug: Azithromycin<br>* Anti-mycobacterial oral drug<br>* Other names: Zithromax;Drug: Pancrelipase<br>* Pancreatic enzyme replacement therapy<br>* Other names: Pertzye;|
| Active Comparator: Healthy Controls<br>Healthy subjects without CF will be given the antimycobacterial drugs in the fasting state, without supplemental pancreatic enzymes Rifampin 10mg/kg oral once daily (max 600mg, round to closest 150mg) Ethambutol 15mg/kg oral once daily (max 2500mg, round to nearest 100mg) Azithromycin 10mg/kg oral once daily (max 500mg, rounded to the nearest 250mg) Blood will be drawn at time points 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | Drug: Ethambutol<br>* Anti-mycobacterial oral drug<br>* Other names: Myambutol;Drug: Rifampin<br>* Anti-mycobacterial oral drug<br>* Other names: Rifadin;Drug: Azithromycin<br>* Anti-mycobacterial oral drug<br>* Other names: Zithromax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Maximal Drug Concentration (Cmax) | Cmax of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls. | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Tmax of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 
| Other PK Measures: Half-life (t1/2) | t1/2 of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 
| Other PK Measures: Drug Clearance | drug clearance of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls Reported here are the Median (range) CL in the CF fasting state compared to HC for Rifampin. | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 
| Other PK Measures: Volume of Distribution (Vd) | Vd of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 
| Covariates of PK Measures: C-reactive Protein (CRP) | Median Concentration of C-reactive Protein. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs. | baseline | 
| Covariates of PK Measures: Circulating Neutrophil Count | Circulating neutrophil count. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs | baseline | 
| Covariates of PK Measures: Body Mass Index | Body mass index (BMI). Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs | baseline | 
| Covariates of PK Measures: Creatinine | Creatinine. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs | baseline | 
| Area Under the Curve (AUC) | AUC of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls. | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, Pharmacokinetics, Pharmacodynamics, Nontuberculous Mycobacteria, Treatment