The Effect o f Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Betrixiban, an Oral FXa Antagonist
- Registration Number
- NCT03397888
- Lead Sponsor
- Portola Pharmaceuticals
- Brief Summary
Single center, prospective open label PK and PD study of betrixaban in subjects with mild and moderate hepatic impairment vs healthy volunteers.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 32
- Cohorts 1 & 2: Man or a woman 18 to 70 with stable chronic hepatic impairment disease due to cirrhosis confirmed by biopsy, ultrasound, CT or MRI (Cohort 1 - Mild impairment, Child-Pugh Category A; Cohort 2 - Moderate Impairment, Child-Pugh Category B). Cohort 3: essentially healthy man or woman without liver disease whose sex, age and weight match patients in Cohorts 1 & 2 in order to result in similar average demographics.
- Body Mass Index between 18 and 35 kg*m-2 and weighs at least 50 kg.
- Contraception. Men must agree to acceptable methods of contraception. Women of child-bearing potential must agree to two acceptable forms of contraception. Post-menopausal women must have had no regular menstrual bleeding for at least one year prior to initial dosing and confirmed by an elevated plasma Follicle-stimulating hormone level test at screening for women not in receipt of hormone replacement therapy (HRT). Women who report surgical sterilization must have had the procedure at least six months prior to dosing, supported by clinical documentation.
- The subject has clinical unremarkable medical history, physical examination, ECG, laboratory values and vital signs, as determined by the investigator. Subjects in Cohorts 1 & 2 may have: abnormal liver function tests, INR up to 2.2, PT up to 6 seconds over control, aPPT up to 45 seconds and platelets down to 45,000/uL.
- The subject smokes <12 cigarettes per day or equivalent and agrees to no or reduced tobacco products while domiciled.
- The subject is able to read and give written informed consent and signed the IRB approved consent form.
- The subject has adequate venous access for blood sampling.
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The subject has a history, symptoms of, or risk factors for bleeding or a stool specimen within 6 months of dosing positive for occult blood.
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The subject has an absolute/relative contraindication to anticoagulation due to: history of intracranial bleeding, severe active bleeding, recent brain, eye, or spinal cord surgery or major surgery within 6 months of dosing.
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The subject has a history of or risk factors for a hypercoagulable or thrombotic condition.
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The subject has a history of any clinically significant cardiac, endocrinologic, hematologic, hepatic (except for Cohorts 1 & 2), immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal or other major disease other than the underlying disease in Cohorts 1 & 2.
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The subject has a calculated creatinine clearance of <60mL/min as determined by Cockcroft-Gault method.
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Concomitant medication use:
- For all subjects, illicit drugs, oral contraceptives, and hormone replacement therapy are excluded within 30 days prior to Day -1.
- For all subjects, over the counter drugs, including dietary supplements and herbal products are excluded within 14 days prior to Day -1.
- Subjects enrolled in Cohort 3 will be excluded if the subject has taken any prescription drugs in the 30 days prior to dosing. Furthermore, the subject will be excluded if he/she does not agree to refrain from concomitant drugs throughout the study unless medically necessary as determined by the Investigator.
- Subjects enrolled in Cohort 1 and 2 may continue taking stable preexisting medications throughout the study with the exception of strong P-gp inhibitors. Strong P-gp inhibitors include but are not limited to: amiodarone, azithromycin, clarithromycin, erythromycin, ketoconazole, and verapamil. Prescribed stable acetaminophen use up to 2,000 mg per day is allowable. Any acetaminophen use with alcohol within 48 hours of dosing is prohibited. Furthermore, the subject will be excluded if he/she does not agree to refrain from additional concomitant drugs throughout the study unless medically necessary as determined by the Investigator.
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The subject has a history of severe trauma or bone fracture within 6 months prior to dosing; or planned surgery within 1 month after dosing.
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The subject has a history of blood donation of more than 500mL within 3 months prior to dosing.
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The subject has received an investigational drug product within 30 days or 5 half-lives of the investigational compound, whichever is greater, from Day -1.
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The subject has positive screen for drugs of abuse at Day -1.
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The subject does not agree to withhold from alcohol consumption from 48 hours prior to dosing through discharge.
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The subject has a medical or surgical condition which may impair drug absorption.
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The subject is pregnant or breastfeeding.
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The subject has any condition which could interfere with or for which the treatment might interfere with the conduct of the study, or would, in the opinion of the Investigator, increase the risk of the subject's participation in the study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 1 Betrixaban Mild Impairment, Child-Pugh Category A Cohort 2 Betrixaban Moderate Impairment, Child-Pugh Category B Cohort 3 Betrixaban Essentially Healthy man or woman without liver disease matched to Cohorts 1 \& 2 for age, sex and weight.
- Primary Outcome Measures
Name Time Method PK - Tmax Day 1 through Day 6 Time to maximum observed plasma concentration (Tmax).
PK - AUC (0-last) Day 1 through Day 6 Area under the plasma concentration-time curve from 0 to last measurable concentration (AUC (0-last)).
PK - (AUC(0-∞)). Day 1 through Day 6 Total area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)).
PK - Plasma half-life (t1/2) Day 1 through Day 6 Plasma half-life (t1/2), distribution half-life and terminal half-life.
PK - Cmax Day 1 through Day 6 Maximum observed plasma concentration (Cmax)
PK - Volume of distribution Day 1 through Day 6 Apparent volume of distribution (Vd/F).
PK - Total clearance Day 1 through Day 6 Apparent total clearance (CL/F).
- Secondary Outcome Measures
Name Time Method Safety- Lab - Coagulation - PT Day -30 through up to Day 21 Safety will be evaluated by analyzing Coagulation - PT (seconds)
Safety - 12 Lead ECG - PR Day -30 through up to Day 21 Safety will be evaluated by assessment of 12 ECG - PR (ms)
Safety - Treatment Emergent AEs Day -1 through up to Day 21 Safety evaluation will study the adverse event (AE) profile
Safety - Demographics Day -30 through Day -2 (Screening) Safety will be evaluated by assessment of Demographics
Safety - Vital Signs Temperature Day -30 through up to Day 21 Safety will be evaluated by assessment of Temperature - Celsius
Safety - Vital Signs Blood Pressure Day -30 through up to Day 21 Safety will be evaluated by assessment of Blood Pressure - mmHg
Safety - Vital Signs Heart Rate Day -30 through up to Day 21 Safety will be evaluated by assessment of Heart Rate - Beats per Minute
Safety - Lab - Serum Chemistry - Potassium Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Potassium (mEq/L)
Safety - 12 Lead ECG - WRS Day -30 through up to Day 21 Safety will be evaluated by assessment of 12 ECG - WRS (ms)
Safety - Lab - Hematology - Platelet Count Day -30 through up to Day 21 Safety will be evaluated by analyzing Platelet Count (Plt/mL)
Safety - Lab - Hematology - Lymphocytes Day -30 through up to Day 21 Safety will be evaluated by analyzing Lymphocytes (K/UL)
Safety - Lab - Hematology - Mean Corpuscular Hemoglobin Volume Day -30 through up to Day 21 Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin Volume (FL)
Safety - Lab - Hematology - white blood cell [WBC] Day -30 through up to Day 21 Safety will be evaluated by analyzing Hematology - WBC (K/UL)
Safety - Lab - Hematology - Eosinophil's Day -30 through up to Day 21 Safety will be evaluated by analyzing Eosinophil's (K/UL)
Safety - Lab - Hematology - Monocytes Day -30 through up to Day 21 Safety will be evaluated by analyzing Monocytes (K/UL)
Safety - Vital Signs Respiratory Rate Day -30 through up to Day 21 Safety will be evaluated by assessment of Respiratory Rate - Breaths per Minute
Safety - Lab - Serum Chemistry - Glucose Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Glucose (mg/dL)
Safety - Lab - Serum Chemistry - Blood Urea Nitrogen Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Blood Urea Nitrogen (mg/dL)
Safety - Lab - Urinalysis - Specific Gravity Day -30 through up to Day 21 Safety will be evaluated by analyzing Urinalysis - Specific Gravity (no unit)
Safety - 12 Lead ECG - RR Day -30 through up to Day 21 Safety will be evaluated by assessment of 12 ECG - RR (ms)
Safety - Physical Exam - Height Day -30 through up to Day 21 Safety will be evaluated by assessment Physical Exam - Height (centimeters)
Safety - Lab - Hematology - Mean Corpuscular Hemoglobin Concentration Day -30 through up to Day 21 Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin Concentration (g/dL)
Safety- Lab - Coagulation - aPTT Day -30 through up to Day 21 Safety will be evaluated by analyzing Coagulation - aPTT (seconds)
Safety - Lab - Serum Chemistry - Creatinine Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Creatinine (mg/dL)
Safety - Lab - Serum Chemistry - AST Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - AST (U/L)
Safety - Lab - Serum Chemistry - ALT Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - ALT (U/L)
Safety - Lab - Serum Chemistry - Albumin Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Albumin(g/dL)
Safety - Lab - Urinalysis - Nitrate Day -30 through up to Day 21 Safety will be evaluated by analyzing Urinalysis - Nitrate (no unit)
Safety - 12 Lead ECG - QT Day -30 through up to Day 21 Safety will be evaluated by assessment of 12 ECG - QT (ms)
Safety - Physical Exam - Weight Day -30 through up to Day 21 Safety will be evaluated by assessment Physical Exam - Weight (kilogram)
Safety - Lab - Hematology - hemoglobin Day -30 through up to Day 21 Safety will be evaluated by analyzing Hematology - hemoglobin (g/dL)
Safety - Lab - Hematology - hematocrit Day -30 through up to Day 21 Safety will be evaluated by analyzing Hematology - hematocrit (%)
Safety - Lab - Hematology - Absolute Basophils Day -30 through up to Day 21 Safety will be evaluated by analyzing Absolute Basophils (K/UL)
Safety - Lab - Hematology - Neutrophils Day -30 through up to Day 21 Safety will be evaluated by analyzing Neutrophils (K/UL)
Safety- Lab - Coagulation - INR Day -30 through up to Day 21 Safety will be evaluated by analyzing Coagulation - INR (no unit)
Safety - Lab - Serum Chemistry - Sodium Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Sodium (mEq/L)
Safety - Lab - Serum Chemistry - Alkaline Phosphatase Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Alkaline Phosphatase (U/L)
Safety - Lab - Blood Virology - HIV II Day-30 through Day -2 (Screening) Safety will be evaluated by analyzing Blood Virology - HIV II (positive/negative)
PD - Anti-Factor Xa Concentration Day 1 through Day 6 Anti-fXa will be analyzed for changes/percent changes from baseline over time.
PD - Thrombin Concentrations Day 1 through Day 6 Thrombin will be analyzed for changes/percent changes from baseline over time.
Safety - 12 Lead ECG - QTcF Day -30 through up to Day 21 Safety will be evaluated by assessment of 12 ECG - QTcF (ms)
Safety - 12 Lead ECG - QTcB Day -30 through up to Day 21 Safety will be evaluated by assessment of 12 ECG - QTcB (ms)
Safety - Lab - Hematology - Absolute Neutrophil Count Day -30 through up to Day 21 Safety will be evaluated by analyzing Absolute Neutrophil Count (K/UL)
Safety - Lab - Hematology - Mean Corpuscular Hemoglobin Day -30 through up to Day 21 Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin (PG)
Safety- Lab - Coagulation - Factor V Leiden Day -30 through up to Day 21 Safety will be evaluated by analyzing Coagulation - Factor V Leiden (positive/negative)
Safety - Lab - Serum Chemistry - Chloride Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Chloride (mEq/L)
Safety - Lab - Serum Chemistry - Carbon Dioxide Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Carbon Dioxide (mEq/L)
Safety - Lab - Serum Chemistry - GGT Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - GGT (U/L)
Safety - Lab - Serum Chemistry - Total Protein Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Total Protein (g/dL)
Safety - Lab - Serum Chemistry - Calcium Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Calcium (mg/dL)
Safety - Lab - Serum Chemistry - Uric Acid Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Uric Acid (mg/dL)
Safety - Lab - Serum Chemistry - LDH Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry LDH (U/L)
Safety - Lab - Hematology - Red Blood Cell Count Day -30 through up to Day 21 Safety will be evaluated by analyzing Red Blood Cell Count (MIL/UL)
Safety - Lab - Hematology - Red Cell Distribution Width Day -30 through up to Day 21 Safety will be evaluated by analyzing Red Cell Distribution Width (%)
Safety - Lab - Hematology - Reticulocyte Day -30 through up to Day 21 Safety will be evaluated by analyzing Reticulocyte (K/UL)
Safety - Lab - Serum Chemistry - Phosphorus Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Phosphorus (mg/dL)
Safety - Lab - Serum Chemistry - Total Bilirubin Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Total Bilirubin (mg/dL)
Safety - Lab - Urine toxicology Panel - Ethanol Day -30 through Day -1 Safety will be evaluated by analyzing Urine toxicology Panel - Ethanol (MG/DL)
Safety - Lab - Urine toxicology Panel - Opiates Day -30 through Day -1 Safety will be evaluated by analyzing Urine toxicology Panel - Opiates (NG/ML)
Safety - Lab - Blood Virology - HIV I Day-30 through Day -2 (Screening) Safety will be evaluated by analyzing Blood Virology - HIV I (positive/negative)
Safety - Lab - Blood Virology - Hepatitis C Day-30 through Day -2 (Screening) Safety will be evaluated by analyzing Blood Virology - Hepatitis C (positive/negative)
Safety - Lab - Serum Chemistry - Fractionated Bilirubin Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Chemistry - Fractionated Bilirubin(mg/dL)
Safety - Lab - Urine toxicology Panel - Amphetamines Day -30 through Day -1 Safety will be evaluated by analyzing Urine toxicology Panel - Amphetamines (NG/ML)
Safety - Lab - Urine toxicology Panel - Barbiturates Day -30 through Day -1 Safety will be evaluated by analyzing Urine toxicology Panel - Barbiturates (NG/ML)
Safety - Lab - Urine toxicology Panel - Cannabinoids Day -30 through Day -1 Safety will be evaluated by analyzing Urine toxicology Panel - Cannabinoids (NG/ML)
Safety - Lab - Urine toxicology Panel - Cocaine Day -30 through Day -1 Safety will be evaluated by analyzing Urine toxicology Panel - Cocaine (NG/ML)
Safety - Lab - Urinalysis - pH Day -30 through up to Day 21 Safety will be evaluated by analyzing Urinalysis - pH (no unit)
Safety - Lab - Urinalysis - Glucose Day -30 through up to Day 21 Safety will be evaluated by analyzing Urinalysis - Glucose (no unit)
Safety - Lab - Urinalysis - Protein Day -30 through up to Day 21 Safety will be evaluated by analyzing Urinalysis - Protein (no unit)
Safety - Lab - Urinalysis - Hemoglobin Day -30 through up to Day 21 Safety will be evaluated by analyzing Urinalysis - Hemoglobin (no unit)
Safety - Lab - Urinalysis - Leukocyte esterase Day -30 through up to Day 21 Safety will be evaluated by analyzing Urinalysis - Leukocyte esterase (no unit)
Safety - Fecal Occult Blood Testing Day -30 through Day -2 (screening) Safety will be evaluated by assessment of Fecal Occult Blood Testing (positive/negative)
Safety - Lab - Blood Virology - Hepatitis B Day-30 through Day -2 (Screening) Safety will be evaluated by analyzing Blood Virology - Hepatitis B (positive/negative)
Safety - Lab - Serum Pregnancy Day -30 through up to Day 21 Safety will be evaluated by analyzing Serum Pregnancy
Safety - Urine Occult Blood Testing Day -30 through Day -2 (screening) Safety will be evaluated by assessment of Urine Occult Blood Testing (positive/negative)
Trial Locations
- Locations (1)
Clinical Pharmacology of Miami
🇺🇸Hialeah, Florida, United States