Clinical trial NCT00942175: A Study of the Effects of Multiple Doses of Dexlansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Participants.
Official title: A Phase 1, Randomized, Open-Label, 2-Period, Crossover Design Study to Assess the Effects of Multiple Oral Doses of Dexlansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Steady-State Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Pharmacology
Stomach Ulcer
Esophagitis, Peptic
Zollinger-Ellison Syndrome
Platelet function
PPI
clopidogrel
Pharmacokinetics and Pharmacodynamics
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2009-07-20
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER

Brief summary: The purpose of this study is to assess the potential effect and safety of multiple oral doses of dexlansoprazole, lansoprazole, omeprazole or esomeprazole, once daily (QD), on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel, and to assess the safety of multiple doses of clopidogrel in healthy participants.

Detailed description: This is a Phase 1, randomized, open-label, single-center, multiple-dose, 2-period, crossover study to assess the effects of multiple oral doses of dexlansoprazole, lansoprazole, omeprazole or esomeprazole on the steady-state pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel in healthy participants.

Participants were randomized equally into eight regimen sequence groups, 20 participants each. Participants randomized to Sequence Groups 1 and 2, 3 and 4, 5 and 6 and 7 and 8 were called proton pump inhibitor (PPI) Groups 1, 2, 3, and 4, respectively. Each sequence group consists of 2 regimens. Sequence Groups 1, 3, 5 and 7 dosed Regimen A (75 mg clopidogrel) for Days 1-9 of Period 1 and then crossed over to one of the following 4 regimens for Days 1-9 of Period 2: Regimen B (75 mg clopidogrel + 30 mg lansoprazole), Regimen C (75 mg clopidogrel + 60 mg dexlansoprazole), Regimen D (75 mg clopidogrel + 80 mg \[2x40 mg\] omeprazole), or Regimen E (75 mg clopidogrel + 40 mg esomeprazole). Sequence Groups 2, 4, 6 and 8 began with either Regimen B, C, D or E for Period 1 and then crossed over to Regimen A for Period 2.

On Day 9 of each period, blood samples were collected at predose and for 24 hours postdose to measure plasma concentrations of the active metabolite of clopidogrel. Platelet function was assessed daily prior to the dose of clopidogrel on Days 7-9 and 24-hours post Day 9 dose in each period. There was a washout interval of 10 to 14 days between the last dose of study drug in Period 1 and the first dose of study drug in Period 2.

Study participants were confined to the study center for 10 consecutive nights in Period 1, followed by a 10- to 14-day washout interval and confined for an additional 10 consecutive nights in Period 2.

Eligibility criteria: Inclusion Criteria:

1. The participant or the participant's legally acceptable representative signs a written, informed consent form prior to the initiation of any study procedures.
2. Weighs at least 50 kg and has a body mass index (BMI) between 18 and 30 kg/m2, inclusive, at Screening and Check-in (Day -1 of Period 1) Visits.
3. Must be a CYP2C19 extensive metabolizer (wt/wt).
4. Females cannot be nursing and must have a negative urine pregnancy test at Day -1 or be of non-childbearing potential. If females are of child bearing potential, must have a negative serum human chorionic gonadotropin (hCG) pregnancy test during Screening and on an acceptable form of contraception, or have had bilateral tubal ligation if performed a minimum of 90 days prior to Day 1.
5. At the Screening and Check-in (Day -1 of Period 1) Visits, must have an estimated creatinine clearance (CLcr) greater than or equal 90 mL/minute as determined from the Cockcroft-Gault formula.
6. Is in good health as determined by a physician based upon medical history, electrocardiogram, and physical examination findings at the Screening and Check-in (Day -1 of Period 1) Visits.
7. Participant's clinical laboratory evaluations (including hematology, clinical chemistry \[fasted for a least 8 hours\], and urinalysis) at the Screening and Check-in (Day -1 of Period 1) Visits are within the reference range for the testing laboratory or are deemed not clinically significant by the investigator and TGRD Medical Monitor.
8. Participant's urine drug screen for selected substances of abuse is negative at the Screening and Check-in (Day -1 of Period 1) Visits.

Exclusion Criteria:

1. Has consumed products containing Seville oranges (sour), grapefruit or grapefruit juice within 14 days prior to the first dose of study drug or is unwilling to agree to abstain from products containing Seville oranges (sour), grapefruit or grapefruit juice while participating in the study.
2. Has current or recent (within 6 months) gastrointestinal disease, a history of malabsorption, esophageal reflux, gastric bleeding or peptic ulcer disease, frequent (more than once per week) occurrence of heartburn, or any surgical intervention (eg, cholecystectomy), which would be expected to influence the absorption of drugs.
3. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as the consumption of more than 4 alcoholic beverages per day) within 1 year prior to the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.
4. Is currently participating in another investigational study or has received any investigational compound within 30 days prior to the Check-in (Day -1 of Period 1) Visit.
5. Has received any known hepatic or renal clearance altering agents (eg, erythromycin, cimetidine, barbiturates, phenothiazines, fluvoxamine, etc.) within 28 days prior to first dose of study drug.
6. Has a history or clinical manifestations of significant metabolic, hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, hepatic, renal, urologic, immunologic, or psychiatric disorder as determined by the investigator which may impact the ability of the participant to take part in or potentially confound the trial results.
7. Has a history of hypersensitivity or allergies to any drug or food or any excipients of clopidogrel, lansoprazole, dexlansoprazole, omeprazole, esomeprazole or other drug with the same mechanism of action or related compounds.
8. Has had an acute, clinically significant illness within 30 days prior to the first dose of study drug.
9. Has a systolic blood pressure greater than 140 mm Hg or has a diastolic blood pressure greater than 90 mm Hg at Screening or Check-in (Day -1 of Period 1).
10. Has a positive test result for hepatitis B surface antigen (HBsAg) or antibody to hepatitis C virus (anti-HCV) at Screening, or a known history of infection with the human immunodeficiency virus (HIV).
11. Has a Day -1 laboratory value assessed by the principal investigator and sponsor medical monitor as clinically significant underlying disease or condition that may prevent the participant from entering the study.
12. Has an alanine aminotransferase, aspartate aminotransferase or Total Bilirubin level that exceeds the upper limit of normal at the Screening or Check-in (Day -1 of Period 1) Visits.
13. Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 6 weeks prior to Check-in (Day -1 of Period 1) Visit, or has a positive cotinine screen at the Screening or Check-in (Day - 1 of Period 1) Visits or anticipates an inability to abstain from these products for the duration of the study.
14. With the exception of acetaminophen, has taken any excluded medication, supplements or food products listed in the Excluded Dietary Items and Medications table located in the study protocol.
15. Has donated blood products (such as plasma) within 30 days, or has donated whole blood or had a significant blood loss (500 mL) within 56 days of the first dose of study drug
16. Has a positive test result for caffeine at the Check-in (Day -1 of Period 1) Visit.
17. Has a history of cancer, except basal cell carcinoma, which has not been in remission for at least 5 years prior to the first dose of study drug.
18. Has received clopidogrel or any PPIs or histamine2-receptor antagonists within 28 days of screening.
19. Participant, in the opinion of the investigator, is unlikely to comply with the protocol or is unsuitable for any other reason.

Primary outcomes:
measure: Pharmacokinetic Parameter Peak Plasma Concentration (Cmax) of Clopidogrel's Active Metabolite.
timeFrame: Day 9 of each period
measure: Pharmacokinetic Parameter Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc]) of Clopidogrel's Active Metabolite.
timeFrame: Day 9 of each period
measure: Pharmacodynamic Parameter Platelet Reactivity Index (PRI) From Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation State (Flow Cytometry).
timeFrame: 24-hour post Day 9 dose in each period.
measure: Pharmacodynamic Parameter Maximum Platelet Aggregation (MPA) From Aggregometry (Turbidimetric) With 5 µM Adenosine Diphosphate.
timeFrame: 24-hour post Day 9 dose in each period.
measure: Pharmacodynamic Parameter MPA From Aggregometry (Turbidimetric) With 20 µM Adenosine Diphosphate.
timeFrame: 24-hour post Day 9 dose in each period.
Secondary outcomes:
Other outcomes:
Locations:
city: Tempe
country: United States
state: Arizona
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References:
citation: Frelinger AL 3rd, Bhatt DL, Lee RD, Mulford DJ, Wu J, Nudurupati S, Nigam A, Lampa M, Brooks JK, Barnard MR, Michelson AD. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol. 2013 Feb 26;61(8):872-9. doi: 10.1016/j.jacc.2012.11.040. Epub 2013 Jan 16.
citation: Frelinger AL 3rd, Lee RD, Mulford DJ, Wu J, Nudurupati S, Nigam A, Brooks JK, Bhatt DL, Michelson AD. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol. 2012 Apr 3;59(14):1304-11. doi: 10.1016/j.jacc.2011.12.024.