Pharmacokinetics of GS-4997 in Adults With Normal and Impaired Hepatic Function



Status:Completed
Conditions:Renal Impairment / Chronic Kidney Disease
Therapuetic Areas:Nephrology / Urology
Healthy:No
Age Range:18 - Any
Updated:4/21/2016
Start Date:August 2015
End Date:December 2015

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A Phase 1, Open-Label, Parallel-Group, Single Dose Study to Evaluate the Pharmacokinetics of GS-4997 in Subjects With Normal and Impaired Hepatic Function

This study will evaluate the pharmacokinetics (PK), safety, and tolerability of GS-4997 in
adults with impaired hepatic function relative to matched, healthy controls. Each
participant in the control group will be matched to a participant with impaired hepatic
function by age (± 10 years), gender, and body mass index (± 20%).


Inclusion Criteria:

All individuals:

- Body mass index (BMI) from 18 to 40 kg/m^2, inclusive

- Creatinine clearance (CrCl) ≥ 60 mL/min (using the Cockcroft-Gault method) based on
serum creatinine and body weight

Individuals with impaired hepatic function:

- Aside from hepatic insufficiency, must be sufficiently healthy for study
participation based upon screening evaluations.

- Must have diagnosis of chronic (> 6 months), stable hepatic impairment with no
clinically significant change in hepatic status within the 3 months (90 days) prior
to study drug administration (Day 1).

- Individuals with severe hepatic impairment must have a score on the
Child-Pugh-Turcotte scale of 10-15 at screening.

- Individuals with moderate hepatic impairment must have a score on the
Child-Pugh-Turcotte scale of 7-9 at screening.

- Individuals with mild hepatic impairment must have a score on the Child-Pugh-Turcotte
scale of 5-6 at screening.

Healthy individuals (matched control):

- Must be in good health based upon screening evaluations.

Exclusion Criteria:

All individuals:

- Pregnant or lactating females

- Have received any investigational compound or device within 30 days prior to study
dosing

- Current alcohol or substance abuse

- A positive test result for human immunodeficiency virus (HIV-1/2) antibody

- Have poor venous access that limits phlebotomy

- Have been treated with systemic steroids, anti-HIV agents, immunosuppressant
therapies, or chemotherapeutic agents within 3 months prior to screening or expected
to receive these agents during the study (eg, corticosteroids, immunoglobulins, and
other immune- or cytokine-based therapies) that would be contraindicated for other
exclusion criteria.

- Significant serious skin disease, such as but not limited to rash, food allergy,
eczema, psoriasis, or urticaria

- Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)

- Unstable cardiac disease, including history of myocardial infarction within 1 year of
screening, recurrent episodes of ventricular tachycardia despite appropriate medical
therapy, decompensated congestive heart failure, or dilated cardiomyopathy with left
ventricular ejection fraction < 40%), or a family history of Long QT Syndrome, or
unexplained death in an otherwise healthy individual between the ages of 1 and 30
years.

- Syncope, palpitations, or unexplained dizziness

- Implanted defibrillator or pacemaker.

- Severe peptic ulcer disease, severe gastroesophageal reflux disease, or other severe
gastric acid hypersecretory conditions.

- Medical or surgical treatment that permanently alters gastric absorption (eg, gastric
or intestinal surgery). A history of cholecystectomy is not exclusionary.

- History of prior allogeneic bone marrow progenitor cell or solid organ
transplantation.

- Currently registered on an organ transplantation list.

- History of bleeding from esophageal varices within 90 days prior to Admission (Day
-1).

- Use of strong CYP3A4 inhibitors (eg, indinavir, nelfinavir, ritonavir,
clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, suboxone,
telithromycin, atazanavir) and strong CYP3A4 inducers (eg, carbamazepine, rifampin,
phenytoin and St. John's wort), within 28 days prior to study drug administration
(Day 1).

- Consumption of grapefruit juice, grapefruits, and Seville orange juice within 2 weeks
prior to study drug administration (Day 1).

- Recent significant changes in the use of nicotine or nicotine containing products

Individuals with impaired hepatic function:

- Aside from hepatic insufficiency, serious or active medical or psychiatric illness
that, in the opinion of the investigator, would interfere with treatment, assessment,
or compliance with the protocol.

- Chronic hepatitis B virus (HBV) infection, defined as a positive test for hepatitis B
surface antigen (HBsAg), unless the patient has been treated with a nucleos(t)ide
analog (eg, tenofovir or entecavir) for at least 6 months and the HBV DNA by
polymerase chain reaction (PCR) assay has been persistently undetectable for at least
6 months.

- Positive test for drugs of abuse, including alcohol at screening or on Day
-1/check-in, with the exception of opioids and tetrahydrocannabinol (THC, marijuana)
under prescription and investigator verification for pain management. Individuals who
screen positive for benzodiazepines may be allowed if prescribed under the care of a
physician and after review by investigator and Sponsor.

- Requires paracentesis > 1 time per month.

- Individuals with hepatic impairment with co-morbid diseases not associated with
hepatic impairment requiring medication(s) must be taking the medication(s) without a
change in dose for > 3 months prior to screening.

- Changes in concomitant medications or dosage used to treat symptoms of hepatic
impairment or associated co-morbid conditions that could lead to clinically
significant changes in medical conditions during the course of the study that would
affect the ability to interpret potential drug-drug interactions within 28 days prior
to dosing.

Healthy individuals (matched control):

- A positive test result for hepatitis C virus (HCV) antibody, hepatitis B surface
antigen (HBsAg), or hepatitis B core antibody (anti-HBc)

- Positive test for drugs of abuse, including alcohol at screening or on Day
-1/check-in.

- Have any serious or active medical or psychiatric illness (including depression)
which, in the opinion of the investigator, would interfere with treatment,
assessment, or compliance with the protocol.

- History of liver disease.

- Have taken any prescription medications or over-the-counter medications including
herbal products within 28 days of commencing study drug dosing with the exception of
vitamins, acetaminophen, ibuprofen, and hormonal contraceptive medications.
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