A Study to Assess the Pharmacokinetics, Safety and Tolerability of Repeat Oral Doses of Darapladib (SB-480848) in Subjects With Severe Renal Impairment

NCT01711723 | Completed Phase 1

• 1 other identifier: 115676
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

Brief Summary

In accordance with the recently revised FDA draft renal impairment guidance (March 2010) which advises the conduct of renal impairment study in drugs that are not predominately eliminated through the renal route, the proposed study will be conducted to formally assess the pharmacokinetics (PK) of darapladib in severely renally impaired subjects. In this is an open-label, non-randomized study eight subjects with severe renal impairment will be recruited along with 8 healthy control subjects matched to the severe renal impairment subjects based on gender, body mass index (plus or minus 20%) and age (plus or minus 10 years). All subjects will receive repeat oral doses of darapladib 160 milligram (mg) for 10 consecutive days. The pharmacokinetics of darapladib and its metabolites; and safety and tolerability will be evaluated. All the subjects will be admitted to the clinic on the evening of Day -1. Subjects may check out of the clinic on Day 2 after all assessments are complete, but must return to the clinic each day (Days 3-8) for dosing and assessments. Subjects will be admitted to the clinic again on the evening of Day 9. After the last dose of the study drug, there will be a follow-up period which will include 2 visits (Day 20-24 and Day 38-52). The total study duration for each subject including the screening, treatment and follow-up periods will be approximately 11 weeks.

Conditions

Atherosclerosis

Keywords

darapladib; Lp-PLA2- inhibitor; healthy volunteer; renal impairment; pharmacokinetics

Outcome Measures

Primary Outcomes (2)

• AUC (0-τ) for darapladib and as data permit for metabolites M4, M3, and M10

  The PK parameter area under the concentration-time curve over the dosing interval (AUC (0-τ)) will be derived from the plasma concentration-time data.

  On scheduled intervals on Day 10

• Cmax for darapladib and as data permit for metabolite s M4, M3, and M10

  The PK parameter maximum observed concentration (Cmax) will be derived from the plasma concentration-time data.

  On scheduled intervals on Day 10

Secondary Outcomes (6)

• Spontaneous AE reporting

  45days

• Clinical laboratory test measurements

  Day-1, Day 11 and post treatment

• Vital signs measurements

  Day-1, Day1, Day5, Day 11 and post treatment

• Nursing/physician observation

  20 days

• Free fraction (% unbound) of darapladib and its metabolites M3, M4, and M10 (as data permit)

  On scheduled intervals on Day 10

Study Arms (2)

Renal Impaired Group

EXPERIMENTAL

Subjects with renal impairment received darapladip 160 mg daily for 10 consecutive days.

Drug: Darapladib 160 mg

Healthy Control Group

EXPERIMENTAL

Healthy volunteers matching with renal impairment subjects for gender, age and BMI; received darapladip 160 mg daily for 10 consecutive days.

Drug: Darapladib 160 mg

Interventions

Darapladib 160 mg DRUG

Subjects in each group received one tablet orally of Darapladib 160 mg daily for 10 consecutive days. Tablets were taken with food, swallowed whole, not chewed.

Healthy Control Group; Renal Impaired Group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A male or female is eligible to enter and participate in this study if he/she is: A healthy subject with normal renal function: Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with clinical abnormalities or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures; Estimated Creatinine clearance ≥ 90mL/min calculated by Cockcroft-Gault equation using serum creatinine OR A renally impaired subject - To be classified as renally impaired, subjects must have: An estimated Glomerular Filtration Rate (eGFR) of \<30 ml/min /1.73 m2 using the four variable Modification of Diet in Renal Disease (MDRD) equation.
• Age between 18 and 75 years inclusive, at the time of signing the informed consent.
• 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; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<140pmol/L) is confirmatory\]; Child-bearing potential and agrees to use one of the contraception methods listed in the protocol 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 (35 ± 7 days after last dose of investigational product)
• Body mass index (BMI) within the range of 19.0-38.0 kg/m2 (inclusive)
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• QTcF ≤ 480 msec in all subjects, including those with bundle branch block at screening ECG.

You may not qualify if:

• Healthy Subjects
• A positive pre-study drug/alcohol screen.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody or positive Hepatitis A IGM antibody result within 3 months of screening.
• A positive test for HIV antibody.
• 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.
• 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, or 5 half-lives of the investigational product (whichever is longer).
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• 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.
• Requiring the use of oral or injectable strong CYP3A4 inhibitors (refer to the protocol).
• Consumption of grapefruit or grapefruit juice \> 8oz within 7 days prior to first dose of study medication.
• Drug abuse within the past 6 months, or current mental condition (psychiatric disorder, senility or dementia), which may affect study compliance or prevent understanding of the aims, investigational procedures or possible consequences of the study.
• History of sensitivity to any of the study medications, 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.
• History of anaphylaxis, or anaphylactoid (resembling anaphylaxis) reactions (refer to the protocol). History of severe allergic responses.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Orlando, Florida, 32809, United States

Location

GSK Investigational Site

Minneapolis, Minnesota, 55404, United States

Location

Related Links

• Results for study 115676 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; Renal Insufficiency

Interventions

darapladib

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 18, 2012
• First Posted: October 22, 2012
• Study Start: October 29, 2012
• Primary Completion: March 25, 2013
• Study Completion: March 25, 2013
• Last Updated: July 26, 2017

Record last verified: 2017-07

Data Sharing

• IPD Sharing: Will share

Locations

US (2)