Pharmacokinetic Issues of Moxifloxacin Plus Rifapentine

New drugs are urgently needed to shorten the duration of tuberculosis (TB) treatment and to
facilitate the delivery of directly observed therapy. Preliminary data indicates that a TB
treatment regimen that includes moxifloxacin plus rifapentine may have excellent
antituberculosis activity that could allow for shortening of total TB treatment duration.
However, little is known about possible pharmacokinetic interactions between the two drugs in
humans. More specifically, moxifloxacin is metabolized via glucuronide and sulfate
conjugation to inactive metabolites. Given that rifapentine induces the activity of phase II
enzymes including glucuronosyltransferase and sulphotransferase, it is possible that
rifapentine may alter the pharmacokinetics of moxifloxacin. This study will be a prospective,
phase I, single center pharmacokinetic study in healthy subjects. The trial will compare the
pharmacokinetics of moxifloxacin alone versus moxifloxacin administered with thrice-weekly
rifapentine, each administered orally. There will be two parts to the trial: Part I (Days
1-4) during which moxifloxacin is administered alone; and Part II (Days 5-19) during which
moxifloxacin is co-administered with thrice-weekly rifapentine. A 24-hour pharmacokinetic
profile of moxifloxacin will be obtained following dose administration of moxifloxacin on Day
4 to obtain baseline steady state data at a dose of 400 mg daily. On Day 5, rifapentine will
be added to the regimen at a dose of 900 mg thrice weekly, and a 48-hour pharmacokinetic
profile for rifapentine and its metabolite, 25-desacetyl-rifapentine will be obtained after
the first dose. On Day 19, 72-hour pharmacokinetic profiles for moxifloxacin, rifapentine,
and 25-desacetyl-rifapentine will be performed. Safety and tolerability assessments will be
performed at designated intervals throughout the study. Beginning on Day 1, subjects will
receive moxifloxacin 400 mg daily for 19 days (Days 1-19). Beginning on Day 5, subjects will
also receive rifapentine 900 mg thrice weekly (to be administered on Days 5, 7, 9, 12, 14, 16
and 19). Study participants will be 16 healthy adults, ages 18-65, recruited through Johns
Hopkins University School of Medicine. The primary study objectives are to: compare, in
healthy volunteers, the pharmacokinetics of moxifloxacin alone versus moxifloxacin
co-administered with thrice-weekly rifapentine and describe the safety and tolerability of
moxifloxacin co-administered with rifapentine. The secondary study objective is to evaluate
for rifapentine autoinduction of metabolism in healthy volunteers receiving thrice-weekly
rifapentine. The primary safety outcome will be the proportion of subjects with any Grade 3
or 4 toxicity associated with study medications or any serious adverse event. The secondary
safety outcomes will be the proportion of subjects with any Grade 1 or 2 toxicity associated
with study medications, and the proportion of subjects discontinuing study medications for
any reason.

Inclusion Criteria:

- Ability and willingness to provide written informed consent.

- Age greater than or equal to 18 years, and less than or equal to 65 years.

- Within 14 or fewer days prior to enrollment, a complete blood count, comprehensive
serum chemistry profile, and HIV antibody test will be performed, with the following
laboratory values:

- Serum amino aspartate transferase (AST) at or within the normal limits for the
laboratory

- Total bilirubin level at, below, or within the normal limits for the laboratory

- Creatinine level at, below, or within the normal limits for the laboratory

- Uric acid at, below, or within the normal limits for the laboratory

- Hemoglobin greater than 12.0 for men, greater than 11.0 for women

- Platelet count greater than or equal to 125,000/cu mm

- Absolute neutrophil count greater than or equal to 1250/cu mm

- Potassium level of at least 3.5 mEq/L

- Serum albumin at or within normal limits for the laboratory

- HIV antibody test negative

- For women of childbearing potential, a negative serum beta-Human Chorionic
Gonadatropin (bHCG) pregnancy test, performed at screening and on Day 0.

- During the study and for 14 days after the last dose of study medication, women of
childbearing potential must agree to practice a double-barrier method of birth control
(e.g., condom plus spermicidal foam, condom plus diaphragm, etc) or to abstain from
heterosexual vaginal intercourse since hormonal contraceptives will be prohibited
during the study. Female subjects must plan on not getting pregnant during the study
and for 14 days after the last dose of study medication.

- Access to a telephone for the duration of the study.

- Within 14 days or fewer prior to enrollment, an electrocardiogram with corrected QT
interval (QTc) less than or equal to 0.44 seconds.

Exclusion Criteria:

- Breastfeeding

- Known intolerance to either of the study drugs or to fluoroquinolone antibiotics

- Use of rifamycin or fluoroquinolone antibiotics in the 30 days prior to enrollment

- Inability to take oral medications

- History of any renal, hepatic, cardiac (except benign heart murmur), or endocrine
disorder; or malignancy; or immunocompromised

- History of any acute or chronic illness that requires current medical therapy

- Prior gastrointestinal surgery involving stomach, biliary system, pancreas, or small
intestine

- Any medical condition that, in the opinion of the investigator, would interfere with
the subject's ability to participate in the protocol

- Any illicit drug use within the preceding 2 months. Subjects must agree to abstain
from alcohol, tobacco, and illicit drug use during the study

- Current use of any prescription medication(s)

- Planned use, during the study from Day 0 through the last PK blood draw, of any of the
following: prescription medication(s), herbal supplement(s), vitamin(s), mineral
supplement(s), or over-the-counter medication(s) with the exception of acetaminophen

- History of prolonged QT syndrome

- Participation in any other investigational drug study within 21 days prior to study
entry and during the study

- Inability to participate in pharmacokinetic visits