The Pharmacokinetic Interaction Between Oral Casopitant and Oral Dolasetron, Granisetron or Rosiglitazone in Subjects

An Open-Label, Three-Part, Two Period, Single Sequence Study to Assess the Pharmacokinetic Interaction Between Repeat Doses of Oral Casopitant and Repeat Oral Doses of Dolasetron, Granisetron or Rosiglitazone When Co-Administered in Healthy Adult Subjects

This A Three-Part Drug-Drug Interaction Study To Evaluate Effects of Casopitant On Dolasetron, Granisetron or Rosiglitazone When Co-Administered in Healthy Adults

Study Overview

• Status: Completed
• Conditions: Nausea and Vomiting, Chemotherapy-Induced
• Intervention / Treatment: Drug: casopitant; Drug: dolasetron; Drug: granisetron; Drug: rosiglitazone

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Evansville, Indiana, United States, 47714
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• An adult healthy male or female.
• Age: 18 to 64 years, inclusive.
• Body mass index (BMI) = 19 to = 37 kg/m2.
• A female if she is of Non-childbearing potential, OR
• A female who has a negative serum pregnancy test within 14 days prior to the first dose of study medication and agrees to use adequate contraception during the study and for 14 days after the last dose of study medication.
• Adequate organ systems function [Hemoglobin is within normal limits ± 10%; Platelets is = 100 X 109/L or = lower limit of normal (LLN); Aspartate aminotransaminase = Upper limit of normal (ULN); Total bilirubin = 1.2 times ULN; Creatine phosphokinase < 1.5 times ULN; Renal Calculated creatinine clearance = 50 mL/min]
• Able to swallow and retain oral medication.
• Able to understand and comply with the requirements, instruction and restrictions stated in the informed consent.
• Signed and dated informed consent.

Exclusion Criteria:

• Clinically relevant abnormality, including any degree of heart failure or clinically significant cardiac disease, identified on the screening exam or any other medical condition or circumstance making the subject unsuitable for participation in the study.
• For Part A (dolasetron-casopitant drug-drug interaction), any subject who exhibits gene duplication for CYP2D6.
• History of drug or other allergy which, in the opinion of the Investigator, contraindicates participation.
• Known immediate hypersensitivity reaction or idiosyncrasy to study drugs or any drug chemically related to the study medications.
• Use of an investigational drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study medication(s).
• Blood donation in excess of 500 mL within 56 days prior to dosing or intends to donate within 30 days of the post-treatment follow-up visit.
• Presence of or suspected iron deficiency.
• Stool positive for occult blood.
• Troponin I level above 10% of the coefficient of variation of the assay.
• For female subjects of childbearing potential, a positive serum pregnancy test.
• Female subject who is lactating.
• Positive urine drug screen (UDS) including alcohol.
• Positive for HIV antibody, hepatitis C antibody or hepatitis B surface antigen (HBsAg).
• Positive urinary cotinine.
• Smoking history of = 4 packs per day/year or smoked more than 2 times within the past 30 days prior to screening.
• History of drug abuse or dependence within 6 months of screening.
• History of alcohol abuse within 6 months of screening or alcohol consumption in the past 6 months exceeding 7 drinks/week for women and 14 drinks/week for men (where 1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor).
• Presence of an active infection.
• Corrected QT interval (QTc) > 450 msecs.
• Pepsinogen level below the lower limit of laboratory reference range (LLRR).
• Active peptic ulcer disease (PUD) or a history of PUD of unknown etiology.
• Use of any prescription or non-prescription drug(s), including oral contraceptives, herbal or dietary supplements or vitamins within 14 days, or 5 half-lives (whichever is longer) prior to the first dose of study medication.
• Consumption of food or drink containing grapefruit or grapefruit juice, apple juice, Seville oranges, kumquats, pomelos, star fruit, red wine, charbroiled meats, cabbage or vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard greens, kohlrabi, brussels sprouts, mustard) within 7 days prior to the first dose of study medication(s).
• History of cholecystectomy or biliary tract disease.
• Any serious or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Subjects in Part A; Subjects will receive 100 milligrams (mg) of oral dolasetron once daily for 3 days during treatment period 1. In treatment period 2, subjects will receive 100 mg oral dolasetron once daily on days 1, 2 and 3 along with 150 mg oral casopitant on day 1 and 50 mg oral casopitant on days 2 and 3. The treatment periods will be separated by will be separated by a 5 - 14 day wash-out period.	Drug: casopitant; The doses of casopitant will be comprised of 150 mg (one 150 mg tablet) and 50 mg (one 50 mg tablet). Casopitant will be taken with 240 milliliters (mL) of water on an empty stomach following at least 2 hour fast.; Drug: dolasetron; The dose of oral dolasetron will be comprised of 100 mg (one 100 mg tablet or two 50 mg tablets). Dolasetron will be taken with 240 mL of water on an empty stomach following at least 2 hour fast.
Experimental: Subjects in Part B; Subjects will receive 2 mg of oral granisetron once daily for 3 days during treatment period 1. In treatment period 2, subjects will receive 2 mg oral granisetron once daily on days 1, 2 and 3 along with 150 mg oral casopitant once daily on day 1 and 50 mg oral casopitant once daily on days 2 and 3. The treatment periods will be separated by will be separated by a 5 - 14 day wash-out period.	Drug: casopitant; The doses of casopitant will be comprised of 150 mg (one 150 mg tablet) and 50 mg (one 50 mg tablet). Casopitant will be taken with 240 milliliters (mL) of water on an empty stomach following at least 2 hour fast.; Drug: granisetron; The dose of oral granisetron will be comprised of 2 mg (two 1 mg tablets). Granisetron will be taken with 240 mL of water on an empty stomach following at least 2 hour fast.
Experimental: Subjects in Part C; Subjects will receive 4 mg of oral rosiglitazone once daily for 3 days during treatment period 1. In treatment period 2, subjects will receive 4 mg oral rosiglitazone once daily on days 1, 2 and 3 along with 150 mg oral casopitant once daily on day 1 and 50 mg oral casopitant once daily on days 2 and 3. The treatment periods will be separated by will be separated by a 5 - 14 day wash-out period.	Drug: casopitant; The doses of casopitant will be comprised of 150 mg (one 150 mg tablet) and 50 mg (one 50 mg tablet). Casopitant will be taken with 240 milliliters (mL) of water on an empty stomach following at least 2 hour fast.; Drug: rosiglitazone; The dose of oral rosiglitazone will be comprised of 4 mg (two 2 mg tablets or one 4 mg tablet). Rosiglitazone will be taken with 240 mL of water on an empty stomach following at least 2 hour fast.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change of AUC and Cmax of dolasetron, granisetron and rosiglitazone after oral administration alone and co-administered with oral casopitant	(comparing AUC & Cmax of Days 1&3 of the Period One and Two)

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety evaluations of AEs and changes in laboratory values, ECGs, vitals evaluated during the study	(Day -1 and Days 1-4 of the Period One and Two, at follow-up visit)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Adams LM, Johnson B, Zhang K, Yue L, Kirby LC, Lebowitz P, Stoltz R. Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron. Support Care Cancer. 2009 Sep;17(9):1187-93. doi: 10.1007/s00520-008-0572-4. Epub 2009 Feb 10.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2007
• Primary Completion (Actual): September 21, 2007
• Study Completion (Actual): September 21, 2007

Study Registration Dates

• First Submitted: August 2, 2007
• First Submitted That Met QC Criteria: August 2, 2007
• First Posted (Estimate): August 6, 2007

Study Record Updates

• Last Update Posted (Actual): August 3, 2017
• Last Update Submitted That Met QC Criteria: August 2, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: safety; pharmacokinetics,; CYP3A4,; drug-drug interaction,; rosiglitazone,; CYP2C8,; granisetron,; dolasetron,; CYP2D6,; casopitant,
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Vomiting; Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Serotonin Agents; Serotonin Antagonists; Neurokinin-1 Receptor Antagonists; Rosiglitazone; Granisetron; Casopitant; Dolasetron
• Other Study ID Numbers: NKV110483

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Clinical Study Report
   Information identifier: NKV110483
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Annotated Case Report Form
   Information identifier: NKV110483
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Dataset Specification
   Information identifier: NKV110483
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Individual Participant Data Set
   Information identifier: NKV110483
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Study Protocol
   Information identifier: NKV110483
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Informed Consent Form
   Information identifier: NKV110483
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: NKV110483
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register