Evaluation Of Hepatic Impairment On AG-013736 Pharmacokinetics

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the effects of mild and moderate impairment of hepatic function on the single-dose pharmacokinetics, safety and tolerability of AG-013736.

Official Title
-----------------
A Phase 1 Study To Evaluate The Pharmacokinetics Of AG-013736 In Subjects With Impaired Hepatic Function

Conditions
-----------------
Hepatic Insufficiency

Intervention / Treatment
-----------------
* Drug: AG-013736
* Drug: AG-013736
* Drug: AG-013736


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of reduced hepatic function (Child Pugh Classification A or B) Body Mass Index of 18-32 kg/m2 Exclusion Criteria: History of febrile illness within 5 days prior to first dose Any condition possibly affecting drug absorption (e.g. gastrectomy) Positive urine drug screen

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hepatic Function - Mild Impairment<br>Subjects with mild hepatic impairment (Child Pugh class A, score 5-6) | Drug: AG-013736<br>* Single oral 5-mg dose of AG-013736, administered as a film-coated, immediate-release tablet.<br>|
| Experimental: Hepatic Function - Moderate Impairment<br>Subjects with moderate hepatic impairment(Child Pugh class B,score 7-9) | Drug: AG-013736<br>* Single oral 5-mg dose of AG-013736, administered as a film-coated, immediate-release tablet.<br>|
| Experimental: Hepatic Function - Normal<br>Group 1 1) subjects with normal hepatic function | Drug: AG-013736<br>* Single oral 5-mg dose of AG-013736, administered as a film-coated, immediate-release tablet.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) |  | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hours (hrs) post-dose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Plasma Elimination Half-life (t1/2) | Plasma elimination half-life is the time measured for the plasma concentration to decrease by one half. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Apparent Oral Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Apparent Volume of Distribution (Vz/F) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the oral bioavailability. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Fraction of Unbound Drug (fu) | Fraction of unbound drug (fu) is defined as the ratio of unbound drug concentration to the total drug concentration. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Unbound Apparent Oral Clearance (CLu/F) | Clearance of an unbound drug is a measure of the rate at which an unbound drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability. Unbound drug clearance is a quantitative measure of the rate at which an unbound drug substance is removed from the blood. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Unbound Apparent Volume of Distribution (Vzu/F) | Volume of distribution of unbound drug is defined as the theoretical volume in which the total amount of unbound drug would need to be uniformly distributed to produce the desired plasma concentration of unbound drug. Unbound apparent volume of distribution after oral dose (Vzu/F) is influenced by the oral bioavailability. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Unbound Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)u] | AUC (0 - ∞)u = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞) for unbound drug. It is obtained from AUCu (0 - t) plus AUCu (t - ∞). | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Unbound Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClastu) | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClastu) for unbound drug. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 
| Unbound Maximum Observed Plasma Concentration (Cmaxu) | Cmaxu is the highest measured unbound plasma concentration during the dosing interval. | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hepatic impairment