Last updated: 07/17/2024 17:31:57
A study to evaluate the effect of itraconazole on the pharmacokinetics (PK) of nemiralisib
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
Official title: A single centre, open label, one sequence, cross-over study to evaluate the effect of itraconazole on the pharmacokinetics of single inhaled doses of nemiralisib in healthy subjects
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Crossover Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC [0-infinity]) of nemiralisib following administration of itraconazole in Period 2
Timeframe: Pre-dose, and 5, 30 minutes, 2 , 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose
Area under the plasma concentration versus time curve from time zero to t (AUC [0-t]) of nemiralisib following administration of itraconazole in Period 2
Timeframe: Pre-dose, and 5, 30 minutes, 2 , 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose
Maximum observed plasma concentration (Cmax) of nemiralisib following administration of itraconazole in Period 2
Timeframe: Pre-dose, and 5, 30 minutes, 2 , 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose
Time to Cmax (Tmax) of nemiralisib following administration of itraconazole in Period 2
Timeframe: Pre-dose, and 5, 30 minutes, 2 , 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose
Terminal phase half-life (T1/2) of nemiralisib following administration of itraconazole in Period 2
Timeframe: Pre-dose, and 5, 30 minutes, 2 , 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose
Secondary outcomes:
Number of subjects with adverse events (AEs)
Timeframe: Up to 41 days
Number of subjects with serious AEs (SAEs)
Timeframe: Screening and up to 41 days
Number of subjects with abnormal clinical chemistry laboratory parameters
Timeframe: Up to 41 days
Number of subjects with abnormal hematology laboratory parameters
Timeframe: Up to 41 days
Number of subjects with abnormal values for urinalysis
Timeframe: Up to 30 days
Number of subjects with abnormal values for blood pressure
Timeframe: Up to 30 days
Number of subjects with abnormal values for body temperature
Timeframe: Up to 30 days
Number of subjects with abnormal pulse rate
Timeframe: Up to 30 days
Number of subjects with abnormal respiratory rate
Timeframe: Up to 30 days
Number of subjects with abnormal electrocardiogram (ECG) findings
Timeframe: Up to 41 days
Forced expiratory volume in 1 second (FEV1) following doing with nemiralisib when dosed alone and concomitantly with itraconazole
Timeframe: Up to Day 4
AUC (0-infinity) of itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
AUC (0-infinity) of hydroxy-itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
AUC (0-t) of itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
AUC (0-t) of hydroxy-itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
Cmax of itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
Cmax of hydroxy-itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
Tmax of itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
Tmax of hydroxy-itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
T1/2 of itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
T1/2 of hydroxy-itraconazole when co-administered with nemiralisib in Period 2
Timeframe: Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1 and Day 5; 24 hours post-dose on Day 5
Interventions:
Enrollment:
20
Primary completion date:
2018-12-03
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Aarti Patel, Robert Wilson, Andrew W Harrell, Kunal S Taskar, Maxine Taylor, Helen Tracey, Kylie Riddell, Alex Georgiou, Anthony P Cahn, Miriam Marotti, and Edith M Hessel. Drug interactions for low dose inhaled nemiralisib – a case study integrating modelling, in vitro and clinical investigations. Drug Metab Dispos.2020;48(4):307-316
DOI: 10.1124/dmd.119.089003
PMID: 32009006
Medical condition
Pulmonary Disease, Chronic Obstructive
Product
itraconazole, nemiralisib
Collaborators
Not applicable
Study date(s)
January 2018 to March 2018
Type
Interventional
Phase
1
Participation criteria
Sex
Female & Male
Age
18 - 75 years
Accepts healthy volunteers
Yes
- 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.
- 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.
Inclusion and exclusion criteria
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.
Trial location(s)
Location
GSK Investigational Site
Overland Park, Kansas, United States, 66211
Status
Study Complete
Study documents
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Study complete
Actual primary completion date
2018-12-03
Actual study completion date
2018-12-03
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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