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

Information source: GlaxoSmithKline
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Atherosclerosis

Intervention: Darapladib (Drug); Diltiazem (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline


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.

Clinical Details

Official title: An Open-Label, Three Period, Single Sequence Study To Determine The Effect Of Repeat Oral Dosing Of Diltiazem On The Pharmacokinetics Of Repeat Oral Dosing Of Darapladib (SB-480848).

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

AUC(0-24h) of darapladib

Cmax of darapladib

Secondary outcome:

Number of subjects with adverse event (AE).

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

Vital signs assessment as a measure of safety and tolerability

Safety laboratory tests assessment as a measure of safety and tolerability

Tmax and t1/2 of darapladib.


Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.


Inclusion Criteria:

- 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) Exclusion Criteria:

- A subject will not be eligible for inclusion in this study if any of the following

criteria apply: 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

- Where participation in the study would result in donation of blood or blood products

in excess of 500 mL within a 56 day period.

- Lactating females.

- 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).

- Exposure to more than four new chemical entities within 12 months prior to the first

dosing day.

- 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 (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.

- Unwillingness or inability to follow the procedures outlines in the protocol.

- Subject is mentally or legally incapacitated.

- Consumption of grapefruit or grapefruit juice within 7 days prior to the first dose

of study medication.

Locations and Contacts

GSK Investigational Site, Baltimore, Maryland 21225, United States
Additional Information

Starting date: May 2013
Last updated: October 4, 2013

Page last updated: August 23, 2015

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