Healthy
Conditions
Keywords
the effect of food timing on PK, the effect of food timing on Safety and Tolerability, AZD0585, Japanese
Brief summary
The purpose of this study is to assess the effect of food timing on pharmacokinetics (PK) of AZD0585 and the effect of food timing on tolerability and safety of AZD0585 in healthy male Japanese subjects.
Detailed description
This study is an open-label, randomized, cross-over design with three single-dose treatment periods and a washout of at least 10 days in between each treatment visit. The study period consists of 5 visits to the study centre: Visit 1 (enrolment), Visit 2 (first single-dose treatment), Visit 3 (second single-dose treatment), Visit 4 (third single-dose treatment) and Visit 5 (follow-up). Target subject population is healthy male Japanese subjects aged 20-45 years. Following an overnight fast of at least 10 hours, a single dose of 4 g AZD0585 will be administered on 3 separate occasions (fasting, before meal, and after meal) in a randomized crossover fashion with different food restrictions.
Interventions
DRUGAZD0585
Following an overnight fast of at least 10 hours, a single dose of 4 g AZD0585 will be administered on 3 separate occasions (fasting, before meal, and after meal) in a randomized crossover fashion with different food restrictions.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy Japanese male, 20 to 45 years of age (inclusive). * Body mass index (BMI) ≥ 18.5 and ≤ 25 (kg/m2). * Medically healthy with clinically insignificant screening results (e.g., laboratory profiles, medical histories, ECGs, physical findings). Hemoglobin level must be ≥ the lower limit of study centre reference range. 12-Lead ECG with QT interval corrected for heart rate using Fridericia's formula (QTcF) should be \> 340 msec and \< 450 msec. * No habitual use of drug(s) and tobacco/nicotine-containing products for a minimum of 3 months prior to first dosing. * Subjects must be willing and able to give written informed consent by signing an Institutional Review Board (IRB)-approved Informed Consent Form prior to admission to this study and follow the restrictions and procedures outlined for the study.
Exclusion criteria
* Past history of psychological or physical disorder which may affect the objectives of this study, in the opinion of the PI. * An individual who has abnormal laboratory values (ie, suggesting hepatic, renal, cardiovascular or endocrine disorders or diabetes mellitus), or an inappropriate current or past medical history for participation based on the decision of the PI. * A history or presence of significant cardiovascular, pulmonary, hepatic, renal, haematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic or psychiatric disease. * Had used fish oil, other EPA- and/or DHA-containing supplements within 2 months prior to first admission day. * Have serum (or plasma) EPA and/or DHA concentrations exceeding the upper limit of reference range for the fatty acids profile, four-fraction test, determined at Visit 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese. | Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). | To investigate the effect of food timing on PK (area under the plasma concentration-time curve from time zero to infinity \[AUC\]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total eicosapentaenoic acid (EPA) and total docosahexaenoic acid (DHA), and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). |
| The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese. | Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). | To investigate the effect of food timing on PK (maximum plasma concentration \[Cmax\]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total EPA and total DHA, and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). Analyses of the outcome measures presented are for baseline-adjusted data for total EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation. The geometric mean was calculated as the exponential of the arithmetic mean calculated from data on a log scale. |
| The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese. | Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). | To investigate the effect of food timing on PK (area under the plasma concentration-time curve from time zero to 72 hours \[AUC0-72\]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total EPA and total DHA, and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). Analyses of the outcome measures presented are for baseline-adjusted data for total EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation. The geometric mean was calculated as the exponential of the arithmetic mean calculated from data on a log scale. |
Countries
Japan
Participant flow
Recruitment details
The enrollment period started 4 March 2015 and the last subject last visit was 12 May 2015. This was a 3-period crossover study with a minimum 10-day washout period between each treatment visit (Period 1=Visit 2; Period 2=Visit 3; Period 3=Visit 4).
Pre-assignment details
Subjects were randomized to 3 sequences (ABC, BCA or CAB; A=fasting, B=before meal, C=after meal) with a 1:1:1 ratio. 72 subjects were enrolled; 42 randomized and 30 excluded (8 did not fulfil eligibility criteria and 22 refused participation).
Participants by arm
| Arm | Count |
|---|---|
| AZD0585 All subjects received a single oral dose of 4 g AZD0585 on 3 separate occasions (fasting, before meal, and after meal) in a randomized crossover fashion with different food restrictions. Each dose was administered on Day 1 of each separate treatment period: Period 1=Visit 2; Period 2=Visit 3; Period 3=Visit 4. | 42 |
| Total | 42 |
Baseline characteristics
| Characteristic | AZD0585 |
|---|---|
| Age, Continuous | 31.0 years STANDARD_DEVIATION 7.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 42 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 42 | 6 / 42 | 1 / 42 |
| serious Total, serious adverse events | 0 / 42 | 0 / 42 | 0 / 42 |
Outcome results
Primary
The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese.
To investigate the effect of food timing on PK (area under the plasma concentration-time curve from time zero to infinity \[AUC\]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total eicosapentaenoic acid (EPA) and total docosahexaenoic acid (DHA), and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal).
Time frame: Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK set included all healthy subjects in the safety population (ie, who received at least 1 administration of AZD0585 and for whom any post-dose data were available) with at least 1 detectable total EPA and total DHA plasma concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese. | Total DHA (n=4, 2, 2) | 0.299 milligram x hour /millilitre (mg⋅h/mL) | Geometric Coefficient of Variation 143 |
| Fasting | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese. | Total EPA (n=37, 33, 41) | 2.44 milligram x hour /millilitre (mg⋅h/mL) | Geometric Coefficient of Variation 66.8 |
| Before Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese. | Total EPA (n=37, 33, 41) | 2.66 milligram x hour /millilitre (mg⋅h/mL) | Geometric Coefficient of Variation 80.15 |
| Before Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese. | Total DHA (n=4, 2, 2) | 0.444 milligram x hour /millilitre (mg⋅h/mL) | Geometric Coefficient of Variation 152 |
| After Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese. | Total EPA (n=37, 33, 41) | 3.80 milligram x hour /millilitre (mg⋅h/mL) | Geometric Coefficient of Variation 37.55 |
| After Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on Pharmacokinetics (PK; AUC) of AZD0585 in Healthy Male Japanese. | Total DHA (n=4, 2, 2) | 0.617 milligram x hour /millilitre (mg⋅h/mL) | Geometric Coefficient of Variation 97.7 |
Comparison: Total EPA: Ratio of Fasting to After meal. Primary comparisons for total EPA were based on a linear mixed-effect model. This model included log-transformed PK parameter (AUC) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.54, 0.77]
Comparison: Total EPA: Ratio of Before meal to After meal. Primary comparisons for total EPA were based on a linear mixed-effect model. This model included log-transformed PK parameter (AUC) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.59, 0.86]
Primary
The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese.
To investigate the effect of food timing on PK (area under the plasma concentration-time curve from time zero to 72 hours \[AUC0-72\]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total EPA and total DHA, and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). Analyses of the outcome measures presented are for baseline-adjusted data for total EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation. The geometric mean was calculated as the exponential of the arithmetic mean calculated from data on a log scale.
Time frame: Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK set included all healthy subjects in the safety population (ie, who received at least 1 administration of AZD0585 and for whom any post-dose data were available) with at least 1 detectable total EPA and total DHA plasma concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese. | Total EPA (n=42, 42, 42) | 1.53 mg⋅h/mL | Geometric Coefficient of Variation 76.1 |
| Fasting | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese. | Total DHA (n=42, 42, 42) | 0.542 mg⋅h/mL | Geometric Coefficient of Variation 80.4 |
| Before Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese. | Total EPA (n=42, 42, 42) | 1.52 mg⋅h/mL | Geometric Coefficient of Variation 112 |
| Before Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese. | Total DHA (n=42, 42, 42) | 0.533 mg⋅h/mL | Geometric Coefficient of Variation 66 |
| After Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese. | Total EPA (n=42, 42, 42) | 2.76 mg⋅h/mL | Geometric Coefficient of Variation 31.1 |
| After Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (AUC0-72) of AZD0585 in Healthy Male Japanese. | Total DHA (n=42, 42, 42) | 0.621 mg⋅h/mL | Geometric Coefficient of Variation 75.8 |
Comparison: Total EPA: Ratio of Fasting to After meal. Primary comparisons for total EPA were based on a linear mixed-effect model. This model included log-transformed PK parameter (AUC0-72) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.45, 0.69]
Comparison: Total EPA: Ratio of Before Meal to After meal. Primary comparisons for total EPA were based on a linear mixed-effect model. This model included log-transformed PK parameter (AUC0-72) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.44, 0.69]
Comparison: Total DHA: Ratio of Fasting to After meal. Primary comparisons for total DHA were based on a linear mixed-effect model. This model included log-transformed PK parameter (AUC0-72) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.73, 1.04]
Comparison: Total DHA: Ratio of Before meal to After meal. Primary comparisons for total DHA were based on a linear mixed-effect model. This model included log-transformed PK parameter (AUC0-72) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.72, 1.02]
Primary
The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese.
To investigate the effect of food timing on PK (maximum plasma concentration \[Cmax\]) of single dose of 4 g AZD0585 in healthy male Japanese by assessing plasma concentrations of total EPA and total DHA, and PK parameters over time under the three proposed conditions (fasting, before meal, and after meal). Analyses of the outcome measures presented are for baseline-adjusted data for total EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation. The geometric mean was calculated as the exponential of the arithmetic mean calculated from data on a log scale.
Time frame: Blood samples were collected from pre-dose (Day -1) up to 72 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK set included all healthy subjects in the safety population (ie, who received at least 1 administration of AZD0585 and for whom any post-dose data were available) with at least 1 detectable total EPA and total DHA plasma concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese. | Total EPA (n=42, 42, 42) | 78.5 microgram/millilitre (mcg/mL) | Geometric Coefficient of Variation 110 |
| Fasting | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese. | Total DHA (n=42, 42, 42) | 42.1 microgram/millilitre (mcg/mL) | Geometric Coefficient of Variation 84.9 |
| Before Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese. | Total EPA (n=42, 42, 42) | 97.1 microgram/millilitre (mcg/mL) | Geometric Coefficient of Variation 168 |
| Before Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese. | Total DHA (n=42, 42, 42) | 52.4 microgram/millilitre (mcg/mL) | Geometric Coefficient of Variation 103 |
| After Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese. | Total DHA (n=42, 42, 42) | 92.6 microgram/millilitre (mcg/mL) | Geometric Coefficient of Variation 42.65 |
| After Meal | The Effect of Food Timing (Fasting, Before Meal, and After Meal) on PK (Cmax) of AZD0585 in Healthy Male Japanese. | Total EPA (n=42, 42, 42) | 221 microgram/millilitre (mcg/mL) | Geometric Coefficient of Variation 34.7 |
Comparison: Total EPA: Ratio of Fasting to After meal. Primary comparisons for total EPA were based on a linear mixed-effect model. This model included log-transformed PK parameter (Cmax) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.27, 0.47]
Comparison: Total EPA: Ratio of Before meal to After meal. Primary comparisons for total EPA were based on a linear mixed-effect model. This model included log-transformed PK parameter (Cmax) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.33, 0.59]
Comparison: Total DHA: Ratio of Fasting to After meal. Primary comparisons for total DHA were based on a linear mixed-effect model. This model included log-transformed PK parameter (Cmax) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.36, 0.57]
Comparison: Total DHA: Ratio of Before meal to After meal. Primary comparisons for total DHA were based on a linear mixed-effect model. This model included log-transformed PK parameter (Cmax) as a response variable and treatment, sequence and period as fixed categorical effects, and subject nested within sequence as a random categorical effect.95% CI: [0.45, 0.71]