Clinical trial NCT02372383: Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis
Official title: Pharmacokinetic Evaluation of Nontuberculous Mycobacterial Antibiotics in Cystic Fibrosis Versus Controls
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cystic Fibrosis
Keywords: Cystic Fibrosis
Pharmacokinetics
Pharmacodynamics
Nontuberculous Mycobacteria
Treatment
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Cystic Fibrosis Foundation
name: Colorado Clinical & Translational Sciences Institute
First posted: 2015-02-26
Enrollment: 31
Sex: ALL
Minimum age (years): 16
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Median Maximal Drug Concentration (Cmax)
timeFrame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
Secondary outcomes:
measure: Other PK Measures: Median Time to Maximal Drug Concentration (Tmax)
timeFrame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
measure: Other PK Measures: Half-life (t1/2)
timeFrame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
measure: Other PK Measures: Drug Clearance
timeFrame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
measure: Other PK Measures: Volume of Distribution (Vd)
timeFrame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
measure: Covariates of PK Measures: C-reactive Protein (CRP)
timeFrame: baseline
measure: Covariates of PK Measures: Circulating Neutrophil Count
timeFrame: baseline
measure: Covariates of PK Measures: Body Mass Index
timeFrame: baseline
measure: Covariates of PK Measures: Creatinine
timeFrame: baseline
measure: Area Under the Curve (AUC)
timeFrame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colroado
state: Colorado
Study officials:
affiliation: University of Colorado, Denver
name: Stacey Martiniano, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.