A Phase 1 Study to Evaluate the Effect of Rifampin on the Pharmacokinetics of Tivozanib in Healthy Subjects

This Phase 1, open-label, two-period, single-sequence study is designed to evaluate the effect of steady-state rifampin on the PK profile, safety, and tolerability of a single 1.5-mg tivozanib dose. On Day 1 of the first period, subjects will receive a single 1.5 mg dose of tivozanib, and remain at the unit for at least 48 hours postdose followed by outpatient visits for PK sampling and safety assessments up to 3 weeks postdose. For Period 2, subjects will be administered 600 mg of rifampin once daily (QD).for 6 days. On the 4th day of Period 2, 1.5mg of tivozanib will be administered with 600mg of rifampin. PK sampling will continue for 3-weeks postdose while the subjects continue to receive 600mg of rifampin daily. An end of study visit will be completed 1-week after the last dose of rifampin.

Inclusion criteria

• Males or females, between 18 and 55 years of age, inclusive.
• Body mass index (BMI) within the range of 18.5 to 31.0 kg/m2, inclusive.
• In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, and vital signs.
• Clinical laboratory evaluations (including a chemistry panel comprised of 20 analytes [Chem-20, includes liver function tests; fasted approximately 10 hours], complete blood count [CBC], and urinalysis) not exceeding 2 x upper limit of normal (ULN) or < lower limit of normal (LLN), unless deemed not clinically significant by the Investigator.
• Nonsmokers (refrained from any tobacco usage, including smokeless tobacco, nicotine patches, etc., for 6 months prior to Screening), verified by a cotinine test at Screening and each study period Check-in.
• Negative test for selected drugs of abuse at Screening (does not include alcohol) and at each study period Check-in (does include alcohol; Appendix A).
• Negative hepatitis panel (including hepatitis B virus surface antigen [HBsAg] and hepatitis C virus antibody [anti-HCV] and negative human immunodeficiency virus [HIV] antibody screens; Appendix A).
• Females who are not pregnant, non-lactating, and either postmenopausal for at least 1 year, surgically sterile (eg, tubal ligation, hysterectomy) for at least 90 days prior to Screening, or agree to use at least 1 of the following forms of contraception from informed consent until 45 days after Study Completion: a non-hormonal intrauterine device with spermicide; female condom with spermicide; contraceptive sponge with spermicide; diaphragm with spermicide; cervical cap with spermicide; a male sexual partner who agrees to use a male condom with spermicide; or a sterile sexual partner. For all females, a serum pregnancy test result must be negative at Screening and at each study period Check-in.
• Male subjects who are either sterile or agree to use, during the period from informed consent until 45 days following Study Completion, 1 of the following approved methods of contraception: a double barrier method (eg, male condom with spermicide, use by female sexual partner of an intrauterine device with spermicide, a female condom with spermicide, contraceptive sponge with spermicide, a diaphragm with spermicide, or use of a cervical cap with spermicide); a sterile sexual partner; a female sexual partner using an intravaginal system (eg, NuvaRing®); or a partner using an oral, implantable, transdermal, or injectable contraceptives.
• Able to comprehend and willing to sign an Informed Consent Form (ICF).

Exclusion criteria

• Significant history or clinical manifestation of any significant metabolic/endocrine, allergic, dermatological, hepatic, renal, hematological, pulmonary, immune, cardiovascular, gastrointestinal, genitourinary, neurological, or psychiatric disorder (as determined by the Investigator or Sponsor's Medical Monitor).
• History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator.
• History of stomach or intestinal surgery, nephrectomy, cholecystectomy, or resection that would potentially alter absorption and/or excretion of orally administered drugs as determined by the Investigator (appendectomy and/or hernia repair may be allowed).
• Diagnosis of alcoholism or drug addiction within 1 year prior to Period 1 Check-in.
• Participation in any other investigational drug study in which receipt of an investigational study drug occurred within 5 half-lives or 30 days, whichever is longer, prior to Period 1 Check-in.
• Use of any prescription medications or products within 14 days prior to Period 1 Check-in.
• Use of any over-the-counter (OTC), non-prescription, systemic preparations (including vitamins, minerals, and phytotherapeutic, herbal, dietary supplements, or plant derived preparations) within 7 days prior to each study period Check-in.
• Consumption of food or beverages containing alcohol, grapefruit, Seville orange, or caffeine within 72 hours prior to each study period Check-in.
• Use of known hepatic or renal clearance altering agents (eg, rifampin, erythromycin, cimetidine, barbiturates, phenothiazines, or herbal/plant derived preparations such as St. John's Wort) for a period of 60 days prior to Period 1 Check-in and for the duration of the study.
• Poor peripheral venous access.
• Donation of blood ≥ 250 mL from 30 days prior to Period 1 Check-in until Study Completion, inclusive, or of plasma from 2 weeks prior to Period 1 Check-in until Study Completion, inclusive.
• Receipt of blood products within 2 months prior to Period 1 Check-in.
• Blood pressure greater than 140/90 mmHg confirmed by repeat at Screening or at Period 1 Check-in.
• Sensitivity to rifampin.
• Any acute or chronic condition that, in the opinion of the Investigator, would limit the subject's ability to complete and/or participate in this clinical study.