Clinical trial NCT02372383
Conditions: Cystic Fibrosis
Keywords: Cystic Fibrosis Pharmacokinetics Pharmacodynamics Nontuberculous Mycobacteria Treatment
Sponsor: University of Colorado, Denver
Start date: 2014-10-01; Completion date: 2016-06-01
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: 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 arm 2: 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 arm 3: 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
Interventions: intervention 1: Ethambutol intervention 2: Rifampin intervention 3: Azithromycin intervention 4: Pancrelipase
Intervention descriptions: intervention 1: Anti-mycobacterial oral drug intervention 2: Anti-mycobacterial oral drug intervention 3: Anti-mycobacterial oral drug intervention 4: Pancreatic enzyme replacement therapy

Protocol documents: