None listed
Conditions
Brief summary
Nonclinical data suggested GS-9688 human metabolism is mediated by a combination of glucuronidation by UGT2B7 and oxidation by multiple CYP enzymes including CYP1A2, CYP3A, CYP2C19 and CYP2C9. GS-9688 was not found to be a substrate for P-gp, BCRP or OATP and is unlikely to be a clinically relevant inhibitor of these transporters in vivo. As such, the objective of this study is to increase understanding of in vivo disposition of GS-9688 in humans. The probe inhibitors and inducers selected for the study are based on the recommendations of the FDA guidance entitled “In Vivo Drug Metabolism/Drug Interaction Studies — Study Design, Data Analysis, and Recommendations for Dosing and Labeling” (2011). Data from this study will inform the potential need for conducting additional drug interaction studies and/or on whether potential interactions are of the magnitude to be clinically meaningful and thus, necessitate a dosage adjustment and/or monitoring of GS-9688. Healthy volunteers are selected for this study to remove the confounding effects of background therapies and to avoid the need to make multiple, short-term changes in treatment regimens of HBV-infected patients for the purpose of examining pharmacokinetics.
Interventions
Cohort 1 (CYP3A inhibitor): Voriconazole (VORI) 200 mg oral tablet (N = 25 for 23 evaluable)
Cohort 2 (UGT inhibitor): Probenecid (PBC) 500 mg oral tablet (N = 25 for 23 evaluable)
Cohort 3 (CYP1A2/CYP3A inhibitor): Ciprofloxacin (CIPRO) 500 mg oral tablet (N = 25 for 23 evaluable)
Cohort 4 (CYP450/UGT Inducer): Rifampin (RIF) 600 mg oral tablet (N = 25 for 23 evaluable)
Following completion of screening and admission assessments (on Day -1), eligible subjects will be enrolled to a treatment i
Cohort 1 (CYP3A inhibitor): Voriconazole (VORI) 200 mg oral tablet (N = 25 for 23 evaluable) Cohort 2 (UGT inhibitor): Probenecid (PBC) 500 mg oral tablet (N = 25 for 23 evaluable) Cohort 3 (CYP1A2/CYP3A inhibitor): Ciprofloxacin (CIPRO) 500 mg oral tablet (N = 25 for 23 evaluable) Cohort 4 (CYP450/UGT Inducer): Rifampin (RIF) 600 mg oral tablet (N = 25 for 23 evaluable) Following completion of screening and admission assessments (on Day -1), eligible subjects will be enrolled to a treatment in one of 4 cohorts. Cohorts may be run in parallel. Within each cohort, study treatments will be administered starting on Day 1 as follows: Treatment A: Single dose of GS-9688 1 mg oral tablet will be administered in the AM on Days 1 and 8. Treatment B: VORI 200 mg twice daily (BID) will be administered for 2 days on Days 7 and 8. The single dose of GS-9688 1 mg oral tablet will be administered in the morning of Day 8 1 hour after VORI dose. Treatment C: PBC 500 mg twice daily (BID) will be administered for 2 days on Days 7 and 8 with a single dose of GS-9688 1 mg oral tablet administered in the morning of Day 8 1 hour after PBC dose. Treatment D: CIPRO 500 mg twice daily (BID) will be administered for 2 days on Days 7 and 8. The single dose of GS-9688 1 mg oral tablet will be administered in the morning of Day 8 1 hour after CIPRO dose. Treatment E: Single dose of GS-9688 2 mg oral tablet will be administered in the AM on Day 1 and Day 8. Treatment F: RIF 600 mg once a day (QD) administered in PM for 7 days (Days 2-8) with a single dose of GS-9688 2 mg oral tablet administered in AM of Days 2 to 8. The last dose of RIF will be administered in the PM on Day 8. Cohort 1: Treatment A & B Cohort 2: Treatment A & C Cohort 3: Treatment A & D Cohort 4: Treatment E & F The investigator will maintain an accurate inventory of all study drug(s). Each dose of the study drug(s) administered at the study center will be administered by qualified study center staff. The dose of study drug(s) administered to subjects in the clinic under the supervision of staff will be accurately recorded, which indicates the date and quantity of each dosage formulation dispensed to individual subjects. Used and unused study drug supplies, including empty containers, are to be returned to the shipping facility from which it came for destruction following drug accountability and drug inventory reconciliation.
Sponsors
Gilead Sciences, Inc
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures; 2. Be aged 18 through 45 years of age, inclusive at screening; 3. Be a nonsmoker. The use of nicotine or nicotine-containing products must be discontinued 90 days prior to the first dose of study drug; 4. Have a calculated body mass index (BMI) of >=19.0 and =<30.0 kg/m2 at screening; 5. Have a creatinine clearance (CLcr) >=90 mL/min (using the Cockcroft-Gault method based on serum creatinine and actual body weight as measured at screening, ie; Male: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) = CLcr (mL/min) Female: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) = 0.85 x CLcr (mL/min) 6. Females of childbearing potential must have a negative serum pregnancy test at screening and clinic admission (Day -1); 7. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception; 8. Male subjects must refrain from sperm donation from clinic admission (eg, Day -1), throughout the study period, and continuing for at least 30 days following the last dose of study drug; 9. Subjects have not donated blood within 56 days of study entry or plasma within 7 days of study entry and must refrain from blood donation from clinic admission, throughout the study period, and continuing for at least 30 days following the last dose of study drug; 10. Screening laboratory and 12-lead ECG evaluations must be without clinically significant abnormalities as assessed by the investigator; 11. Have liver disease or liver function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin below the upper limit of normal at screening; 12. Have either a normal 12-lead ECG or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the sponsor; 13. Must be willing and able to comply with all study requirements; 14. Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs.
Exclusion criteria
1. Be a lactating female; 2. Have received any study drug within 30 days prior to study dosing; 3. Have current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance or subject safety; 4. Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody, HBsAg, or HCV antibody; 5. Have poor venous access that limits phlebotomy; 6. Have taken any prescription medications or over-the-counter medications, including herbal products, within 28 days prior to start of study drug dosing, with the exception of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications 7. Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or is expected to receive these agents during the study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies); 8. Have a history of any of the following: a. Significant serious skin disease, such as but not limited to rash, food allergy, eczema, psoriasis, or urticaria b. Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatotoxicity) c. Known hypersensitivity to the study drugs their metabolites or to formulation excipients d. Significant cardiac disease (including history of myocardial infarction based on ECG and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or dilated cardiomyopathy with left ventricular ejection fraction < 40%), a family history of long QT syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years e. Syncope, palpitations, or unexplained dizziness f. Implanted defibrillator or pacemaker g. Liver disease, including Gilbert disease h. Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid hypersecretory conditions requiring prolonged (> 6 months) medical treatment. i. Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary; 9. Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance with the protocol. This would include renal, cardiac, hematological, hepatic, pulmonary (including chronic asthma), endocrine (including diabetes), central nervous, gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, active infection, or malignancy that are clinically significant or requiring treatment.
Outcome results
None listed