Pharmacokinetic Interaction of Darapladib and CYP 3A4 in Healthy Subjects

An Open-label, Single-sequence Study to Evaluate the Potential CYP 3A4 Pharmacokinetic Interaction of Darapladib (SB-480848) in Healthy Subjects

This study will determine the effect of single and repeat administration of darapladib, a novel, selective, orally active inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2) currently under clinical development on the pharmacokinetics of a single oral dose of midazolam, a cytochrome P450 3A4 (CYP3A4) probe substrate. This study will investigate the inductive and inhibitory effect of darapladib on CYP3A4 metabolic pathway.

Study Overview

• Status: Completed
• Conditions: Atherosclerosis
• Intervention / Treatment: Drug: Darapladib; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21225
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.
• Body mass index within the range 19-37 kilogram per meter square (kg/m2) (inclusive).
• A female subject is eligible to participate if she is of: non-childbearing potential defined as pre-menopausal females with tubal ligation or hysterectomy or postmenopausal defined as 12 months of spontaneous amenorrhea; child-bearing potential and is abstinent or agrees to use the appropriate 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; 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 QTcF (corrected QT calculated using Fridericia's formula)< 450 milliseconds

Exclusion Criteria:

• 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 milliliter [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 midazolam and flumazenil, 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 midazolam or flumazenil administration.
• Any condition that, in the opinion of the investigator, presents undue risk from the study medications, including midazolam and flumazenil, or procedures.
• Requiring the use of oral or injectable strong CYP3A4 inhibitors or use of other CYP3A4 inhibitor/inducers within 14 days prior to dosing.
• History of anaphylaxis, anaphylactoid reactions or severe allergic response.
• 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 HIV antibody.
• Pregnant females as determined by positive hCG test at screening or prior to dosing.
• Where participation in the study would result in donation of blood or blood products in excess of 500mL 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Darapladib; The subjects will receive a single oral dose of midazolam 5 mg on Day 1. The subjects will receive darapladib 160 mg once daily on Days 3-14. The subjects will also receive a single dose of midazolam 5 mg on Day3 and 14.	Drug: Darapladib; The subjects will receive darapladib 160 mg once daily on Days 3-14. It is provided as Enteric coated, free base (micronized) 160 mg tablet.; Drug: Midazolam; The subjects will receive a single oral dose of midazolam 5 mg on Day 1, 3 and14. It is provided as syrup. Each mL of syrup contains midazolam hydrochloride equivalent to 2 mg midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum concentration (Cmax), and area under the time-concentration curve (AUC[0-inf]) of midazolam at Day 1and 14	The effects of repeat oral dosing of darapladib (160mg enteric coated [EC] tablet once daily [QD]) on the pharmacokinetic parameters - Cmax and AUC(0-infinity[inf]) of a single oral dose of midazolam (5 mg) will be evaluated	Day 1 and 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC(0-inf), Cmax, time to maximum concentration (tmax) and terminal half-life (t1/2) of midazolam at Days 3 and 14	The effects of single oral dose of darapladib (160mg EC tablet QD) as compared to multiple oral doses of darapladib on the pharmacokinetic parameters - Cmax, AUC(0-inf), tmax and t1/2 of the single oral dose of midazolam (5mg) will be evaluated	Day 3 and 14
tmax and t1/2 of midazolam at Days 1 and 14	The effects of repeat oral dosing of darapladib (160mg EC tablet QD) on the other pharmacokinetic parameters- tmax and t1/2 of a single oral dose of midazolam (5mg) will be evaluated	Day 1 and 14
AUC(0-inf), Cmax, tmax and t1/2 of midazolam at Days 1 and 3	The effects of single oral dose of darapladib (160mg EC tablet QD) on the other pharmacokinetic parameters- AUC(0-inf), Cmax, tmax and t1/2 of a single oral dose of midazolam (5mg QD) will be evaluated	Day 1 and 3
Safety and tolerability of repeated oral doses of darapladib (160mg) in combination with midazolam (5mg) as assessed by frequency and severity of adverse events (AE), 12-Lead ECG, vital signs, oxygen saturation/pulse oximetry and safety laboratory tests	An AE is any untoward medical occurrence temporally associated with the use of the medicinal product, whether or not considered associated with the product. A serious AE is any medical occurrence that results in death, is life-threatening, require hospitalization or prolongation of an existing hospital stay, results in disability or incapacity, congenital anomaly, or is an "Hy's Law event (type of drug-induced liver injury)	Up to 56 days

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

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): June 19, 2013
• Primary Completion (Actual): September 12, 2013
• Study Completion (Actual): September 12, 2013

Study Registration Dates

• First Submitted: June 6, 2013
• First Submitted That Met QC Criteria: June 6, 2013
• First Posted (Estimate): June 10, 2013

Study Record Updates

• Last Update Posted (Actual): May 15, 2017
• Last Update Submitted That Met QC Criteria: May 12, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Drug interaction, healthy volunteer, SB-480848, Lp-PLA2, darapladib, atherosclerosis, midazolam
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Phospholipase A2 Inhibitors; Midazolam; Darapladib
• Other Study ID Numbers: 115678

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. Individual Participant Data Set
   Information identifier: 115678
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Annotated Case Report Form
   Information identifier: 115678
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Dataset Specification
   Information identifier: 115678
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: 115678
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Clinical Study Report
   Information identifier: 115678
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Informed Consent Form
   Information identifier: 115678
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: 115678
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No