Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, Pharmacokinetics, Pharmacodynamics, Nontuberculous Mycobacteria, 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.
Interventions
DRUGEthambutol
Anti-mycobacterial oral drug
DRUGRifampin
Anti-mycobacterial oral drug
DRUGAzithromycin
Anti-mycobacterial oral drug
DRUGPancrelipase
Pancreatic enzyme replacement therapy
Sponsors
Cystic Fibrosis Foundation
Colorado Clinical & Translational Sciences Institute
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 45 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Maximal Drug Concentration (Cmax) | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 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 |
| Other PK Measures: Half-life (t1/2) | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 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 |
| Other PK Measures: Drug Clearance | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 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. |
| Other PK Measures: Volume of Distribution (Vd) | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 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 |
| Covariates of PK Measures: C-reactive Protein (CRP) | baseline | 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. |
| Covariates of PK Measures: Circulating Neutrophil Count | baseline | Circulating neutrophil count. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs |
| Covariates of PK Measures: Body Mass Index | baseline | Body mass index (BMI). Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs |
| Covariates of PK Measures: Creatinine | baseline | Creatinine. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs |
| Area Under the Curve (AUC) | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose | 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. |
Countries
United States
Participant flow
Recruitment details
20 CF subjects and 10 Healthy controls will be studied
Participants by arm
| Arm | Count |
|---|---|
| CF Subjects Fasting State 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
Ethambutol: Anti-mycobacterial oral drug
Rifampin: Anti-mycobacterial oral drug
Azithromycin: Anti-mycobacterial oral drug
Food/Enzymes State Subjects with CF will then cross-over and be given the same dose of the 3 antimycobacterial drugs with a standardized meal plus a typical meal-dose of pancreatic enzymes (Pancrelipase). CF subjects will be randomized to either receive the medications in the Fasting or Food/Enzymes state first. | 20 |
| Healthy Controls (Fasting Only) 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
Ethambutol: Anti-mycobacterial oral drug
Rifampin: Anti-mycobacterial oral drug
Azithromycin: Anti-mycobacterial oral drug | 10 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| First Intervention (1 Day) | Unable to collect blood | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Healthy Controls (Fasting Only) | Total | CF Subjects |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 29 Participants | 19 Participants |
| Age, Continuous | 25.3 years | 20.6 years | 18.3 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 10 participants | 30 participants | 20 participants |
| Sex: Female, Male Female | 6 Participants | 13 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 17 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 21 | 0 / 20 |
| other Total, other adverse events | 0 / 10 | 0 / 21 | 0 / 20 |
| serious Total, serious adverse events | 0 / 10 | 0 / 21 | 0 / 20 |
Outcome results
Primary
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.
Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Healthy Controls | Median Maximal Drug Concentration (Cmax) | Ethambutol | 3.0 mg/L |
| Healthy Controls | Median Maximal Drug Concentration (Cmax) | Rifampin | 16.56 mg/L |
| Healthy Controls | Median Maximal Drug Concentration (Cmax) | Azithromycin | 1.1 mg/L |
| CF Fasting | Median Maximal Drug Concentration (Cmax) | Ethambutol | 4.2 mg/L |
| CF Fasting | Median Maximal Drug Concentration (Cmax) | Rifampin | 12.5 mg/L |
| CF Fasting | Median Maximal Drug Concentration (Cmax) | Azithromycin | 2.0 mg/L |
| CF Food | Median Maximal Drug Concentration (Cmax) | Rifampin | 11.2 mg/L |
| CF Food | Median Maximal Drug Concentration (Cmax) | Azithromycin | 2.2 mg/L |
| CF Food | Median Maximal Drug Concentration (Cmax) | Ethambutol | 4.3 mg/L |
Secondary
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.
Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Healthy Controls | Area Under the Curve (AUC) | Ethambutol | 21.4 mg*h/L |
| Healthy Controls | Area Under the Curve (AUC) | Rifampin | 118.3 mg*h/L |
| Healthy Controls | Area Under the Curve (AUC) | Azithromycin | 5.6 mg*h/L |
| CF Fasting | Area Under the Curve (AUC) | Ethambutol | 21.8 mg*h/L |
| CF Fasting | Area Under the Curve (AUC) | Rifampin | 76 mg*h/L |
| CF Fasting | Area Under the Curve (AUC) | Azithromycin | 6.8 mg*h/L |
| CF Food | Area Under the Curve (AUC) | Rifampin | 79.2 mg*h/L |
| CF Food | Area Under the Curve (AUC) | Azithromycin | 6 mg*h/L |
| CF Food | Area Under the Curve (AUC) | Ethambutol | 23.6 mg*h/L |
Secondary
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
Time frame: baseline
Population: This Outcome Measure was only analyzed at the Fasting period and was not collected during the Food period of the study. Therefore, 0 participants are analyzed for the CF Food arm for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls | Covariates of PK Measures: Body Mass Index | 23.0 kg/m^2 |
| CF Fasting | Covariates of PK Measures: Body Mass Index | 21.9 kg/m^2 |
Secondary
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
Time frame: baseline
Population: This Outcome Measure was only analyzed at the Fasting period and was not collected during the Food period of the study. Therefore, 0 participants are analyzed for the CF Food arm for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls | Covariates of PK Measures: Circulating Neutrophil Count | 3.0 10^3 cells/uL |
| CF Fasting | Covariates of PK Measures: Circulating Neutrophil Count | 3.8 10^3 cells/uL |
Secondary
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.
Time frame: baseline
Population: This Outcome Measure was only analyzed at the Fasting period and was not collected during the Food period of the study. Therefore, 0 participants are analyzed for the CF Food arm for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls | Covariates of PK Measures: C-reactive Protein (CRP) | 0.2 mg/dL |
| CF Fasting | Covariates of PK Measures: C-reactive Protein (CRP) | 0.8 mg/dL |
Secondary
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
Time frame: baseline
Population: This Outcome Measure was only analyzed at the Fasting period and was not collected during the Food period of the study. Therefore, 0 participants are analyzed for the CF Food arm for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls | Covariates of PK Measures: Creatinine | 1.0 mg/dL |
| CF Fasting | Covariates of PK Measures: Creatinine | 0.9 mg/dL |
Secondary
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.
Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Healthy Controls | Other PK Measures: Drug Clearance | Ethambutol | 45.3 L/h |
| Healthy Controls | Other PK Measures: Drug Clearance | Rifampin | 5.1 L/h |
| Healthy Controls | Other PK Measures: Drug Clearance | Azithromycin | 88.6 L/h |
| CF Fasting | Other PK Measures: Drug Clearance | Ethambutol | 42.4 L/h |
| CF Fasting | Other PK Measures: Drug Clearance | Rifampin | 7.9 L/h |
| CF Fasting | Other PK Measures: Drug Clearance | Azithromycin | 73.6 L/h |
| CF Food | Other PK Measures: Drug Clearance | Rifampin | 7.6 L/h |
| CF Food | Other PK Measures: Drug Clearance | Azithromycin | 82.8 L/h |
| CF Food | Other PK Measures: Drug Clearance | Ethambutol | 37.3 L/h |
Secondary
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
Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Healthy Controls | Other PK Measures: Half-life (t1/2) | Ethambutol | 5.3 hours |
| Healthy Controls | Other PK Measures: Half-life (t1/2) | Rifampin | 3.8 hours |
| Healthy Controls | Other PK Measures: Half-life (t1/2) | Azithromycin | 6.2 hours |
| CF Fasting | Other PK Measures: Half-life (t1/2) | Ethambutol | 4.3 hours |
| CF Fasting | Other PK Measures: Half-life (t1/2) | Rifampin | 3.4 hours |
| CF Fasting | Other PK Measures: Half-life (t1/2) | Azithromycin | 5.2 hours |
| CF Food | Other PK Measures: Half-life (t1/2) | Rifampin | 3.4 hours |
| CF Food | Other PK Measures: Half-life (t1/2) | Azithromycin | 6.6 hours |
| CF Food | Other PK Measures: Half-life (t1/2) | Ethambutol | 4.7 hours |
Secondary
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
Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Healthy Controls | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Ethambutol | 2.3 hours |
| Healthy Controls | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Rifampin | 1.5 hours |
| Healthy Controls | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Azithromycin | 2.0 hours |
| CF Fasting | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Ethambutol | 2.3 hours |
| CF Fasting | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Rifampin | 1.5 hours |
| CF Fasting | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Azithromycin | 2.0 hours |
| CF Food | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Rifampin | 2.5 hours |
| CF Food | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Azithromycin | 2.0 hours |
| CF Food | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | Ethambutol | 2.0 hours |
Secondary
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
Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Healthy Controls | Other PK Measures: Volume of Distribution (Vd) | Ethambutol | 352.8 L |
| Healthy Controls | Other PK Measures: Volume of Distribution (Vd) | Rifampin | 31.3 L |
| Healthy Controls | Other PK Measures: Volume of Distribution (Vd) | Azithromycin | 717.0 L |
| CF Fasting | Other PK Measures: Volume of Distribution (Vd) | Ethambutol | 274.6 L |
| CF Fasting | Other PK Measures: Volume of Distribution (Vd) | Rifampin | 39.7 L |
| CF Fasting | Other PK Measures: Volume of Distribution (Vd) | Azithromycin | 549.2 L |
| CF Food | Other PK Measures: Volume of Distribution (Vd) | Rifampin | 37.4 L |
| CF Food | Other PK Measures: Volume of Distribution (Vd) | Azithromycin | 621.3 L |
| CF Food | Other PK Measures: Volume of Distribution (Vd) | Ethambutol | 354.3 L |