A Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics (PK) of Nemiralisib

GlaxoSmithKline20 enrolled

Overview

Nemiralisib is a potent anti-inflammatory agent for the treatment of chronic obstructive pulmonary disease (COPD) and other inflammatory lung diseases. The Cytochrome P450 3A4 (CYP3A4) is a major route of clearance for nemiralisib. The co-administration of drug therapies, which modulate CYP3A4, may alter the exposure of nemiralisib. Hence, this clinical drug interaction study with itraconazole (a potent CYP3A4 inhibitor) is required. The study will evaluate the PK, safety and tolerability of nemiralisib when administered alone and when administered concomitantly with repeat doses of itraconazole in healthy males and females. Subjects will receive treatment with nemiralisib alone in Period 1 and itraconazole followed by nemiralisib in Period 2 in single sequence crossover manner. Approximately 20 subjects will be enrolled such that approximately 16 evaluable subjects complete the study. Each subject will participate in the study for approximately 7 weeks including screening visit, 2 treatment periods and a follow up visit.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Nemiralisib will be given as 100 mcg via ELLIPTA Dry Powder Inhaler with 30 doses per inhaler/ 100 mcg total dose. ELLIPTA® is a registered trademark of GlaxoSmithKline group of companies.

ItraconazoleDRUG

Itraconazole will be given as 100 mg per capsule per day administered orally with water

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects must be 18 to 75 years of age inclusive, at the time of signing the informed consent. * Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac evaluation. * Normal spirometry at Screening (FEV1 and forced vital capacity \[FVC\] \>=80 percent of predicted. Measurements to be taken in triplicate. The highest value of each individual component must be \>=80 percent of predicted). * A subject with a clinical abnormality or laboratory parameter(s) (except for liver function tests) outside the reference range for the population being studied may be included only if the investigator, in consultation with the medical monitor if needed, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Body weight \>50 kilograms (kg) and body mass index (BMI) within the range 18.0-35.0 kg per meter square (kg/m\^2) (inclusive). * Male and/or female: A male subject must agree to use contraception during the treatment period and for at least 10 days after the last dose of study treatment and refrain from donating sperm during this period; a female subject is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP). * Capable of giving signed informed consent. Exclusion Criteria: * History or presence of cardiovascular, respiratory (except childhood asthma, which has now remitted), hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data. * Abnormal blood pressure. * Liver function test results above the upper limit of normal (ULN). * Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). * QT interval corrected for heart rate by Fridericia's formula (QTcF) \>450 milliseconds (msec). * Past or intended use of over-the-counter or prescription medication including herbal medications within 14 days prior to dosing. * Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 90 days. * Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day. * Current enrolment or past participation within the last 30 days before signing of consent in this or any other clinical study involving an investigational study treatment or any other type of medical research. * Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C antibody test result at screening. * Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment. * Positive human immunodeficiency virus (HIV) antibody test (according to local policies). * Positive drug/alcohol test at screening or on admission (Day -1). * Regular use of known drugs of abuse. * Regular alcohol consumption within 6 months prior to the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 grams (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. * Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or nicotine-containing products within 6 months of screening, or a total pack year history of \>5 pack years. \[number of pack years = (number of cigarettes per day/20) x number of years smoked\]. * Sensitivity to any of the study treatments, or components thereof (including lactose and Magnesium Stearate), or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study. * Unwillingness to follow the lifestyle restrictions.

Locations (1)

GSK Investigational Site

Overland Park, Kansas, United States

Outcomes

Primary Outcomes

Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of Nemiralisib in Plasma

Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate pharmacokinetic parameters of nemiralisib in both treatment period 1 and 2. Pharmacokinetic analysis was conducted using standard non-compartmental methods. Pharmacokinetic population comprised of all participants enrolled in the study who took at least 1 dose of nemiralisib and for whom a nemiralisib pharmacokinetic sample was obtained and analyzed.

Time frame: Period 1: Pre-dose, and 5, 30 minutes, 2, 6, 12, 24, 48, 72, 96 and 120 hours post-dose on Day 1. Period 2: Pre-dose, and 5 min, 30 min, 2, 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose on Day 5

Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]) of Nemiralisib in Plasma

Blood samples were collected from participants at indicated time frames after the administration of study treatment to investigate pharmacokinetic parameters of Nemiralisib in both treatment period 1 and 2. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

Maximum Observed Plasma Concentration (Cmax) of Nemiralisib in Plasma

Apparent Terminal Half-life (t1/2) of Nemiralisib in Plasma

Time to Maximum Observed Plasma Concentration (Tmax) of Nemiralisib in Plasma

Blood samples were collected at indicated time points after administration of repeated doses of itraconazole along with Nemiralisib. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

Secondary Outcomes

AUC(0-inf) of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2

Time frame: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5

AUC(0-t) of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2

Blood samples were collected at indicated time points after administration of repeated doses of Itraconazole along with Nemiralisib. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

Time frame: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5

Cmax of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2

Blood samples were collected at indicated time points after administration of repeated doses of Itraconazole and Hydroxy Itraconazole along with Nemiralisib. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

Time frame: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5

T1/2 of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2

Time frame: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5

Tmax of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2

Data from ClinicalTrials.gov

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Time frame: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5

Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per Medical or scientific judgement. Safety population comprised of all participants enrolled in the study, who took at least one dose of study treatment.

Time frame: Up to 35 days

Change From Baseline of Clinical Chemistry Parameters When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered: Calcium, Glucose, Potassium and Sodium

Blood samples were collected for the analysis of clinical chemistry parameters including calcium, glucose, potassium and sodium. Day -1 was defined as Baseline for clinical chemistry parameters. Change from Baseline is calculated as the value at specified time point minus the Baseline value.

Time frame: Baseline (Day -1) and Day 6

Change From Baseline of Clinical Chemistry Parameters When Nemiralisib 100 mcg When Co-administered With Itraconazole 200 mg Repeated Dose: Calcium, Glucose, Potassium and Sodium

Time frame: Baseline (Day -1), Day 2, 4, 6, 8 and 10

Change From Baseline of Clinical Chemistry Parameters When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered: Alkaline Phosphate, Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)

Blood samples were collected for the analysis of clinical chemistry parameters including alkaline phosphate, ALT and AST at indicated time points. Day -1 was defined as Baseline for clinical chemistry parameters. Change from Baseline is calculated as the value at specified time point minus the Baseline value.