GSK1349572 Hepatic Impairment Study

NCT01231529 | Completed Phase 1

• 1 other identifier: 113097
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

GSK1349572 is an integrase inhibitor that is currently in clinical development for the treatment of human immunodeficiency virus (HIV) infection. GSK1349572 is metabolized primarily by uridine diphosphate glucuronosyltransferase (UGT)1A1 with a minor role of Cytochrome P450 (CYP)3A. Hepatic impairment could potentially alter the clearance and plasma protein binding of GSK1349572. This study will evaluate the single dose pharmacokinetics and safety of GSK1349572 in healthy subjects and in subjects with mild or moderate hepatic impairment based on Child-Pugh category. This is a single-dose, open-label, parallel group, two-part, adaptive study in adult males and females with mild or moderate hepatic impairment and matched, healthy control subjects with normal hepatic function. Healthy control subjects (16) will be matched for gender, age, and BMI to the subjects in the mild (8) or moderate (8) hepatic impairment category. In Part 1, approximately 8 subjects with moderate hepatic impairment (cohort 1) and 8 matched, control subjects (cohort 2) will each receive GSK1349572 50 mg as a single dose in the fasted state followed by pharmacokinetic sampling for total concentrations of GSK1349572 in plasma. Free (unbound) plasma concentrations of GSK1349572 will also be evaluated at sparse, selected time points. If the geometric mean total plasma area under the concentration curve (AUC) of GSK1349572 is increased by \> 2-fold in moderately impaired subjects compared to matched controls, Part 2 will be conducted to evaluate GSK1349572 pharmacokinetics in another group of subjects with mild impairment (8, cohort 3) and matched, control subjects (8, cohort 4). Vital signs, electrocardiograms (ECGs), and adverse events will be monitored throughout the study. A follow-up visit will occur 7-10 days after the dose of study drug.

Conditions

Healthy Subjects; Hepatic Impairment; Infection, Human Immunodeficiency Virus; HIV Infections

Outcome Measures

Primary Outcomes (7)

• Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC(0-t))

  72 hours

• Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC(0-infinity),)

  72 hours

• Maximum observed concentration (Cmax)

  72 hours

• Concentration at 24 hours post dose (C24)

  24 hours

• apparent terminal phase half-life (t1/2)

  72 hours

• apparent clearance (CL/F) following oral dosing

  72 hours

• Apparent volume of distribution after extravascular (e.g., oral) administration (Vz/F)

  72 hours

Secondary Outcomes (10)

• Number of subjects with adverse events

  72 hours

• Unbound concentration in plasma of GSK1349572 at 3 hours post dose

  3 hours

• Time of occurrence of Cmax (tmax)

  24 hours

• Number of subjects using concurrent medications

  72 hours

• Change from baseline in clinical laboratory tests

  72 hours

Study Arms (4)

Part 1 Cohort 1

EXPERIMENTAL

8 subjects with moderate hepatic impairment defined by a Child-Pugh score of 7 to 9 will receive a single oral dose of GSK1349572 50 mg in the morning followed by 72 hour serial PK sampling. There will be a screening visit within 30 days prior to the dose of study drug and a follow-up visit within 7-10 days after the study drug.

Drug: GSK1349572

Part 1 Cohort 2

EXPERIMENTAL

8 healthy subjects matched by gender, age and BMI to the subjects in Cohort 1 will receive a single oral dose of GSK1349572 50 mg in the morning followed by 72 hour serial PK sampling. There will be a screening visit within 30 days prior to the dose of study drug and a follow-up visit within 7-10 days after the study drug.

Drug: GSK1349572

Part 2 Cohort 3

EXPERIMENTAL

8 subjects with mild hepatic impairment defined by a Child-Pugh score of 5 to 6 will receive a single oral dose of GSK1349572 50 mg in the morning followed by 72 hour serial PK sampling. There will be a screening visit within 30 days prior to the dose of study drug and a follow-up visit within 7-10 days after the study drug. This cohort will only be done if the AUC from Cohort 1 is greater than or equal to 2 times the AUC from Cohort 2.

Drug: GSK1349572

Part 2 Cohort 4

EXPERIMENTAL

8 healthy subjects matched by gender, age and BMI to the subjects in Cohort 3 will receive a single oral dose of GSK1349572 50 mg in the morning followed by 72 hour serial PK sampling. There will be a screening visit within 30 days prior to the dose of study drug and a follow-up visit within 7-10 days after the study drug. This cohort will only be done if the AUC from Cohort 1 is greater than or equal to 2 times the AUC from Cohort 2.

Drug: GSK1349572

Interventions

GSK1349572 DRUG

All subjects will receive a single dose of GSK1349572 50 mg. GSK1349572 is an experimental drug in the integrase inhibitor class being developed for the treatment of HIV infection. GSK1349572 is not approved by the FDA.

Part 1 Cohort 1; Part 1 Cohort 2; Part 2 Cohort 3; Part 2 Cohort 4

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A male or female is eligible for study participation if he/she: Is healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
• OR (Part 1 subjects only) Is considered to have moderate hepatic insufficiency (of any etiology) and has been clinically stable for at least 1 month prior to screening. To be classified as having moderate hepatic insufficiency, subjects must have: A Child-Pugh score of 7-9 and previous confirmation of liver cirrhosis by liver biopsy or other medical imaging technique (including laparoscopy, computed tomography (CT) scan, magnetic resonance imaging (MRI) or ultrasonography) associated with an unambiguous medical history (such as evidence of portal hypertension) OR (Part 2 subjects only) Is considered to have mild hepatic insufficiency (of any etiology) and has been clinically stable for at least 1 month prior to screening. To be classified as having mild hepatic insufficiency, subjects must have: A Child-Pugh score of 5-6 and previous confirmation of liver cirrhosis by liver biopsy or other medical imaging technique (including laparoscopy, CT scan, MRI or ultrasonography) associated with an unambiguous medical history (such as evidence of portal hypertension).
• Aged between 18 and and 70 years of age inclusive, at the time of signing the informed consent.
• A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<147 pmol/L) is confirmatory\] or Child-bearing potential and agrees to use one of the contraception methods listed for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 3 days after the last dose of study medication.
• Body weight greater than or equal to 50 kg for men and women and body mass index (BMI) within the range 19- 41 kg/m2 for hepatically impaired subjects; healthy matched control subjects will be matched to BMI +/- 20% and must also remain in the BMI range of 19- 41 kg/m2.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

You may not qualify if:

• A positive Hepatitis B surface antigen or positive Hepatitis C antibody result at screening.
• A positive test for HIV antibody at screening.
• The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
• History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Pregnant females as determined by positive serum or urine human chorionic gonadotrophin (hCG) test at screening or prior to dosing.
• Lactating females.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
• If heparin is used during pharmacokinetic (PK) sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
• Consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication.
• Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs. Subjects with a history of cholecystectomy and inflammatory bowel disease should be excluded. Subjects with a history of peptic ulceration or pancreatitis within the preceding 6 months of screening should be excluded.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• History of regular use of tobacco or nicotine-containing products within 3 months prior to screening.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>1.5x upper limit of normal (ULN); alkaline phosphatase or bilirubin ≥ 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). A single repeat is allowed for eligibility determination.

Sponsors & Collaborators

• ViiV Healthcare: lead
• Shionogi: collaborator
• GlaxoSmithKline: collaborator

Study Sites (1)

GSK Investigational Site

Minneapolis, Minnesota, 55404, United States

Location

Related Publications (1)

• Song IH, Borland J, Savina PM, Chen S, Patel P, Wajima T, Peppercorn AF, Piscitelli SC. Pharmacokinetics of Single-Dose Dolutegravir in HIV-Seronegative Subjects With Moderate Hepatic Impairment Compared to Healthy Matched Controls. Clin Pharmacol Drug Dev. 2013 Oct;2(4):342-348. doi: 10.1002/cpdd.55. Epub 2013 Aug 16.

  PMID: 26097786 BACKGROUND

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; HIV Infections

Interventions

dolutegravir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 14, 2010
• First Posted: November 1, 2010
• Study Start: November 19, 2010
• Primary Completion: June 4, 2011
• Study Completion: June 4, 2011
• Last Updated: July 31, 2019

Record last verified: 2019-07

Locations

US (1)