Evaluation of effect of rifampin or rifabutin on single dose PK of TMC207 in healthy
volunteers
32 (16 per treatment group) healthy male or female subjects, 18 - 45 years old will be
enrolled. Subjects will receive two single oral doses of 400mg TMC207, first on Study Day 1
followed by a 28-day wash-out, the second on Study Day 29. On Study Day 28, any abnormal
safety labs will be reviewed by study physician and be determined not to meet the exclusion
criteria before administration of the second dose of TMC207. Rifabutin 300mg (Group 1) or
rifampin 600mg (Group 2) will be administered once daily during Period 2 from Study Day 20
through Study Day 41. The primary endpoint for the study (pharmacokinetics, safety and
tolerability of TMC207 (and its M2 metabolite) will be determined on the final study visit,
Day 57 (28 days after the last TMC207 dose in Period 2).
Minimum age: 18 Years.
Maximum age: 45 Years.
Gender(s): Both.
Inclusion Criteria:
- Aged between 18 and 45 years, extremes included.
- Non tobacco/nicotine using (at least 3 months prior to screening).
- Body Mass Index (BMI, weight in kg divided by the square of height in meters) of 18. 0
to <35. 0 kg/m^2
- Informed Consent Form (ICF) signed voluntarily before the first trial-related
activity.
- Able to comply with protocol requirements.
- Healthy on the basis of a medical evaluation or history that reveals the absence of
any clinically relevant abnormality and includes a physical examination, medical
history, electrocardiogram (ECG), vital signs, ophthalmologic exam, the results of
blood biochemistry, and hematology tests, and a urinalysis carried out at screening
(See Section 7. 2).
- Subjects will be enrolled in this study only if they have undergone
vasectomy/complete hysterectomy, tubal ligation, or other sterilizing procedure, or
the subject is a post-menopausal woman for more than two years, or if sexually active
subjects agree to use two of the following forms of adequate contraception during the
study and for 12 weeks after the final dose: abstinence, condoms with or without
spermicide gel, diaphragm with spermicide gel, hormonal or non-hormonal intrauterine
device, oral contraceptive pills, and depot progesterone injections. If a subject is
usually not sexually active but becomes active, the subject and his or her partner
must use two of the listed contraceptive methods.
Exclusion Criteria:
Medical History
- History or evidence of current use of alcohol, barbiturate, amphetamine,
recreational, or narcotic drug use, which in the investigator's opinion would
compromise subject's safety and/or compliance with the trial procedures.
- Any clinically significant (as deemed by the Principal Investigator) history of acute
illness (resolved within 4 weeks of screening), asthma, or presence of
cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal (including
eating disorders), endocrine, metabolic, immunologic, dermatologic, neurologic,
psychological, or psychiatric disease.
- Currently significant diarrhea, gastric stasis, or constipation that in the
investigator's opinion could influence drug absorption or bioavailability.
- Any history of significant skin disease such as, but not limited to, rash or
eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria.
Subjects with a history of skin disease may be enrolled into the study after
consultation with the Sponsor Medical Monitor.
- Previously demonstrated clinically significant allergy or hypersensitivity to any of
the excipients of the investigational medication administered in this trial (i. e.,
rifabutin, rifampin, and TMC207).
- Subjects with QTcB [Bazett correction] interval > 450ms at screening
- Subjects with any other clinically significant Electrocardiogram (ECG) abnormality at
screening, such as arrhythmia, ischemia, or evidence of heart failure or with a
family history of Long QT Syndrome.
- History or evidence of ophthalmologic diseases except for routine corrected
hyperopia, myopia, and presbyopia.
- Recent history (within past 30 days) of vertigo/nausea.
Specific Treatments
- Current use of any azole antifungal agent
- Use of concomitant medication, including over-the-counter products and dietary
supplements, without approval from study staff. Subjects will be treated based on
symptom presentation, with the exception of medications that affect p450 and 3a
metabolic pathways (refer to the MOP for a list of acceptable medications). During
outpatient time periods, subjects will be required to discuss with the study staff
and receive approval before self-administering any medication. After gaining
approval, subjects will also be asked to record any medication taken during
outpatient time periods in a provided log.
- Participation in an investigational drug trial within 60 days prior to the first
intake of trial medication and during the duration of the study.
- Donation of blood or significant loss of blood within 56 days or plasma donation
within 7 days preceding the first intake of trial medication.
- Having received TMC207 in a previous trial.
Based on Laboratory Abnormalities
- Positive HIV-1 or HIV-2 test by Enzyme-linked immunosorbent assay (ELISA) at
screening.
- Hepatitis A, B, or C infection (confirmed by hepatitis A antibody IgM, hepatitis B
surface antigen, or hepatitis C virus antibody, respectively) at screening.
- A positive urine drug test at screening. Urine will be tested to check the current
use of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids; along with
serum alcohol level.
- Subjects with the following laboratory abnormalities at screening as defined by the
National Institute of Health (NIH), National Institute of Allergy and Infectious
Diseases (NIAID), Division of Microbiology and Infectious Diseases (DMID) Adult
Toxicity Table (Appendix C) and in accordance with the normal ranges of the clinical
laboratory:
1. Serum creatinine grade 1 or greater [> 1. 0 x Upper limit of lab normal range
(ULN)],
2. Pancreatic lipase grade 1 or greater (> 1. 0 x ULN),
3. Hemoglobin grade 1 or greater (= 10. 5 g/dL),
4. Platelet count grade 1 or greater (= 99000/mm^3),
5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or
greater (> 1. 0 x ULN),
6. Total bilirubin grade 1 or greater (> 1. 0 x ULN),
7. Creatine kinase grade 1 or greater (>1. 0 x ULN),
8. Troponin grade 1 or greater (1. 0 x UNL), or
9. Any other toxicity grade 2 or above, including: proteinuria (spot urine) > 1+
and gross hematuria. For the second dose of TMC207, any other toxicity grade 3
or above, including: proteinuria (spot urine) > 1+ and gross hematuria