Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis

Pharmacokinetic Evaluation of Nontuberculous Mycobacterial Antibiotics in Cystic Fibrosis Versus Controls

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Ethambutol; Drug: Rifampin; Drug: Azithromycin; Drug: Pancrelipase

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colroado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fasting; 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; Anti-mycobacterial oral drug; Other Names: Myambutol; Drug: Rifampin; Anti-mycobacterial oral drug; Other Names: Rifadin; Drug: Azithromycin; Anti-mycobacterial oral drug; Other Names: Zithromax
Experimental: Food/Enzymes; 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; Anti-mycobacterial oral drug; Other Names: Myambutol; Drug: Rifampin; Anti-mycobacterial oral drug; Other Names: Rifadin; Drug: Azithromycin; Anti-mycobacterial oral drug; Other Names: Zithromax; Drug: Pancrelipase; Pancreatic enzyme replacement therapy; Other Names: Zenpep; Creon; Pertzye
Active Comparator: Healthy Controls; 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; Anti-mycobacterial oral drug; Other Names: Myambutol; Drug: Rifampin; Anti-mycobacterial oral drug; Other Names: Rifadin; Drug: Azithromycin; Anti-mycobacterial oral drug; Other Names: Zithromax

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Cystic Fibrosis Foundation; Colorado Clinical & Translational Sciences Institute
• Investigators: Principal Investigator: Stacey Martiniano, MD, University of Colorado, Denver

Publications and helpful links

General Publications

• Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Daley CL, Anthony M, Nick JA, Sagel SD. Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis. J Cyst Fibros. 2021 Sep;20(5):772-778. doi: 10.1016/j.jcf.2021.04.011. Epub 2021 May 21.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: June 20, 2014
• First Submitted That Met QC Criteria: February 20, 2015
• First Posted (Estimate): February 26, 2015

Study Record Updates

• Last Update Posted (Actual): February 11, 2021
• Last Update Submitted That Met QC Criteria: January 20, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Treatment; Pharmacokinetics; Cystic Fibrosis; Pharmacodynamics; Nontuberculous Mycobacteria
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin; Azithromycin; Pancrelipase; Ethambutol; Pancreatin
• Other Study ID Numbers: 14-1043; UL1TR001082 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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