Drug-drug Interaction Study of Eltrombopag and Cyclosporine in Healthy Subjects

NCT02281370 | Completed Phase 1

• 1 other identifier: 201583
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

A drug-drug interaction study between eltrombopag and cyclosporine is being conducted to support the use of these drugs together in subjects, such as those with severe aplastic anemia or immune thrombocytopenia purpura. The primary objective of the study is to evaluate the effect of cyclosporine on the pharmacokinetics of eltrombopag. This is a Phase I, open-label, randomized, three-period cross-over study in healthy adult subjects. The study consists of a screening visit and three treatment periods. All subjects will be randomized to receive one of the three treatments in each treatment period separated by washout periods of 3-10 days. The total duration of a subject's participation in the study from screening to final discharge is up to approximately 6 weeks (assuming 3 day washouts between treatment periods). Approximately 39 healthy subjects will be enrolled with the goal of completing at least 10 subjects per sequence (total 30).

Conditions

Purpura, Thrombocytopenic, Idiopathic

Keywords

cyclosporine; drug-drug interaction; pharmacokinetics; eltrombopag; SB-497115

Outcome Measures

Primary Outcomes (2)

• Plasma eltrombopag area under time-concentration curve from time zero to infinity (AUC[0-inf])

  Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, and 72 hours post-dose in each treatment period

• Plasma eltrombopag maximum observed concentration (Cmax)

  Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, and 72 hours post-dose in each treatment period

Secondary Outcomes (5)

• Composite of plasma eltrombopag pharmacokinetic (PK) parameters

  Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, and 72 hours post-dose in each treatment period

• Vital signs assessment

  Up to 6 weeks

• Composite clinical laboratory assessments including hematology, clinical chemistry and urinalysis parameters

  Up to 6 weeks

• Number of participants with adverse events (AEs)

  From the start of study treatment until the end of treatment period 3 (assessed up to 18 days)

• Electrocardiogram (ECG) assessment

  Up to 6 weeks

Study Arms (3)

SEQUENCE D0, D1, D2

EXPERIMENTAL

Participants will receive treatment D0 in treatment period 1, D1 in treatment period 2 and D2 in treatment period 3 (one treatment per period). Where D0=eltrombopag 50 milligram (mg), D1= cyclosporine 200 mg + eltrombopag 50 mg, and D2= cyclosporine 600 mg + eltrombopag 50 mg. Treatment periods will be separated by washout periods of 3-10 days

Drug: Eltrombopag; Drug: Cyclosporine

SEQUENCE D1, D0, D2

EXPERIMENTAL

Participants will receive treatment D1 in treatment period 1, D0 in treatment period 2 and D2 in treatment period 3 (one treatment per period). Where D0=eltrombopag 50 mg, D1= cyclosporine 200 mg + eltrombopag 50 mg, and D2= cyclosporine 600 mg + eltrombopag 50 mg. Treatment periods will be separated by washout periods of 3-10 days

Drug: Eltrombopag; Drug: Cyclosporine

SEQUENCE D1, D2, D0

EXPERIMENTAL

Participants will receive treatment D1 in treatment period 1, D2 in treatment period 2 and D0 in treatment period 3 (one treatment per period). Where D0=eltrombopag 50 mg, D1= cyclosporine 200 mg + eltrombopag 50 mg, and D2= cyclosporine 600 mg + eltrombopag 50 mg. Treatment periods will be separated by washout periods of 3-10 days

Drug: Eltrombopag; Drug: Cyclosporine

Interventions

Eltrombopag DRUG

White to off white bi-convex round tablets containing eltrombopag 50 mg for oral administration

SEQUENCE D0, D1, D2; SEQUENCE D1, D0, D2; SEQUENCE D1, D2, D0

Cyclosporine DRUG

Soft gelatine capsule containing cyclosporine 100 mg for oral administration. Cyclosporine will be administered at the doses of 200 mg (2 x 100 mg capsules) or 600 mg (6 x 100 mg capsules)

SEQUENCE D0, D1, D2; SEQUENCE D1, D0, D2; SEQUENCE D1, D2, D0

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 64 years of age inclusive.
• Healthy subjects.
• Body weight \>=60 kilograms (kg) for men and women and body mass index (BMI) within the range 24.7-32.0 kg/meter squared (m\^2) inclusive.
• Male: Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception during the study.
• Female of non-child bearing potential.
• Female of child-bearing potential who has a negative serum or urine pregnancy test and is willing to practice acceptable methods of birth control during the study.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

You may not qualify if:

• Alanine aminotransferase (ALT) and bilirubin \>1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• QT interval corrected (QTc) \> 450 millisecond (msec): The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read.
• For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used.
• Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St. John's Wort) within 7 days.
• Requiring the use of oral or injectable strong Cytochrome P3A4 (CYP3A4) and Breast cancer resistance protein (BRCP) inhibitors or use of other CYP3A4 and BCRP inhibitors/inducers within 14 days prior to dosing.
• History of regular alcohol consumption within 1 month of the study.
• Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or nicotine-containing products within 30 days prior to screening.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• 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.
• Platelet counts or creatinine levels that exceed the upper limit of the normal range.
• Presence of hepatitis B surface antigen (HBsAg) or presence of hepatitis B core antibody (HBcAb), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment - A positive pre-study drug/alcohol screen.
• A positive test for human immune virus (HIV) antibody.
• 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 has participated in a clinical trial and has received an investigational product within 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

Related Publications (1)

• Aslanis V, Zhang J, Lomeli B, Grosch K, Ouatas T. Effect of cyclosporine coadministration on the pharmacokinetics of eltrombopag in healthy volunteers. Cancer Chemother Pharmacol. 2018 Nov;82(5):847-855. doi: 10.1007/s00280-018-3677-6. Epub 2018 Aug 31.

  PMID: 30171280 DERIVED

Related Links

• Results for study 201583 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Purpura, Thrombocytopenic, Idiopathic

Interventions

eltrombopag; Cyclosporine

Condition Hierarchy (Ancestors)

Purpura, Thrombocytopenic; Purpura; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Cytopenia; Hemorrhagic Disorders; Autoimmune Diseases; Immune System Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 30, 2014
• First Posted: November 3, 2014
• Study Start: November 5, 2014
• Primary Completion: December 24, 2014
• Study Completion: December 24, 2014
• Last Updated: November 13, 2017

Record last verified: 2017-11

Locations

US (1)