Drug Interaction Study Between Dolutegravir and Prednisone

This study has been completed.
Sponsor:
Collaborators:
Shionogi
GlaxoSmithKline
Information provided by:
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01425099
First received: August 18, 2011
Last updated: November 3, 2011
Last verified: October 2011
  Purpose

Dolutegravir (DTG, GSK1349572 is an integrase inhibitor that is currently in Phase 3 clinical development for the treatment of human immunodeficiency virus (HIV) infection. DTG is primarily metabolized by UDP-glucuronosyltransferase (UGT1A1) with cytochrome P450 (CYP)3A4 pathway as a minor route. Corticosteroids have demonstrated induction effects on UGTs and CYP3A4. Corticosteroids are often used in HIV-infected subjects and have the potential to reduce DTG exposure due to enzyme induction when co-administered. The primary objective of this study is to determine whether concomitant prednisone administration can affect the pharmacokinetics (PK) of DTG.

The study is a two part, two period, open label study. Part 1 will evaluate the effect of a high prednisone dose on DTG PK with the potential for an additional Part 2 depending on the results from Part 1. In Part 1, approximately 12 healthy subjects will receive DTG 50mg q24h for 5 days in Period 1. Subjects will then be administered DTG 50mg q24h in combination with prednisone 60mg for 5 days followed by a 5 day taper (total duration of 10 days) in Period 2. PK data of DTG will be obtained from Part 1 and used to inform decision making on the need for Part 2. If DTG exposure is reduced by more than 50% in Part 1, Part 2 will be carried out where a second cohort of subjects will receive DTG 50mg q24h DTG for 5 days in Period 1 followed by DTG 50mg q24h in combination with prednisone 20mg for 5 days followed by a 5 day taper (total duration of 10 days) in Period 2. Safety evaluations and serial PK samples for DTG will be collected during each treatment period. A follow-up visit will occur 7-14 days after the last dose of study drug. All doses of study drugs will be taken following a moderate fat meal. This study will be conducted at one center in the United States, with healthy adult male and female subjects.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: Dolutegravir
Drug: Prednisone
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: An Adaptive, Two Part, Two Period, Single Sequence, Drug Interaction Study Between Dolutegravir 50 mg and Prednisone in Adult Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Composite of DTG pharmacokinetic parameters on Day 5 and Day 10: AUC(0-t), Cmax, C0, Ct, Cmin, CL/F, and t½. [ Time Frame: Up to 24 hours post dose on Days 5 and 10 ] [ Designated as safety issue: No ]
    Samples will be collected at predose and 1, 2, 3, 4, 8, 12 and 24 hours post dose


Secondary Outcome Measures:
  • Safety and tolerability parameters as assessed by change from baseline in vital signs (BP and HR), number of subjects with adverse events and toxicity grading of clinical laboratory tests [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Enrollment: 12
Study Start Date: September 2011
Study Completion Date: October 2011
Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1
In Part 1, approximately 12 healthy subjects will receive DTG 50mg q24h for 5 days in Period 1. Subjects will then be administered DTG 50mg q24h in combination with prednisone 60mg for 5 days followed by a 5 day taper (60 mg Days 1-5, 50 mg Day 6, 40 mg Day 7, 30 mg Day 8, 20 mg Day 9 and 10 mg Day 10 - total duration of 10 days) in Period 2. There will be a screening visit 30 days before the first dose and a follow-up visit 7-14 days after the last dose of drug.
Drug: Dolutegravir
Dolutegravir is an experimental drug in the integrase inhibitor class for the treatment of HIV.
Other Name: GSK1349572
Drug: Prednisone
Prednisone is a commonly used corticosteroid used for a variety of medical condiitons
Experimental: Part 2
If DTG Cτ is reduced by more than 50% in Part 1, Part 2 will be carried out where a second cohort of subjects will receive DTG 50mg q24h DTG for 5 days in Period 1 followed by DTG 50mg q24h in combination with prednisone 20mg for 5 days followed by a 5 day taper (20 mg Days 1-5, 10 mg Days 6 and 7, 5 mg Days 8-10 - total duration of 10 days) in Period 2. There will be a screening visit 30 days before the first dose and a follow-up visit 7-14 days after the last dose of drug.
Drug: Dolutegravir
Dolutegravir is an experimental drug in the integrase inhibitor class for the treatment of HIV.
Other Name: GSK1349572
Drug: Prednisone
Prednisone is a commonly used corticosteroid used for a variety of medical condiitons

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • ALT, alkaline phosphatase and bilirubin less than or equal to 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and ECG. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator feels that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • Male or female between 18 and 65 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 or of child-bearing potential and agrees to use one of the contraception methods listed in the protocol. Female subjects must agree to use contraception until the follow-up visit.
  • Body weight greater than or equal to 50 kg for males and 45 kg for females and BMI within the range 18.5- 31.0 kg/m2 (inclusive).
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

  • 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.
  • 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).
  • 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 GSK Medical Monitor, contraindicates their participation.
  • Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • If heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
  • History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks/week for men or >7 drinks/week for women.
  • Consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication.
  • Pregnant females as determined by positive serum or urine human chorionic gonadotrophin (hCG) test at screening or prior to dosing.
  • Lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • 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, peptic ulceration, lower or upper GI bleed, inflammatory bowel disease or pancreatitis should be excluded.
  • History of glaucoma, psychiatric illness, diabetes or borderline diabetes (or gestational diabetes), hypertension or other disorder that may be made worse by corticosteroid administration.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
  • A positive test for HIV antibody.
  • History of Gilbert's disease.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  • The subject's systolic blood pressure at screening visit is outside the range of 90-140mmHg, or diastolic blood pressure is outside the range of 45-90mmHg or heart rate is outside the range of 50-100bpm for female subjects or 45-100 bpm for male subjects.
  • Exclusion criteria for screening ECG as listed in the protocol.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01425099

Locations
United States, New York
GSK Investigational Site
Buffalo, New York, United States, 14202
Sponsors and Collaborators
ViiV Healthcare
Shionogi
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare
  More Information

No publications provided by ViiV Healthcare

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier: NCT01425099     History of Changes
Other Study ID Numbers: 115696
Study First Received: August 18, 2011
Last Updated: November 3, 2011
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Prednisone
Dolutegravir
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on October 01, 2014