Clinical trial NCT01873339: Pharmacokinetic Interaction of Darapladib and CYP 3A4 in Healthy Subjects
Official title: An Open-label, Single-sequence Study to Evaluate the Potential CYP 3A4 Pharmacokinetic Interaction of Darapladib (SB-480848) in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Atherosclerosis
Keywords: Drug interaction, healthy volunteer, SB-480848, Lp-PLA2, darapladib, atherosclerosis, midazolam
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-06-10
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Maximum concentration (Cmax), and area under the time-concentration curve (AUC[0-inf]) of midazolam at Day 1and 14
timeFrame: Day 1 and 14
Secondary outcomes:
measure: AUC(0-inf), Cmax, time to maximum concentration (tmax) and terminal half-life (t1/2) of midazolam at Days 3 and 14
timeFrame: Day 3 and 14
measure: tmax and t1/2 of midazolam at Days 1 and 14
timeFrame: Day 1 and 14
measure: AUC(0-inf), Cmax, tmax and t1/2 of midazolam at Days 1 and 3
timeFrame: Day 1 and 3
measure: 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
timeFrame: Up to 56 days
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: