Study to Determine the Effect of Repeated Administration of Diltiazem on the Pharmacokinetics of Darapladib (Sb-480848).

NCT01852565 | Completed Phase 1 DMC

• 1 other identifier: 115679
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

Darapladib (SB-480848) is a novel, selective, orally active inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2) currently under clinical development by GlaxoSmithKline as a potential anti-atherosclerosis agent for reduction of major adverse cardiovascular (CV) events in patient populations with chronic coronary heart disease and after an acute coronary syndrome. This study will determine the effect of repeated administration of diltiazem on the pharmacokinetics of a repeated administration of darapladib. A drug interaction study with a moderate CYP3A4 inhibitor is warranted to provide guidance to prescribing physicians.

Conditions

Atherosclerosis

Keywords

CYP3A4; Lp-PLA2; Atherosclerosis; healthy volunteer; Drug interaction

Outcome Measures

Primary Outcomes (2)

• AUC(0-24h) of darapladib

  The area under the concentrations-time curve (AUC0-24) from the time of administration of darapladib up to 24 h after administration.

  Up to 32 days. (PK samples will be collected on Days 8, 9, 26 and 27 at predose. Day 10 and Day 28 predose and at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 32, 48, 72, and 96 hours post-dose)

• Cmax of darapladib

  The maximum concentration (Cmax) was obtained directly from the measured concentration-time curves.

  Up to 32 days. (PK samples will be collected on Days 8, 9, 26 and 27 at predose. Day 10 and Day 28 predose and at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 32, 48, 72, and 96 hours post-dose)

Secondary Outcomes (5)

• Number of subjects with adverse event (AE).

  Up to 70 days.

• 12-Lead electrocardiogram (ECG) assessment as a measure of safety and tolerability

  Up to 42 days. (Screening Day 32 and Follow up [Day 38 to 42]).

• Vital signs assessment as a measure of safety and tolerability

  Up to 42 days (Screening, Day -1, 15, 16, 22, 28, 32 and Follow up [Day 38 to 42]).

• Safety laboratory tests assessment as a measure of safety and tolerability

  Up to 42 days (Screening, Day -1, 15, 32 and Follow up [Day 38 to 42]).

• Tmax and t1/2 of darapladib.

  Up to 32 days (PK samples will be collected on Days 8, 9, 26 and 27 at predose. Day 10 and Day 28 predose and at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 32, 48, 72, and 96 hours post-dose.

Study Arms (1)

Darapladib+Diltizem Arm

EXPERIMENTAL

Each subject will receive darapladib EC tablet 160 mg once daily for 10 days followed by darapladib EC tablet 160 mg once daily + diltiazem 240mg once daily for 14 days and then diltiazem 240mg once daily alone for three days

Drug: Darapladib; Drug: Diltiazem

Interventions

Darapladib DRUG

Enteric coated, free base (micronized) white round tablet, 160mg, Oral/repeat dose/10 days (Treatment Period 1), 14 days (Treatment Period 2)

Darapladib+Diltizem Arm

Diltiazem DRUG

Extended release, Blue capsule imprinted with cardizem CD and 240mg on one end, 240 mg, Oral/repeat dose/17 days

Darapladib+Diltizem Arm

Eligibility Criteria

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

You may qualify if:

• Male or female aged between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• 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 an alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase or bilirubin laboratory result outside the reference range may be included only if both the Investigator and the GSK Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• BMI within the range 19-37 kilogram per square meter (kg/m2) (inclusive).
• 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 \[for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli-international units per milliliter (MlU/ml) and estradiol \< 40 picogram/milliliter \[(pg/ml) (\<147 pmol/L) is confirmatory\].
• A female subject is eligible to participate if she is of Child-bearing potential and is abstinent or agrees to use one of the contraception methods 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 the final follow-up visit.
• A female subject is eligible to participate if she is of Child-bearing potential and has only same-sex partners, when this is her preferred and usual lifestyle.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
• Single QT duration corrected for heart rate by Fridericia's formula (QTcF) \< 450 Millisecond (msec)

You may not qualify if:

• Criteria Based Upon Medical Histories
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• 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.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• History of sensitivity to any of the study medications, including diltiazem, 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.
• Any contraindications for diltiazem administration.
• Any condition that, in the opinion of the investigator, presents undue risk from the study medications, including diltiazem, or procedures.
• Requiring the use of oral or injectable strong Cytochrome P450 (CYP3) A4 inhibitors or use of other CYP3A4 inhibitor/inducers within 14 days prior to dosing.
• History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions
• Clinical criteria for diagnosing anaphylaxis or severe allergic response. Criteria Based Upon Diagnostic Assessments
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• A positive pre-study drug/alcohol screen.
• A positive test for human immunodeficiency virus (HIV) antibody.
• Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at screening or prior to dosing.
• Other Criteria

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Links

• Results for study 115679 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Atherosclerosis

Interventions

darapladib; Diltiazem

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: May 9, 2013
• First Posted: May 13, 2013
• Study Start: May 14, 2013
• Primary Completion: September 30, 2013
• Study Completion: September 30, 2013
• Last Updated: July 13, 2017

Record last verified: 2017-07

Data Sharing

• IPD Sharing: Will share

Locations

US (1)