Healthy
Conditions
Keywords
HSV, Herpes, volunteers, drug-drug interaction
Brief summary
CYP2C8 is involved in the metabolism of many drugs. So, it is important to assess in vivo the inhibitory effect of ASP2151 on that enzyme to determine any possible drug interactions. The aim of this trial is to investigate the potential for interaction of ASP2151 with the CYP2C8 probe substrate montelukast.
Interventions
DRUGMontelukast
DRUGASP2151
Sponsors
Maruho Europe Limited
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* A body mass index (Quetelet index) in the range 18.0-30.9. * Sufficient intelligence to understand the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial. * Willingness to give written consent to participate after reading the information and consent form, and after having the opportunity to discuss the trial with the investigator or his delegate. * Willingness to give written consent to have data entered into The Overvolunteering Prevention System.
Exclusion criteria
* Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the volunteer. * Any of the following liver function tests higher than 1.5 times the ULN at the screening visit: aspartate aminotransferase (AST), alanine aminotransferase (ALT), ALP, bilirubin, gamma glutamyl transpeptidase (gamma-GT). * Platelet counts outside normal limits. * Presence of acute or chronic illness or history of chronic illness sufficient to invalidate the volunteer's participation in the trial or make it unnecessarily hazardous. * Clinically significant impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary heart disease, or history of any psychotic mental illness. * History of bleeding diathesis. * Surgery (eg stomach bypass) or medical condition that might affect absorption of medicines. * Presence or history of severe adverse reaction to any drug, history of multiple drug allergies (multiple defined as \>3), or sensitivity to trial medication. * Use, during the 28 days before the first dose of trial medication, of any prescription medicine, or any other medicine or herbal remedy (such as St John's wort) known to interfere with the CYP3A4, CYP2C19, CYP2C8 or CYP2C9 metabolic pathway (unless judged as not clinical significant by the investigator and sponsor). See Appendix 1: for common CYP3A4, CYP2C19, CYP2C8 and CYP2C9 interactors/substrates. * Use, during the 7 days before the first dose of trial medication, of any over the counter medicine, with the exception of paracetamol (acetaminophen). * Participation in another clinical trial of a new chemical entity or a prescription medicine within the previous 3 months. * Presence or history of drug or alcohol abuse, or intake of more than 21 units of alcohol weekly or more than 10 cigarettes daily. * Blood pressure and heart rate in seated position at the screening examination outside the ranges 90-140 mm Hg systolic, 40-90 mm Hg diastolic; heart rate 40\_100 beats/min. However, if the investigator deems the result to be not clinically significant the subject may be included. * Possibility that the volunteer will not cooperate with the requirements of the protocol. * Evidence of drug abuse on urine testing. * Positive test for hepatitis B, hepatitis C, HIV1 or HIV2. * Loss of more than 400 mL blood during the 3 months before the trial, eg as a blood donor. * Objection by General Practitioner (GP) to volunteer entering trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Peak Plasma Concentration (Cmax) of Montelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
| Half-Life (t1/2) of Montelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
| Apparent Volume of Distribution (Vd/f) of Montelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
| Apparent Total Body Clearance (CL/f) of Montelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
| Time of Peak Concentration (Tmax) of Montelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
| Area Under the Curve (AUC) of Montelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and Non-Serious Adverse Events | Up to 32 days after the last dose | Refer to the result of adverse event. |
Other
| Measure | Time frame |
|---|---|
| Half-Life (t1/2) of ASP2151 | Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention |
| Peak Plasma Concentration (Cmax) of Methyl Hydroxymontelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
| Apparent Total Body Clearance (CL/f) of ASP2151 | Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention |
| Apparent Volume of Distribution (Vd/f) of ASP2151 | Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention |
| Time of Peak Concentration (Tmax) of Methyl Hydroxymontelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
| Area Under the Curve (AUC) of Methyl Hydroxymontelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
| Half-Life (t1/2) of Methyl Hydroxymontelukast | Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention |
| Peak Plasma Concentration (Cmax) of ASP2151 | Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention |
| Time of Peak Concentration (Tmax) of ASP2151 | Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention |
| Area Under the Curve (AUC) of ASP2151 | Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention |
Countries
United Kingdom
Participant flow
Recruitment details
Participants took part in the study at one investigative site in United Kingdom from 03-December 2014 to 01-April 2015
Participants by arm
| Arm | Count |
|---|---|
| Montelukast, Then Montelukast + ASP2151 10mg montelukast alone followed by 10mg montelukast + 400mg ASP2151
Montelukast
ASP2151 | 12 |
| Montelukast + ASP2151, Then Montelukast 10mg montelukast + 400mg ASP2151 followed by 10mg montelukast alone
Montelukast
ASP2151 | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Total | Montelukast + ASP2151, Then Montelukast | Montelukast, Then Montelukast + ASP2151 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 12 Participants | 12 Participants |
| Age, Continuous | 30.8 year STANDARD_DEVIATION 7.1 | 33.2 year STANDARD_DEVIATION 5.8 | 28.5 year STANDARD_DEVIATION 7.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 12 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 10 Participants | 9 Participants |
| Region of Enrollment United Kingdom | 24 Participants | 12 Participants | 12 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 24 Participants | 12 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 7 / 24 | 2 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
Apparent Total Body Clearance (CL/f) of Montelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Apparent Total Body Clearance (CL/f) of Montelukast | 3.72 L/h | Standard Deviation 1.079 |
| ASP2151 | Apparent Total Body Clearance (CL/f) of Montelukast | 3.04 L/h | Standard Deviation 0.857 |
Primary
Apparent Volume of Distribution (Vd/f) of Montelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Apparent Volume of Distribution (Vd/f) of Montelukast | 26.72 L | Standard Deviation 10.482 |
| ASP2151 | Apparent Volume of Distribution (Vd/f) of Montelukast | 23.76 L | Standard Deviation 7.854 |
Primary
Area Under the Curve (AUC) of Montelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Area Under the Curve (AUC) of Montelukast | 2799.2 h*ng/mL | Geometric Coefficient of Variation 29.7 |
| ASP2151 | Area Under the Curve (AUC) of Montelukast | 3418.5 h*ng/mL | Geometric Coefficient of Variation 30 |
Primary
Half-Life (t1/2) of Montelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Half-Life (t1/2) of Montelukast | 4.87 h | Geometric Coefficient of Variation 27.8 |
| ASP2151 | Half-Life (t1/2) of Montelukast | 5.37 h | Geometric Coefficient of Variation 18.5 |
Primary
Peak Plasma Concentration (Cmax) of Montelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Peak Plasma Concentration (Cmax) of Montelukast | 415.6 ng/mL | Geometric Coefficient of Variation 24.9 |
| ASP2151 | Peak Plasma Concentration (Cmax) of Montelukast | 505.9 ng/mL | Geometric Coefficient of Variation 25.7 |
Primary
Time of Peak Concentration (Tmax) of Montelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Montelukast | Time of Peak Concentration (Tmax) of Montelukast | 3 h |
| ASP2151 | Time of Peak Concentration (Tmax) of Montelukast | 3 h |
Secondary
Number of Participants With Serious and Non-Serious Adverse Events
Refer to the result of adverse event.
Time frame: Up to 32 days after the last dose
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Montelukast | Number of Participants With Serious and Non-Serious Adverse Events | Non-serious adverse event | 7 participants |
| Montelukast | Number of Participants With Serious and Non-Serious Adverse Events | serious adverse event | 0 participants |
| ASP2151 | Number of Participants With Serious and Non-Serious Adverse Events | Non-serious adverse event | 2 participants |
| ASP2151 | Number of Participants With Serious and Non-Serious Adverse Events | serious adverse event | 0 participants |
Other Pre-specified
Apparent Total Body Clearance (CL/f) of ASP2151
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Apparent Total Body Clearance (CL/f) of ASP2151 | 19.95 L/h | Standard Deviation 6.525 |
Other Pre-specified
Apparent Volume of Distribution (Vd/f) of ASP2151
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Apparent Volume of Distribution (Vd/f) of ASP2151 | 246.9 L | Standard Deviation 104.44 |
Other Pre-specified
Area Under the Curve (AUC) of ASP2151
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Area Under the Curve (AUC) of ASP2151 | 20928.2 h*ng/mL | Geometric Coefficient of Variation 29.4 |
Other Pre-specified
Area Under the Curve (AUC) of Methyl Hydroxymontelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Area Under the Curve (AUC) of Methyl Hydroxymontelukast | 150.19 h*ng/mL | Geometric Coefficient of Variation 46.6 |
| ASP2151 | Area Under the Curve (AUC) of Methyl Hydroxymontelukast | 188.62 h*ng/mL | Geometric Coefficient of Variation 59 |
Other Pre-specified
Half-Life (t1/2) of ASP2151
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Half-Life (t1/2) of ASP2151 | 8.406 h | Geometric Coefficient of Variation 17.4 |
Other Pre-specified
Half-Life (t1/2) of Methyl Hydroxymontelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Half-Life (t1/2) of Methyl Hydroxymontelukast | 4.87 h | Geometric Coefficient of Variation 24.7 |
| ASP2151 | Half-Life (t1/2) of Methyl Hydroxymontelukast | 4.83 h | Geometric Coefficient of Variation 25.3 |
Other Pre-specified
Peak Plasma Concentration (Cmax) of ASP2151
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Peak Plasma Concentration (Cmax) of ASP2151 | 1679.7 ng/mL | Geometric Coefficient of Variation 32.4 |
Other Pre-specified
Peak Plasma Concentration (Cmax) of Methyl Hydroxymontelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Montelukast | Peak Plasma Concentration (Cmax) of Methyl Hydroxymontelukast | 19.18 ng/mL | Geometric Coefficient of Variation 40.5 |
| ASP2151 | Peak Plasma Concentration (Cmax) of Methyl Hydroxymontelukast | 23.28 ng/mL | Geometric Coefficient of Variation 51.9 |
Other Pre-specified
Time of Peak Concentration (Tmax) of ASP2151
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24h after post doses in first or second intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Montelukast | Time of Peak Concentration (Tmax) of ASP2151 | 3 h |
Other Pre-specified
Time of Peak Concentration (Tmax) of Methyl Hydroxymontelukast
Time frame: Blood samples were taken at pre-dose of Day 1 and 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48 and 72h after post doses in first or second intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Montelukast | Time of Peak Concentration (Tmax) of Methyl Hydroxymontelukast | 4.51 h |
| ASP2151 | Time of Peak Concentration (Tmax) of Methyl Hydroxymontelukast | 5 h |