Pharmacokinetic Interaction of Darapladib and CYP 3A4 in Healthy Subjects

NCT01873339 | Completed Phase 1 DMC

• 1 other identifier: 115678
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Atherosclerosis

Keywords

Drug interaction, healthy volunteer, SB-480848, Lp-PLA2, darapladib, atherosclerosis, midazolam

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• AUC(0-inf), Cmax, time to maximum concentration (tmax) and terminal half-life (t1/2) of midazolam at Days 3 and 14

  Day 3 and 14

• tmax and t1/2 of midazolam at Days 1 and 14

  Day 1 and 14

• AUC(0-inf), Cmax, tmax and t1/2 of midazolam at Days 1 and 3

  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

  Up to 56 days

Study Arms (1)

Darapladib

EXPERIMENTAL

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; Drug: Midazolam

Interventions

Darapladib DRUG

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.

Darapladib

Midazolam DRUG

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

Darapladib

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.
• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Links

• Results for study 115678 can be found on the GSK Clinical Study Register.
• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Atherosclerosis

Interventions

darapladib; Midazolam

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; 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: June 6, 2013
• First Posted: June 10, 2013
• Study Start: June 19, 2013
• Primary Completion: September 12, 2013
• Study Completion: September 12, 2013
• Last Updated: May 15, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will share

Locations

US (1)