Study in Healthy Volunteers to Investigate the Effects of Quinidine on the Pharmacokinetics of NKTR-118

A Randomized, 2-Part, Crossover, Single Center Study to Evaluate Effect of Quinidine on the Pharmacokinetics of NKTR-118 and the Concomitant Effect of Quinidine and NKTR-118 on Morphine-induced Miosis

Study in healthy volunteers to investigate the effects of Quinidine on the Pharmacokinetics of NKTR-118

Study Overview

• Status: Completed
• Conditions: Drug Induced Constipation
• Intervention / Treatment: Drug: Nektar 118; Drug: Quinidine; Drug: Quinidine placebo; Drug: Morphine

Detailed Description

A Randomized, 2-Part, Crossover, Single Center Study to Evaluate Effect of Quinidine on the Pharmacokinetics of NKTR-118 and the Concomitant Effect of Quinidine and NKTR-118 on Morphine-induced Miosis

• Study Type: Interventional
• Enrollment (Actual): 214
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Overland Park, Kansas, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of signed and dated, written informed consent prior to any study-specific procedures.
• Male and female (nonchildbearing potential, nonlactating) healthy volunteers aged 18 to 55 years inclusive, with suitable veins for cannulation or repeated venipuncture.
• Female volunteers must be nonpregnant and nonlactating. Women of childbearing potential must have negative pregnancy test (screening and admission) and be using a highly-effective form of birth control for 3 months before enrollment.
• Male volunteers should be willing to use barrier contraception ie, condoms, from the first day of dosing until 3 months after dosing with the IP. The female partner should use contraception during this period.
• Volunteers must have a BMI between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg.

Exclusion Criteria:

• Any clinically significant disease or disorder (eg, cardiovascular, pulmonary, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine) which, may put the volunteer at risk of participation in the study, or influence of the ADME of drugs.
• Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IP.
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results as judged by the Investigator.
• History (personal or family) of torsades de pointes, any other polymorphic ventricular tachycardia, long QT syndrome, sudden death or Brugada syndrome, or personal history of sustained (greater than 30 s) monomorphic ventricular tachycardia.
• Abnormal vital signs, after 10 minutes supine rest as defined in protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: NKTR-118/ Quinidine; One 25-mg NKTR-118 tablet will be administered once with 3 Quinidine 200mg tablets in the morning of period 1 or period 2 (part 1)	Drug: Nektar 118; Oral 25 mg tablet; Drug: Quinidine; Oral 200 mg tablet
Placebo Comparator: NKTR-118/ Placebo; One 25-mg NKTR-118 tablet will be administered once with 3 Placebo tablets in the morning of period 1 or period 2 (part 1)	Drug: Nektar 118; Oral 25 mg tablet; Drug: Quinidine placebo; Oral Tablet
Active Comparator: NKTR-118/ Quinidine/ Morphine; One 25-mg NKTR-118 tablet will be administered with 3 Quinidine 200mg tablets with Morphine inj 5mg/70kg once in the morning on period 3 or period 4 (Part 2)	Drug: Nektar 118; Oral 25 mg tablet; Drug: Quinidine; Oral 200 mg tablet; Drug: Quinidine placebo; Oral Tablet; Drug: Morphine; 10 mg/ml, intravenously
Placebo Comparator: NKTR-118/ Placebo/ Morphine; One 25-mg NKTR-118 tablet will be administered with 3 placebo tables with Morphine inj 5mg/70kg once in the morning of period 3 or period 4 (part 2)	Drug: Nektar 118; Oral 25 mg tablet; Drug: Morphine; 10 mg/ml, intravenously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Description of the pharmacokinetic (PK) profile for NKTR- 118 in terms of maximum observed plasma concentration (Cmax), time to Cmax (tmax), apparent terminal half-life (t1/2λz).	At predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours postdose.
Description of the PK profile for NKTR- 118 in terms of apparent terminal rate constant (λz), area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC).	At predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours postdose.
Description of the PK profile for NKTR 118 in terms of area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration [AUC(0-t)].	At predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours postdose.
Description of the PK profile for NKTR 118 in terms of area under the plasma concentration-time curve from time zero to 24 hours [AUC(0-24)].	At predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours postdose.
Description of the PK profile for NKTR 118 in terms of apparent oral clearance from plasma (CL/F), and apparent volume of distribution during the terminal phase (Vz/F).	At predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours postdose.

Secondary Outcome Measures

Outcome Measure	Time Frame
Description of the safety profile in terms of adverse events, clinical laboratory assessments , vital signs (blood pressure and pulse rate), physical examinations, electrocardiograms and Columbia-Suicide Severity Rating Scale.	From baseline up to 21 days.
Description of results from pupillary measurements in terms of size change from baseline on both eyes in mm. (Measurements in 4 different conditions: dark, 0.04 lux, 0.4 lux and 4 lux)	Measurments from baseline day -1, and at 0.5, 1, 2, 3, 4, 6, and 24 hours post dose.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Phil Leese, MD, Quintiles Kansas United states

Publications and helpful links

Helpful Links

• Clinical_Study_Report_Synopsis_D3820C00011

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: February 10, 2012
• First Submitted That Met QC Criteria: February 14, 2012
• First Posted (Estimate): February 15, 2012

Study Record Updates

• Last Update Posted (Estimate): October 15, 2014
• Last Update Submitted That Met QC Criteria: October 13, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Phase 1; Drug-drug interaction; NKTR-118; Healthy male and female volunteers
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Constipation; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Anti-Infective Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Membrane Transport Modulators; Cytochrome P-450 Enzyme Inhibitors; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Adrenergic alpha-Antagonists; Morphine; Quinidine; Quinidine gluconate
• Other Study ID Numbers: D3820C00011