Tuberculosis
Conditions
Keywords
Imatinib, Rifabutin, Isoniazid
Brief summary
The purpose of this study is to evaluate the safety, pharmacokinetics, and effects of imatinib on myelopoiesis in adults when given with and without isoniazid and rifabutin. The results of this trial will determine the imatinib dose to be studied in a subsequent Phase IIB treatment trial of imatinib as an adjunctive therapy with an antimicrobial regimen (rifabutin, pyrazinamide (PZA), isoniazid (INH) and ethambutol) for drug-sensitive TB.
Detailed description
With existing anti-tubercular drug therapies, treatment of drug-susceptible TB takes at least 6 months and success rates for multi-drug resistant tuberculosis (MDR-TB) and extensively drug resistant TB (XDR-TB) are a dismal 50 and 20%, respectively, highlighting the urgent need for new TB drugs. The cancer drug imatinib limits mycobacterial infections in culture and animal models by reducing both entry into macrophages and augmenting phagolysosomal fusion (autophagy), which may facilitate antigen presentation and pathogen killing. Additionally, imatinib induces increases in myeloid cells (myelopoiesis), and an innate immune response to infection that mimics so-called emergency hematopoiesis, a response that Mycobacterium tuberculosis (Mtb) appears to suppress. Importantly, these mechanisms can be induced in animal models by oral doses substantially lower than those used in people to combat cancer. The dose-dependence has important implications for TB clinical studies in humans, as it suggests that imatinib could improve TB treatment using doses that impart minimal, if any, toxicity. This study will evaluate the safety, pharmacokinetics, and effects of imatinib on myelopoiesis in adults when given with and without isoniazid and rifabutin (antibiotics to treat mycobacterial infections). Participants will be enrolled into one of two cohorts. In Cohort 1, participants will be enrolled in a dose-escalating fashion to receive one of four doses of imatinib alone for 14 days, followed by imatinib in combination with rifabutin and isoniazid for another 14 days. In Cohort 2, participants will receive rifabutin and isoniazid for 14 days, followed by 14 days of rifabutin and isoniazid in combination with one of the two selected doses of imatinib. The exact doses of imatinib administered in Cohort 2 will be determined after analyzing data from Cohort 1. After safety evaluations of participants enrolled into the first two dose levels of Cohort 1, the intervention of imatinib followed by imatinib in combination with rifabutin and isoniazid was discontinued. The study protocol was amended to evaluate the effects of imatinib alone, at 3 escalating doses. Total study duration for participants will be 50 days, during which time participants will attend several study visits. Study visits may include a physical exam, electrocardiogram, blood and urine collection, and pharmacokinetic assessments.
Interventions
DRUGImatinib
Tablets, administered orally
DRUGIsoniazid
300 mg tablets, administered orally
DRUGRifabutin
300 mg capsules, administered orally
Sponsors
Emory University
University of Pennsylvania
Aurum Institute
University of Florida
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Adult age between 18 years and 55 years * Body mass index (BMI) greater than 18.5 kg/m\^2 * At least 8 years formal education, with appropriate reading and comprehension skills * Able and willing to provide written informed consent * Males must agree to using contraception during the study and for 2 weeks after the last dose of study drug. * If a female participant is of reproductive potential, the participant (and her partner) must agree to use of one of the following combinations of birth control during the study and for 2 weeks after the last dose of study drug (or tubal ligation as a single method): * Use of a double-barrier method of contraception: condoms (male or female) and a diaphragm or cervical cap with spermicide; * Use of an intrauterine device (IUD) and a barrier method: condoms (male or female, with or without spermicide) or a diaphragm or cervical cap with spermicide; * For those in the imatinib only study arms: use of hormone-based contraceptives (pill, patch, implant, ring, or injectable) and a barrier method: condoms (male or female, with or without spermicide) or a diaphragm or cervical cap with spermicide (participants in study arms receiving isoniazid and rifabutin are not eligible if they are relying hormonal contraceptives other than an IUD) * Tubal ligation. * Women who are post-menopausal, defined as age greater than 45 and no menses for at least 1 year, or who have had a hysterectomy, are considered not of reproductive potential.
Exclusion criteria
* Current or imminent treatment for significant infection * Pregnant or breastfeeding * HIV positive status as determined by a U.S. Food and Drug Administration (FDA)-approved HIV assay * Hepatitis B infection, as determined by an FDA-approved hepatitis B surface antigen assay * Hepatitis C infection, as determined by an FDA-approved positive Hepatitis C antibody assay * Known infection with Mycobacterium tuberculosis (MTB) * History of allergy or hypersensitivity to imatinib, isoniazid or rifabutin. * History of enrollment in other clinical trials with investigational agents within 8 weeks * Cardiac arrhythmia requiring medication, or any clinically significant electrocardiogram (ECG) abnormality * Exam consistent with congestive heart failure (e.g., edema) * Random blood glucose greater than 140 mg/dL or history of unstable diabetes mellitus requiring hospitalization for hyper or hypoglycemia within the past year prior to start of screening * Use of systemic corticosteroids within the past 28 days * Any of the following readings from a complete blood count that fall outside the normal ranges as listed here: * White blood cell count: 3.4 10E3/microliter (mcL) - 11 10E3/mcL * Hemoglobin: Female- 11.1 - 16.7 gm/dL, Male- 12.5 - 16.5 gm/dL * Platelet count: 150-400 10E3/mcL * Absolute neutrophil count: Female- 0.91-5.53 10E3/mcL, Male- 0.67-6.41 10E3/mcL * Absolute lymphocyte count: Female- 0.65-3.05 10E3/mcL, Male- 0.72-3.29 10E3/mcL * Any of the following chemistry panel and liver function test readings that fall outside the normal ranges as listed here: * Serum potassium: 3.5-5.4 mmol/L * Alkaline phosphatase (ALP): 34 - 104 unit/L * Alanine aminotransferase (ALT): 4 - 52 unit/L * Aspartate aminotransferase (AST): 13 - 39 unit/L * Total Bilirubin: 0.2 - 1.0 mg/dL * Creatinine: Female- 0.60-1.20 mg/dL, Male- 0.7-1.3mg/dL * Cirrhosis of the liver, or any known active or chronic liver disease * Current or past alcohol or elicit/recreational drug use, which in the expert judgment of the Investigator, will interfere with the participant's ability to comply with the protocol requirements. * Any experimental medications for less than 8 weeks prior to screening or anticipated use during the trial * Current (within 30 days prior to the first dose of study drug) or anticipated use of antimetabolites; alkylating agents; or other drugs or herbal preparations (including St. John's wort), known to affect activity of the CYP3A4 enzyme pathway * Consumption of grapefruit, grapefruit juice, or grapefruit-related citrus fruits (e.g., pomelos) within 7 days before assessment for eligibility * Unwilling to avoid grapefruit or grapefruit-related citrus fruits/pomelo during the course of the study * Unwilling to avoid alcohol for the duration of the study * Unwilling to abstain from taking acetaminophen-containing medications during the 28-day study drug dosing period, due to increased risk of liver toxicity * History of major medical disorders including metabolic, endocrine, hypothyroid, hepatic, renal, hematologic, pulmonary, gastrointestinal, autoimmune or cardiovascular disorders * Uncontrolled hypertension (persistent measurements at or above 150/100) * Participants who are, in the opinion of the Investigator, unable to comply with the dosing schedule and protocol evaluations * Diarrhea defined as 4 or more stools per day * Active involvement (by the participant or the participant's partner) in In Vitro Fertilization or another assisted reproductive technology procedure * Emory students currently enrolled in a course taught by the principal investigator (PI) or a Co-Investigator * Emory employees currently working under supervision of the PI or a Co-Investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Myelomonocytic Cells in the Blood | Days 1, 7, 14, 21, 28, 42 | Immunologic effects of the study treatment are assessed by counting myelomonocytic cells in blood samples. An increase in myelomonocytic cells is used to determine the appropriate therapeutic dose of imatinib. |
| Frequency of Grade 3 or 4 Adverse Events (AEs) | Measured through Day 50 | The number of grade 3 or 4 adverse events occurring among study participants is presented here. Adverse events are graded using the FDA Guidance Document, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials Guidance for Industry, September 2007, or other guidance, as applicable. |
| Frequency of Serious Adverse Events (SAEs) | Measured through Day 50 | The number of serious adverse events occurring among study participants is presented here. Adverse events are graded using the FDA Guidance Document, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials Guidance for Industry, September 2007, or other guidance, as applicable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) for Imatinib | Day 14, Day 28 | Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to imatinib. |
| Elimination Rate Constant (Ke) of Imatinib | Day 14, Day 28 | Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that imatinib is removed from the body. |
| Maximum Concentration (Cmax) of Isoniazid | Day 28 | Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of the drug in blood following dosing. |
| Half-life (T1/2) of Isoniazid | Day 28 | Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when the drug in blood is half of the maximum concentration. |
| Area Under the Curve (AUC) for Isoniazid | Day 28 | Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to the drug. |
| White Blood Cell Count | Days 1, 7, 14, 21, 28, 42 | The normal range for white blood cell counts is between 4,000 and 11,000 cells per microliter. White blood cell counts increase during infections, autoimmune diseases and some types of cancer. Low white blood cell counts occur with immune system diseases and certain types of cancer. |
| Maximum Concentration (Cmax) of Rifabutin | Day 28 | Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of the drug in blood following dosing. |
| Half-life (T1/2) of Rifabutin | Day 28 | Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when the drug in blood is half of the maximum concentration. |
| Area Under the Curve (AUC) for Rifabutin | Day 28 | Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to the drug. |
| Elimination Rate Constant (Ke) of Rifabutin | Day 28 | Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that the drug is removed from the body. |
| Elimination Rate Constant (Ke) of Isoniazid | Day 28 | Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that the drug is removed from the body. |
| Maximum Concentration (Cmax) of Imatinib | Day 14, Day 28 | Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of imatinib in blood following dosing. |
| Half-life (T1/2) of Imatinib | Day 14, Day 28 | Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when imatinib in blood is half of the maximum concentration. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through the Winship Cancer Institute, Georgia Clinical & Translational Science Alliance (Georgia CTSA) Clinical Research Center, and Emory University Hospital in Atlanta, Georgia, USA. Participant enrollment began on October 27, 2020 and study visits were completed by August 30, 2022.
Pre-assignment details
A total of 42 individuals were screened and 18 did not meet eligibility criteria or withdrew prior to the baseline assessment, resulting in 24 study participants initiating study activities.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. | 16 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. | 6 |
| Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days. | 2 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Exposure to coronavirus disease 2019 (COVID-19) | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Poor venous access | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Imatinib (100 mg) | Total |
|---|---|---|---|---|
| Age, Customized 18-25 years | 7 Participants | 3 Participants | 0 Participants | 10 Participants |
| Age, Customized 26-35 years | 7 Participants | 1 Participants | 1 Participants | 9 Participants |
| Age, Customized 36-45 years | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Age, Customized 46-55 years | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 5 Participants | 2 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 4 Participants | 2 Participants | 14 Participants |
| Region of Enrollment United States | 16 Participants | 6 Participants | 2 Participants | 24 Participants |
| Sex: Female, Male Female | 11 Participants | 3 Participants | 2 Participants | 16 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 0 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 14 | 0 / 6 | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 16 / 16 | 12 / 14 | 5 / 6 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 0 / 16 | 0 / 14 | 0 / 6 | 0 / 3 | 0 / 2 |
Outcome results
Primary
Frequency of Grade 3 or 4 Adverse Events (AEs)
The number of grade 3 or 4 adverse events occurring among study participants is presented here. Adverse events are graded using the FDA Guidance Document, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials Guidance for Industry, September 2007, or other guidance, as applicable.
Time frame: Measured through Day 50
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Frequency of Grade 3 or 4 Adverse Events (AEs) | 4 Grade 3 or 4 adverse events |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Frequency of Grade 3 or 4 Adverse Events (AEs) | 6 Grade 3 or 4 adverse events |
| Imatinib (100 mg) | Frequency of Grade 3 or 4 Adverse Events (AEs) | 0 Grade 3 or 4 adverse events |
Primary
Frequency of Serious Adverse Events (SAEs)
The number of serious adverse events occurring among study participants is presented here. Adverse events are graded using the FDA Guidance Document, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials Guidance for Industry, September 2007, or other guidance, as applicable.
Time frame: Measured through Day 50
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Frequency of Serious Adverse Events (SAEs) | 0 serious adverse events |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Frequency of Serious Adverse Events (SAEs) | 0 serious adverse events |
| Imatinib (100 mg) | Frequency of Serious Adverse Events (SAEs) | 0 serious adverse events |
Primary
Number of Myelomonocytic Cells in the Blood
Immunologic effects of the study treatment are assessed by counting myelomonocytic cells in blood samples. An increase in myelomonocytic cells is used to determine the appropriate therapeutic dose of imatinib.
Time frame: Days 1, 7, 14, 21, 28, 42
Population: The analysis population includes participants who completed the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 1 | 3197 cells per microliter (µL) | Standard Deviation 933 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 7 | 3241 cells per microliter (µL) | Standard Deviation 1393 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 14 | 3418 cells per microliter (µL) | Standard Deviation 1640 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 21 | 3021 cells per microliter (µL) | Standard Deviation 1479 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 28 | 2356 cells per microliter (µL) | Standard Deviation 1059 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 42 | 3629 cells per microliter (µL) | Standard Deviation 1548 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 42 | 4425 cells per microliter (µL) | Standard Deviation 403 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 1 | 4340 cells per microliter (µL) | Standard Deviation 480 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 21 | 2560 cells per microliter (µL) | Standard Deviation 721 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 28 | 1140 cells per microliter (µL) | Standard Deviation 98 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 7 | 3680 cells per microliter (µL) | Standard Deviation 1414 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Number of Myelomonocytic Cells in the Blood | Day 14 | 3195 cells per microliter (µL) | Standard Deviation 1265 |
| Imatinib (100 mg) | Number of Myelomonocytic Cells in the Blood | Day 7 | 3075 cells per microliter (µL) | Standard Deviation 64 |
| Imatinib (100 mg) | Number of Myelomonocytic Cells in the Blood | Day 14 | 3195 cells per microliter (µL) | Standard Deviation 21 |
| Imatinib (100 mg) | Number of Myelomonocytic Cells in the Blood | Day 42 | 3255 cells per microliter (µL) | Standard Deviation 841 |
| Imatinib (100 mg) | Number of Myelomonocytic Cells in the Blood | Day 21 | 2785 cells per microliter (µL) | Standard Deviation 332 |
| Imatinib (100 mg) | Number of Myelomonocytic Cells in the Blood | Day 1 | 3390 cells per microliter (µL) | Standard Deviation 283 |
| Imatinib (100 mg) | Number of Myelomonocytic Cells in the Blood | Day 28 | 2480 cells per microliter (µL) | Standard Deviation 198 |
Secondary
Area Under the Curve (AUC) for Imatinib
Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to imatinib.
Time frame: Day 14, Day 28
Population: The analysis population includes those who were participating in the study at the indicated time point. Participants in the Imatinib (100 mg) group, who received imatinib alone, had a single PK analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Area Under the Curve (AUC) for Imatinib | After 14 days of imatinib | 4.76 hour*mcg/mL |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Area Under the Curve (AUC) for Imatinib | After 14 days of imatinib plus rifabutin and isoniazid | 7.52 hour*mcg/mL |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Area Under the Curve (AUC) for Imatinib | After 14 days of imatinib | 9.46 hour*mcg/mL |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Area Under the Curve (AUC) for Imatinib | After 14 days of imatinib plus rifabutin and isoniazid | 7.49 hour*mcg/mL |
| Imatinib (100 mg) | Area Under the Curve (AUC) for Imatinib | After 14 days of imatinib | 5.80 hour*mcg/mL |
Secondary
Area Under the Curve (AUC) for Isoniazid
Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to the drug.
Time frame: Day 28
Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Area Under the Curve (AUC) for Isoniazid | 9.79 hour*mcg/mL |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Area Under the Curve (AUC) for Isoniazid | 16.11 hour*mcg/mL |
Secondary
Area Under the Curve (AUC) for Rifabutin
Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to the drug.
Time frame: Day 28
Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Area Under the Curve (AUC) for Rifabutin | 3.68 hour*mcg/mL |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Area Under the Curve (AUC) for Rifabutin | 5.11 hour*mcg/mL |
Secondary
Elimination Rate Constant (Ke) of Imatinib
Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that imatinib is removed from the body.
Time frame: Day 14, Day 28
Population: The analysis population includes those who were participating in the study at the indicated time point. Participants in the Imatinib (100 mg) group, who received imatinib alone, had a single PK analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Elimination Rate Constant (Ke) of Imatinib | After 14 days of imatinib | 0.06 1/hour |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Elimination Rate Constant (Ke) of Imatinib | After 14 days of imatinib plus rifabutin and isoniazid | 0.07 1/hour |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Elimination Rate Constant (Ke) of Imatinib | After 14 days of imatinib | 0.05 1/hour |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Elimination Rate Constant (Ke) of Imatinib | After 14 days of imatinib plus rifabutin and isoniazid | 0.09 1/hour |
| Imatinib (100 mg) | Elimination Rate Constant (Ke) of Imatinib | After 14 days of imatinib | 0.06 1/hour |
Secondary
Elimination Rate Constant (Ke) of Isoniazid
Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that the drug is removed from the body.
Time frame: Day 28
Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Elimination Rate Constant (Ke) of Isoniazid | 0.44 1/hour |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Elimination Rate Constant (Ke) of Isoniazid | 0.28 1/hour |
Secondary
Elimination Rate Constant (Ke) of Rifabutin
Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that the drug is removed from the body.
Time frame: Day 28
Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Elimination Rate Constant (Ke) of Rifabutin | 0.07 1/hour |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Elimination Rate Constant (Ke) of Rifabutin | 0.09 1/hour |
Secondary
Half-life (T1/2) of Imatinib
Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when imatinib in blood is half of the maximum concentration.
Time frame: Day 14, Day 28
Population: The analysis population includes those who were participating in the study at the indicated time point. Participants in the Imatinib (100 mg) group, who received imatinib alone, had a single PK analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Half-life (T1/2) of Imatinib | After 14 days of imatinib | 11.32 hours |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Half-life (T1/2) of Imatinib | After 14 days of imatinib plus rifabutin and isoniazid | 9.91 hours |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Half-life (T1/2) of Imatinib | After 14 days of imatinib | 15.01 hours |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Half-life (T1/2) of Imatinib | After 14 days of imatinib plus rifabutin and isoniazid | 7.83 hours |
| Imatinib (100 mg) | Half-life (T1/2) of Imatinib | After 14 days of imatinib | 11.00 hours |
Secondary
Half-life (T1/2) of Isoniazid
Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when the drug in blood is half of the maximum concentration.
Time frame: Day 28
Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Half-life (T1/2) of Isoniazid | 1.59 hours |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Half-life (T1/2) of Isoniazid | 2.44 hours |
Secondary
Half-life (T1/2) of Rifabutin
Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when the drug in blood is half of the maximum concentration.
Time frame: Day 28
Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Half-life (T1/2) of Rifabutin | 9.65 hours |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Half-life (T1/2) of Rifabutin | 8.14 hours |
Secondary
Maximum Concentration (Cmax) of Imatinib
Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of imatinib in blood following dosing.
Time frame: Day 14, Day 28
Population: The analysis population includes those who were participating in the study at the indicated time point. Participants in the Imatinib (100 mg) group, who received imatinib alone, had a single PK analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Maximum Concentration (Cmax) of Imatinib | After 14 days of imatinib | 0.41 micrograms per milliliter (mcg/mL) |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Maximum Concentration (Cmax) of Imatinib | After 14 days of imatinib plus rifabutin and isoniazid | 0.71 micrograms per milliliter (mcg/mL) |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Maximum Concentration (Cmax) of Imatinib | After 14 days of imatinib | 0.69 micrograms per milliliter (mcg/mL) |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Maximum Concentration (Cmax) of Imatinib | After 14 days of imatinib plus rifabutin and isoniazid | 0.69 micrograms per milliliter (mcg/mL) |
| Imatinib (100 mg) | Maximum Concentration (Cmax) of Imatinib | After 14 days of imatinib | 0.51 micrograms per milliliter (mcg/mL) |
Secondary
Maximum Concentration (Cmax) of Isoniazid
Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of the drug in blood following dosing.
Time frame: Day 28
Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Maximum Concentration (Cmax) of Isoniazid | 3.14 mcg/mL |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Maximum Concentration (Cmax) of Isoniazid | 3.66 mcg/mL |
Secondary
Maximum Concentration (Cmax) of Rifabutin
Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of the drug in blood following dosing.
Time frame: Day 28
Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Maximum Concentration (Cmax) of Rifabutin | 0.37 mcg/mL |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Maximum Concentration (Cmax) of Rifabutin | 0.53 mcg/mL |
Secondary
White Blood Cell Count
The normal range for white blood cell counts is between 4,000 and 11,000 cells per microliter. White blood cell counts increase during infections, autoimmune diseases and some types of cancer. Low white blood cell counts occur with immune system diseases and certain types of cancer.
Time frame: Days 1, 7, 14, 21, 28, 42
Population: The analysis population includes participants who completed the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 1 | 5558 cells/µL | Standard Deviation 1099 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 7 | 5391 cells/µL | Standard Deviation 1222 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 14 | 5841 cells/µL | Standard Deviation 1648 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 21 | 4875 cells/µL | Standard Deviation 1430 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 28 | 4141 cells/µL | Standard Deviation 1295 |
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 42 | 5841 cells/µL | Standard Deviation 1684 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 42 | 5800 cells/µL | Standard Deviation 282 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 1 | 6300 cells/µL | Standard Deviation 1272 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 21 | 3650 cells/µL | Standard Deviation 636 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 28 | 1600 cells/µL | Standard Deviation 282 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 7 | 5900 cells/µL | Standard Deviation 1697 |
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | White Blood Cell Count | Day 14 | 5150 cells/µL | Standard Deviation 2192 |
| Imatinib (100 mg) | White Blood Cell Count | Day 7 | 5500 cells/µL | Standard Deviation 283 |
| Imatinib (100 mg) | White Blood Cell Count | Day 14 | 5400 cells/µL | Standard Deviation 1273 |
| Imatinib (100 mg) | White Blood Cell Count | Day 42 | 5300 cells/µL | Standard Deviation 1414 |
| Imatinib (100 mg) | White Blood Cell Count | Day 21 | 4750 cells/µL | Standard Deviation 212 |
| Imatinib (100 mg) | White Blood Cell Count | Day 1 | 5900 cells/µL | Standard Deviation 566 |
| Imatinib (100 mg) | White Blood Cell Count | Day 28 | 4800 cells/µL | Standard Deviation 424 |