The Effect o f Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Betrixiban, an Oral FXa Antagonist

Portola Pharmaceuticals32 enrolled

Overview

Single center, prospective open label PK and PD study of betrixaban in subjects with mild and moderate hepatic impairment vs healthy volunteers.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

Conditions

Hepatic Impairment

Interventions

BetrixabanDRUG

80 mg capsule

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. 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. 2. Body Mass Index between 18 and 35 kg\*m-2 and weighs at least 50 kg. 3. 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. 4. 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. 5. The subject smokes \<12 cigarettes per day or equivalent and agrees to no or reduced tobacco products while domiciled. 6. The subject is able to read and give written informed consent and signed the IRB approved consent form. 7. The subject has adequate venous access for blood sampling. Exclusion Criteria: 1. 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. 2. 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. 3. The subject has a history of or risk factors for a hypercoagulable or thrombotic condition. 4. 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. 5. The subject has a calculated creatinine clearance of \<60mL/min as determined by Cockcroft-Gault method. 6. Concomitant medication use: 1. For all subjects, illicit drugs, oral contraceptives, and hormone replacement therapy are excluded within 30 days prior to Day -1. 2. For all subjects, over the counter drugs, including dietary supplements and herbal products are excluded within 14 days prior to Day -1. 3. 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. 4. 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. 7. 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. 8. The subject has a history of blood donation of more than 500mL within 3 months prior to dosing. 9. 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. 10. The subject has positive screen for drugs of abuse at Day -1. 11. The subject does not agree to withhold from alcohol consumption from 48 hours prior to dosing through discharge. 12. The subject has a medical or surgical condition which may impair drug absorption. 13. The subject is pregnant or breastfeeding. 14. 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.

Locations (1)

Clinical Pharmacology of Miami

Hialeah, Florida, United States

Outcomes

Primary Outcomes

PK - Plasma half-life (t1/2)

Plasma half-life (t1/2), distribution half-life and terminal half-life.

Time frame: Day 1 through Day 6

PK - Tmax

Time to maximum observed plasma concentration (Tmax).

Time frame: Day 1 through Day 6

PK - Cmax

Maximum observed plasma concentration (Cmax)

Time frame: Day 1 through Day 6

PK - AUC (0-last)

Area under the plasma concentration-time curve from 0 to last measurable concentration (AUC (0-last)).

Time frame: Day 1 through Day 6

PK - (AUC(0-∞)).

Total area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)).

Time frame: Day 1 through Day 6

PK - Volume of distribution

Apparent volume of distribution (Vd/F).

Time frame: Day 1 through Day 6

PK - Total clearance

Apparent total clearance (CL/F).

Time frame: Day 1 through Day 6

Secondary Outcomes

Safety - Treatment Emergent AEs

Safety evaluation will study the adverse event (AE) profile

Time frame: Day -1 through up to Day 21

Safety - Demographics

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Safety will be evaluated by assessment of Demographics

Time frame: Day -30 through Day -2 (Screening)

Safety - Vital Signs Temperature

Safety will be evaluated by assessment of Temperature - Celsius

Time frame: Day -30 through up to Day 21

Safety - Vital Signs Respiratory Rate

Safety will be evaluated by assessment of Respiratory Rate - Breaths per Minute

Time frame: Day -30 through up to Day 21

Safety - Vital Signs Heart Rate

Safety will be evaluated by assessment of Heart Rate - Beats per Minute

Time frame: Day -30 through up to Day 21

Safety - Vital Signs Blood Pressure

Safety will be evaluated by assessment of Blood Pressure - mmHg

Time frame: Day -30 through up to Day 21

Safety - 12 Lead ECG - PR

Safety will be evaluated by assessment of 12 ECG - PR (ms)

Time frame: Day -30 through up to Day 21

Safety - 12 Lead ECG - RR

Safety will be evaluated by assessment of 12 ECG - RR (ms)

Time frame: Day -30 through up to Day 21

Safety - 12 Lead ECG - WRS

Safety will be evaluated by assessment of 12 ECG - WRS (ms)

Time frame: Day -30 through up to Day 21

Safety - 12 Lead ECG - QT

Safety will be evaluated by assessment of 12 ECG - QT (ms)

Time frame: Day -30 through up to Day 21

Safety - 12 Lead ECG - QTcF

Safety will be evaluated by assessment of 12 ECG - QTcF (ms)

Time frame: Day -30 through up to Day 21

Safety - 12 Lead ECG - QTcB

Safety will be evaluated by assessment of 12 ECG - QTcB (ms)

Time frame: Day -30 through up to Day 21

Safety - Physical Exam - Height

Safety will be evaluated by assessment Physical Exam - Height (centimeters)

Time frame: Day -30 through up to Day 21

Safety - Physical Exam - Weight

Safety will be evaluated by assessment Physical Exam - Weight (kilogram)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - hemoglobin

Safety will be evaluated by analyzing Hematology - hemoglobin (g/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - hematocrit

Safety will be evaluated by analyzing Hematology - hematocrit (%)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - white blood cell [WBC]

Safety will be evaluated by analyzing Hematology - WBC (K/UL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Platelet Count

Safety will be evaluated by analyzing Platelet Count (Plt/mL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Absolute Neutrophil Count

Safety will be evaluated by analyzing Absolute Neutrophil Count (K/UL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Absolute Basophils

Safety will be evaluated by analyzing Absolute Basophils (K/UL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Eosinophil's

Safety will be evaluated by analyzing Eosinophil's (K/UL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Lymphocytes

Safety will be evaluated by analyzing Lymphocytes (K/UL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Mean Corpuscular Hemoglobin

Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin (PG)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Mean Corpuscular Hemoglobin Concentration

Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin Concentration (g/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Mean Corpuscular Hemoglobin Volume

Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin Volume (FL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Monocytes

Safety will be evaluated by analyzing Monocytes (K/UL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Neutrophils

Safety will be evaluated by analyzing Neutrophils (K/UL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Red Blood Cell Count

Safety will be evaluated by analyzing Red Blood Cell Count (MIL/UL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Red Cell Distribution Width

Safety will be evaluated by analyzing Red Cell Distribution Width (%)

Time frame: Day -30 through up to Day 21

Safety - Lab - Hematology - Reticulocyte

Safety will be evaluated by analyzing Reticulocyte (K/UL)

Time frame: Day -30 through up to Day 21

Safety- Lab - Coagulation - PT

Safety will be evaluated by analyzing Coagulation - PT (seconds)

Time frame: Day -30 through up to Day 21

Safety- Lab - Coagulation - INR

Safety will be evaluated by analyzing Coagulation - INR (no unit)

Time frame: Day -30 through up to Day 21

Safety- Lab - Coagulation - aPTT

Safety will be evaluated by analyzing Coagulation - aPTT (seconds)

Time frame: Day -30 through up to Day 21

Safety- Lab - Coagulation - Factor V Leiden

Safety will be evaluated by analyzing Coagulation - Factor V Leiden (positive/negative)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Sodium

Safety will be evaluated by analyzing Serum Chemistry - Sodium (mEq/L)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Potassium

Safety will be evaluated by analyzing Serum Chemistry - Potassium (mEq/L)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Chloride

Safety will be evaluated by analyzing Serum Chemistry - Chloride (mEq/L)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Carbon Dioxide

Safety will be evaluated by analyzing Serum Chemistry - Carbon Dioxide (mEq/L)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Glucose

Safety will be evaluated by analyzing Serum Chemistry - Glucose (mg/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Blood Urea Nitrogen

Safety will be evaluated by analyzing Serum Chemistry - Blood Urea Nitrogen (mg/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Creatinine

Safety will be evaluated by analyzing Serum Chemistry - Creatinine (mg/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - AST

Safety will be evaluated by analyzing Serum Chemistry - AST (U/L)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - ALT

Safety will be evaluated by analyzing Serum Chemistry - ALT (U/L)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - GGT

Safety will be evaluated by analyzing Serum Chemistry - GGT (U/L)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Total Protein

Safety will be evaluated by analyzing Serum Chemistry - Total Protein (g/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Albumin

Safety will be evaluated by analyzing Serum Chemistry - Albumin(g/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Alkaline Phosphatase

Safety will be evaluated by analyzing Serum Chemistry - Alkaline Phosphatase (U/L)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Calcium

Safety will be evaluated by analyzing Serum Chemistry - Calcium (mg/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Phosphorus

Safety will be evaluated by analyzing Serum Chemistry - Phosphorus (mg/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Total Bilirubin

Safety will be evaluated by analyzing Serum Chemistry - Total Bilirubin (mg/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Fractionated Bilirubin

Safety will be evaluated by analyzing Serum Chemistry - Fractionated Bilirubin(mg/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - Uric Acid

Safety will be evaluated by analyzing Serum Chemistry - Uric Acid (mg/dL)

Time frame: Day -30 through up to Day 21

Safety - Lab - Serum Chemistry - LDH

Safety will be evaluated by analyzing Serum Chemistry LDH (U/L)

Time frame: Day -30 through up to Day 21

Safety - Lab - Urine toxicology Panel - Amphetamines

Safety will be evaluated by analyzing Urine toxicology Panel - Amphetamines (NG/ML)

Time frame: Day -30 through Day -1

Safety - Lab - Urine toxicology Panel - Barbiturates

Safety will be evaluated by analyzing Urine toxicology Panel - Barbiturates (NG/ML)

Time frame: Day -30 through Day -1

Safety - Lab - Urine toxicology Panel - Cannabinoids

Safety will be evaluated by analyzing Urine toxicology Panel - Cannabinoids (NG/ML)

Time frame: Day -30 through Day -1

Safety - Lab - Urine toxicology Panel - Cocaine

Safety will be evaluated by analyzing Urine toxicology Panel - Cocaine (NG/ML)

Time frame: Day -30 through Day -1

Safety - Lab - Urine toxicology Panel - Ethanol

Safety will be evaluated by analyzing Urine toxicology Panel - Ethanol (MG/DL)

Time frame: Day -30 through Day -1

Safety - Lab - Urine toxicology Panel - Opiates

Safety will be evaluated by analyzing Urine toxicology Panel - Opiates (NG/ML)

Time frame: Day -30 through Day -1

Safety - Lab - Urinalysis - Specific Gravity

Safety will be evaluated by analyzing Urinalysis - Specific Gravity (no unit)

Time frame: Day -30 through up to Day 21

Safety - Lab - Urinalysis - pH

Safety will be evaluated by analyzing Urinalysis - pH (no unit)

Time frame: Day -30 through up to Day 21

Safety - Lab - Urinalysis - Glucose

Safety will be evaluated by analyzing Urinalysis - Glucose (no unit)

Time frame: Day -30 through up to Day 21

Safety - Lab - Urinalysis - Protein

Safety will be evaluated by analyzing Urinalysis - Protein (no unit)

Time frame: Day -30 through up to Day 21

Safety - Lab - Urinalysis - Hemoglobin

Safety will be evaluated by analyzing Urinalysis - Hemoglobin (no unit)

Time frame: Day -30 through up to Day 21

Safety - Lab - Urinalysis - Leukocyte esterase

Safety will be evaluated by analyzing Urinalysis - Leukocyte esterase (no unit)

Time frame: Day -30 through up to Day 21

Safety - Lab - Urinalysis - Nitrate

Safety will be evaluated by analyzing Urinalysis - Nitrate (no unit)

Time frame: Day -30 through up to Day 21

Safety - Urine Occult Blood Testing

Safety will be evaluated by assessment of Urine Occult Blood Testing (positive/negative)

Time frame: Day -30 through Day -2 (screening)

Safety - Fecal Occult Blood Testing

Safety will be evaluated by assessment of Fecal Occult Blood Testing (positive/negative)

Time frame: Day -30 through Day -2 (screening)

Safety - Lab - Blood Virology - HIV I

Safety will be evaluated by analyzing Blood Virology - HIV I (positive/negative)

Time frame: Day-30 through Day -2 (Screening)

Safety - Lab - Blood Virology - HIV II

Safety will be evaluated by analyzing Blood Virology - HIV II (positive/negative)

Time frame: Day-30 through Day -2 (Screening)

Safety - Lab - Blood Virology - Hepatitis B

Safety will be evaluated by analyzing Blood Virology - Hepatitis B (positive/negative)

Time frame: Day-30 through Day -2 (Screening)

Safety - Lab - Blood Virology - Hepatitis C

Safety will be evaluated by analyzing Blood Virology - Hepatitis C (positive/negative)

Time frame: Day-30 through Day -2 (Screening)

Safety - Lab - Serum Pregnancy

Safety will be evaluated by analyzing Serum Pregnancy

Time frame: Day -30 through up to Day 21

PD - Anti-Factor Xa Concentration

Anti-fXa will be analyzed for changes/percent changes from baseline over time.

Time frame: Day 1 through Day 6

PD - Thrombin Concentrations

Thrombin will be analyzed for changes/percent changes from baseline over time.

Time frame: Day 1 through Day 6