Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis

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.

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.