Study to Determine the Effect of Itraconazole on the Pharmacokinetics of Rilapladib (SB659032) in Healthy Volunteers

NCT02130661 | Withdrawn Phase 1

• 1 other identifier: 201274
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Rilapladib is a potent and selective inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2), which was previously under development for the treatment of atherosclerosis and is currently being developed for the treatment of Alzheimer's disease. This study is a single-center, open-label, two-part study. The two study parts will run independently. Subjects dosed in one part of this study will not be permitted to participate in the other part. Part A will investigate the pharmacokinetic profile of rilapladib and its metabolites, SB-664601 and GSK1174379, after single dose and steady state dosing of rilapladib 250 milligram (mg) along with the biliary and urinary elimination pathways of rilapladib 250 mg. Part B will determine the effect of repeat administration of itraconazole on the PK of a single oral dose of rilapladib 25 mg. Healthy male and female subjects, aged 18-65 years, will be recruited for this study. Ten subjects will be recruited for Part A and 20 subjects will be recruited for Part B.

Conditions

Alzheimer's Disease

Keywords

drug interaction; healthy volunteer; rilapladib; SB-659032; Alzheimer's disease; itraconazole

Outcome Measures

Primary Outcomes (5)

• Maximum observed concentration (Cmax), time of occurrence of Cmax (Tmax), area under the concentration-time curve over the dosing interval (AUC(0-Tau)) of rilapladib parent compound after single and repeat dosing, in part A of the study.

  Cmax, Tmax and AUC (0-Tau) will be used to evaluate the pharmacokinetics of rilapladib after single and repeat dosing of rilapladib 250 mg.

  Day (D)1: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 hours (hrs) post-dose, and D14: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D16), 96 (D18), 144 (D20), 240 (D24) and 336 (D28) hrs post-dose. Pre-dose on Days 11, 12 and 13

• Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC(0-infinity)), and terminal phase half-life (T1/2) of rilapladib after repeat dosing, in part A of the study

  AUC(0-infinity) and T1/2 of rilapladib will be used to evaluate the pharmacokinetics of rilapladib and its metabolites after repeat dosing of rilapladib 250 mg.

  D1: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 hrs post-dose, and D14: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D16), 96 (D18), 144 (D20), 240 (D24) and 336 (D28) hrs post-dose. Pre-dose on Days 11, 12 and 13

• Cmax, Tmax, AUC(0-tau), and area under the concentration-time curve from time zero (pre-dose) to time of last quantifiable concentration (AUC(0-t)) of SB-664601 and GSK1174379 after single and repeat dosing, in part A of the study

  Cmax, Tmax, AUC(0-tau), and AUC(0-t) will be used to evaluate the pharmacokinetics of SB-664601 and GSK1174379 after single and repeat dosing of rilapladib 250 mg.

  D1: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 hrs post-dose, and D14: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D16), 96 (D18), 144 (D20), 240 (D24) and 336 (D28) hrs post-dose. Pre-dose on Days 11, 12 and 13

• AUC(0-infinity) and T1/2 of SB-664601 and GSK1174379 after repeat dosing, as data permit, in part A of the study.

  AUC(0-infinity) and T1/2 will be used to evaluate the pharmacokinetics of SB-664601 and GSK1174379 after repeat dosing of rilapladib 250 mg.

  D1: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 hrs post-dose, and D14: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D16), 96 (D18), 144 (D20), 240 (D24) and 336 (D28) hrs post-dose. Pre-dose on Days 11, 12 and 13

• AUC(0 infinity), AUC(0 t), and Cmax of rilapladib alone and in the presence of itraconazole in part B of the study.

  AUC(0 infinity), AUC(0 t), and Cmax will be used to evaluate the effect of repeat oral dosing of itraconazole on the pharmacokinetics of single dose rilapladib 25 mg.

  D1 : Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D3), 96 (D5), 144 (D7) hours post dose, and on D 11: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D13), 96 (D15), 144 (D17) hours post dose

Secondary Outcomes (10)

• Safety and tolerability of repeat oral doses of rilapladib 250 mg assessed by adverse events (AEs), in part A of the study.

  Up to Day 38

• Safety and tolerability of repeat oral doses of rilapladib 250 mg assessed by 12-lead electrocardiogram (ECG) parameters, in part A of the study.

  Up to Day 38

• Safety and tolerability of repeat oral doses of rilapladib 250 mg assessed by measuring vital signs, in part A of the study.

  Up to Day 38

• Safety and tolerability of repeat oral doses of rilapladib 250 mg assessed by laboratory tests, in part A of the study.

  Up to Day 38

• Tmax and T1/2 of rilapladib alone and in the presence of itraconazole, in part B of the study.

  D1 : Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D3), 96 (D5), 144 (D7) hours post dose, and on D 11: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D13), 96 (D15), 144 (D17) hours post dose

Study Arms (2)

Part A

EXPERIMENTAL

Subjects will receive 250 mg of rilapladib once daily (QD) for 14 days (Days 1-14)

Drug: Rilapladib 250 mg

Part B

EXPERIMENTAL

Subjects will receive 25 mg of rilapladib QD for 1 day (Day 1), 200 mg of itraconazole twice daily (BID) for 1 day (Day 8) and QD for 2 days (Days 9-10). Subjects will receive 25 mg of rilapladib + 200 mg of itraconazole for 1 day (Day 11) and 200 mg of itraconazole QD for 6 days (Day 12-17)

Drug: Rilapladib 25 mg; Drug: Itraconazole

Interventions

Rilapladib 25 mg DRUG

White, round, biconvex, film coated tablet of 25 mg. Taken orally along with food.

Part B

Rilapladib 250 mg DRUG

White, round, biconvex, film coated tablet of 250 mg. Taken orally along with food.

Part A

Itraconazole DRUG

100 mg capsule with a blue opaque cap and pink transparent body. Taken orally along with food.

Part B

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.

You may not qualify if:

• A subject with an alanine aminotransferase (ALT), alkaline phosphatase or bilirubin laboratory result outside the reference range may be included only if the Investigator and GSK Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors.
• 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/milliliter (MIU/mL) and estradiol \< 40 picogram (pg)/mL (\<147 picomole/Litre \[pmol/L\]) is confirmatory\].
• Body weight \>= 50 kilogram (kg) and body mass index (BMI) within the range 19-32 kg/square meter (m\^2) (inclusive).
• Based on single QT duration corrected for heart rate by Fridericia's formula (QTcF): QTcF \<450millisecond (msec); or QTcF \<480 msec in subjects with right bundle branch block.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Criteria Based Upon Medical History
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), or prior cholecystectomy.
• History of asthma, anaphylaxis or anaphylactoid reactions, or severe allergic responses.
• Lifetime history of suicide attempt or active suicidal ideation within the past six months.
• Current major depressive episode or a previous episode of depression requiring medical intervention.
• History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency).
• History of sensitivity to compounds with a chemical structure related to rilapladib or itraconazole, 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 itraconazole administration.
• Requiring the use of oral or injectable strong Cytochrome P450 3A4 (CYP3A4) inhibitors or use of other CYP3A4 inhibitors/inducers within 14 days prior to dosing.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

MeSH Terms

Conditions

Alzheimer Disease

Interventions

rilapladib; Itraconazole

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines

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: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2014
• First Posted: May 5, 2014
• Study Start: October 1, 2017
• Primary Completion: January 1, 2018
• Study Completion: January 1, 2018
• Last Updated: December 13, 2016

Record last verified: 2016-12