Breast Cancer
Conditions
Keywords
Breast cancer, Healthy volunteers, Pharmacokinetics, AZD9496, Safety, Tolerability
Brief summary
This is a phase 1 open label single centre study of AZD9496 administered orally in healthy volunteers. The study design involves single administration of different forms, formulations and doses of AZD9496. The study is designed to investigate these different AZD9496 variants. The study will evaluate the pharmacokinetic profiles and the safety and tolerability of the different forms, formulations and doses of AZD9496 This is a fixed sequence study with 5-sequential treatment periods in healthy volunteers. Each volunteer will receive 5 single doses of AZD9496 in different forms, formulations and doses.
Detailed description
A phase 1, open-label, single centre study to assess the pharmacokinetics, Safety and tolerability of different forms, formulations and doses of AZD9496 in healthy volunteers. This is a fixed sequence study with 5-sequential treatment periods. Each subject will receive 5 single doses of AZD9496 in different forms, formulations and doses. * Treatment period one will assess AZD9496 Variant A: 100mg. * Treatment period two will assess AZD9496 Reference form: 100mg. * Treatment period 3 will assess one of AZD9496 Variants, B, C or D: 100mg. * Treatment period 4 will assess one of AZD9496 Variants, B, C or D: 100mg. * Treatment period 5 will assess one of AZD9496 Variants A, B, C or D: \*300mg. \*Based on a review of pharmacokinetic and safety results from Treatment Periods 1, 3 and 4, a lower dose of 200 mg may be administered in Treatment Period 5.
Interventions
DRUGAZD9496 (Reference)
AZD9496 (Reference)
DRUGAZD9496 Variant A
AZD9496 Variant A.
DRUGAZD9496 Variant B
AZD9496 Variant B
DRUGAZD9496 Variant C
AZD9496 Variant C
DRUGAZD9496 Variant D
AZD9496 Variant D
Sponsors
Parexel
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provision of signed and dated, written informed consent prior to any study specific procedures. 2. Healthy male and/or female subjects aged 18 to 65 years with suitable veins for cannulation or repeated venipuncture. 3. Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria: Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH levels in the post-menopausal range (OR) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation 4. Male subjects aged 18 to 39 years must be vasectomized. Male subjects aged 40 to 65 years must either be vasectomized or have no intention of fathering a child for a period of 6 months after receiving the last dose of IMP. 5. Have a body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive. 6. Values for AST, ALT, TBL, GGT and ALP must be at or below the upper limit of normal ranges at screening.
Exclusion criteria
1. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. 2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. 3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP. 4. Previous history of venous or arterial thromboembolism or thrombophilia. 5. History of endometrial polyps, endometrial cancer, atypical endometrial hyperplasia, or other endometrial disorders unless subjects have undergone total hysterectomy and there is no evidence of active disease (females only). 6. Any clinically significant abnormalities in clinical chemistry (other than Inclusion no.6), hematology, or urinalysis results at screening, as judged by the investigator. 7. Any clinically significant abnormal findings in supine vital signs, after 10 minutes of supine rest, at screening and/or admission to the unit, defined as: (a) Systolic blood pressure \< 90 mmHg or ≥ 150 mmHg (b) Diastolic blood pressure \< 50 mmHg or ≥ 95 mmHg and (c) Heart rate \< 45 or \> 90 beats per minute 8. Any clinically important abnormalities in rhythm, conduction or morphology of the resting 12-lead ECG that, as judged by the investigator, that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or pronounced left ventricular hypertrophy. 9. Prolonged QTcF \> 460 ms for females and QTcF \> 450 ms for males or family history of long QT syndrome. 10. PR (PQ) interval shortening \< 110 ms or evidence of ventricular pre-excitation). 11. PR (PQ) interval prolongation \> 240 ms, intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block. 12. Persistent or intermittent complete bundle branch block with QRS \> 120 ms or evidence of pronounced ventricular hypertrophy or pre-excitation. 13. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody. 14. Known or suspected history of drug abuse, as judged by the investigator. 15. Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening. 16. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol, as judged by the investigator. 17. Positive screen for drugs of abuse, alcohol or cotinine at screening or on each admission to the unit. 18. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD9496. 19. Excessive intake of caffeine/xanthine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator. 20. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP. 21. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life Note: Hormonal replacement therapy is not allowed for females. 22. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening 23. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion is 3 months after the final dose from previous study or 1 month after the last visit of previous study, whichever is the longest. ote: Subjects consented and screened, but not dosed in this study or a previous phase I study, are not excluded. 24. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives 25. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements. 26. Subjects who are vegans or have medical dietary restrictions. 27. Subjects who cannot communicate reliably with the investigator. 28. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | To evaluate maximum observed plasma concentration (Cmax) for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation. |
| Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | Regular Pharmacokinetic measurement: At Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | To evaluate the area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC (0-t) of AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation |
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | To evaluate maximum plasma concentration (Cmax) of capsule variants by comparing with reference AZD9496 |
| Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | To evaluate area under curve from time zero to time with last observation (AUC0-t) of variants by comparing with reference AZD9496 |
| Pharmacokinetics: Area Under the Curve From Time Zero to Infinity for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | Regular Pharmacokinnetic measurement Pre-dose, 0.5, 1, 1.5, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24, and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | To evaluate area under the curve from time zero to time infinity (AUC 0-infinity) of variants by comparing with reference AZD9496 |
| Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | Regular pharmacokinetic measurement pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | To evaluate area under the curve from time zero to infinity (AUC 0-infinity) for AZD9496 and its metabolites |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Apparent Oral Clearance (CL/F) of AZD9496 and Its Metabolites at Each Treatment Period | Day 1, Day 2, Day 3 and Day 4 | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | To evaluate time to reach maximum observed plasma concentration (Tmax) for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation. |
| Pharmacokinetics: Mean Residence Time (MRT) of AZD9496 and Its Metabolites at Each Treatment Period | Day 1, Day 2, Day 3, Day 4 | — |
| Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | Day 1, Day 2, Day 3, Day 4 | — |
| Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | To evaluate effective half-life (t½,eff), for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation. |
| Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | To evaluate metabolite to parent ratios (MRAUC0-t, MRCmax, MRAUC) at each treatment period. |
| Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | — |
| Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period | — |
| Pharmacokinetics: Apparent Volume of Distribution (Vss/F) of AZD9496 and Its Metabolites at Each Treatment Period | Day 1, Day 2, Day 3 and Day 4 | — |
Countries
United States
Participant flow
Recruitment details
At the United States (US, 1 site), 14 healthy participants were treated with AZD9496 (1 dose at fasted state) in 5 treatment periods: Formulation Variants A, B & C (doses 1,3, & 4), reference (dose 2) and formulation Variant B (dose 5). Each subject was involved in the study for approximately 10 to 12 weeks.
Pre-assignment details
A screening period of maximum of -28 days.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All enrolled participants who received at least one dose of AZD9496. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period 3: Variant B (100mg) | Withdrawal by Subject | 0 | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 49.6 Years STANDARD_DEVIATION 6.22 |
| Sex/Gender, Customized Female | 0 Participants |
| Sex/Gender, Customized Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 14 |
| other Total, other adverse events | 2 / 14 | 1 / 14 | 1 / 12 | 0 / 12 | 1 / 12 | 5 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 14 |
Outcome results
Primary
Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period
To evaluate area under the curve from time zero to infinity (AUC 0-infinity) for AZD9496 and its metabolites
Time frame: Regular pharmacokinetic measurement pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable. Data not available for all participants.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | AZD9496 | NA ng*h/mL | — |
| Treatment Period 1 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | M5 | 5.93 ng*h/mL | Geometric Coefficient of Variation 95.53 |
| Treatment Period 2 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | M3 | 253.2 ng*h/mL | Geometric Coefficient of Variation 58.97 |
| Treatment Period 2 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | AZD9496 | 1238 ng*h/mL | Geometric Coefficient of Variation 46.88 |
| Treatment Period 2 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | M5 | 24.09 ng*h/mL | Geometric Coefficient of Variation 76 |
| Treatment Period 3 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | M3 | 99.9 ng*h/mL | Geometric Coefficient of Variation 64.1 |
| Treatment Period 3 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | AZD9496 | 968.1 ng*h/mL | Geometric Coefficient of Variation 30.12 |
| Treatment Period 3 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | M5 | 11.15 ng*h/mL | Geometric Coefficient of Variation 65.47 |
| Treatment Period 4 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | AZD9496 | 604.7 ng*h/mL | Geometric Coefficient of Variation 18.37 |
| Treatment Period 4 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | M3 | 56.9 ng*h/mL | Geometric Coefficient of Variation 30.78 |
| Treatment Period 5 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | M3 | 420.6 ng*h/mL | Geometric Coefficient of Variation 76.41 |
| Treatment Period 5 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | AZD9496 | 2790 ng*h/mL | Geometric Coefficient of Variation 22.97 |
| Treatment Period 5 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period | M5 | 54.84 ng*h/mL | Geometric Coefficient of Variation 47.54 |
Primary
Pharmacokinetics: Area Under the Curve From Time Zero to Infinity for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference
To evaluate area under the curve from time zero to time infinity (AUC 0-infinity) of variants by comparing with reference AZD9496
Time frame: Regular Pharmacokinnetic measurement Pre-dose, 0.5, 1, 1.5, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24, and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable. Data not available for all participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | NA Ratio | — |
| Treatment Period 2 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | 0.6186 Ratio | Geometric Coefficient of Variation 37.26 |
| Treatment Period 3 | Pharmacokinetics: Area Under the Curve From Time Zero to Infinity for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | 0.4055 Ratio | Geometric Coefficient of Variation 48.13 |
Primary
Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period
To evaluate the area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC (0-t) of AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation
Time frame: Regular Pharmacokinetic measurement: At Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 383.4 ng*h/mL | Geometric Coefficient of Variation 60.54 |
| Treatment Period 1 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 4.872 ng*h/mL | Geometric Coefficient of Variation 98.91 |
| Treatment Period 1 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 46.71 ng*h/mL | Geometric Coefficient of Variation 124.65 |
| Treatment Period 2 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 196.6 ng*h/mL | Geometric Coefficient of Variation 80.92 |
| Treatment Period 2 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 1207 ng*h/mL | Geometric Coefficient of Variation 53.01 |
| Treatment Period 2 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 23.11 ng*h/mL | Geometric Coefficient of Variation 73.68 |
| Treatment Period 3 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 111.7 ng*h/mL | Geometric Coefficient of Variation 62 |
| Treatment Period 3 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 677.8 ng*h/mL | Geometric Coefficient of Variation 50.08 |
| Treatment Period 3 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 11.05 ng*h/mL | Geometric Coefficient of Variation 62.2 |
| Treatment Period 4 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 523.0 ng*h/mL | Geometric Coefficient of Variation 26.77 |
| Treatment Period 4 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 7.614 ng*h/mL | Geometric Coefficient of Variation 57.93 |
| Treatment Period 4 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 78.23 ng*h/mL | Geometric Coefficient of Variation 65.96 |
| Treatment Period 5 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 411.3 ng*h/mL | Geometric Coefficient of Variation 57.56 |
| Treatment Period 5 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 2322 ng*h/mL | Geometric Coefficient of Variation 32.12 |
| Treatment Period 5 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 46.42 ng*h/mL | Geometric Coefficient of Variation 49.23 |
Primary
Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference
To evaluate area under curve from time zero to time with last observation (AUC0-t) of variants by comparing with reference AZD9496
Time frame: Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | 0.3175 Ratio | Geometric Coefficient of Variation 46.35 |
| Treatment Period 2 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | 0.5227 Ratio | Geometric Coefficient of Variation 50.95 |
| Treatment Period 3 | Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | 0.4033 Ratio | Geometric Coefficient of Variation 33.15 |
95% CI: [25.77, 39.12]
95% CI: [42.16, 69.6]
95% CI: [34.79, 48.86]
Primary
Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period.
To evaluate maximum observed plasma concentration (Cmax) for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation.
Time frame: Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 64.85 ng/mL | Geometric Coefficient of Variation 73.54 |
| Treatment Period 1 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 1.102 ng/mL | Geometric Coefficient of Variation 85.27 |
| Treatment Period 1 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 10.30 ng/mL | Geometric Coefficient of Variation 98.93 |
| Treatment Period 2 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 62.98 ng/mL | Geometric Coefficient of Variation 76.91 |
| Treatment Period 2 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 381.0 ng/mL | Geometric Coefficient of Variation 55.83 |
| Treatment Period 2 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 7.409 ng/mL | Geometric Coefficient of Variation 75.18 |
| Treatment Period 3 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 23.56 ng/mL | Geometric Coefficient of Variation 74.3 |
| Treatment Period 3 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 138.2 ng/mL | Geometric Coefficient of Variation 75.35 |
| Treatment Period 3 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 2.454 ng/mL | Geometric Coefficient of Variation 80.35 |
| Treatment Period 4 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 91.83 ng/mL | Geometric Coefficient of Variation 52.13 |
| Treatment Period 4 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 1.520 ng/mL | Geometric Coefficient of Variation 42.67 |
| Treatment Period 4 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 14.47 ng/mL | Geometric Coefficient of Variation 39.01 |
| Treatment Period 5 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 98.72 ng/mL | Geometric Coefficient of Variation 54.8 |
| Treatment Period 5 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 550.9 ng/mL | Geometric Coefficient of Variation 41.85 |
| Treatment Period 5 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 11.71 ng/mL | Geometric Coefficient of Variation 49.6 |
Primary
Pharmacokinetics: Maximum Plasma Concentration (Cmax) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference
To evaluate maximum plasma concentration (Cmax) of capsule variants by comparing with reference AZD9496
Time frame: Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | 0.1702 Ratio | Geometric Coefficient of Variation 90.94 |
| Treatment Period 2 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | 0.3440 Ratio | Geometric Coefficient of Variation 110.4 |
| Treatment Period 3 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference | 0.2285 Ratio | Geometric Coefficient of Variation 89.4 |
95% CI: [11.79, 24.58]
95% CI: [23.84, 55.2]
95% CI: [16.84, 34.48]
Secondary
Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period
To evaluate effective half-life (t½,eff), for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation.
Time frame: Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: The PK analysis set consisted of all subjects in the safety analysis set for whom at least 1 of the primary PK parameters for AZD9496 could be calculated for at least Treatment Period 2 and 1 other treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data. Data not available for all participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 1.34 Hours | Standard Deviation 0.45 |
| Treatment Period 1 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 1.15 Hours | Standard Deviation 0.27 |
| Treatment Period 1 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 1.16 Hours | Standard Deviation 0.36 |
| Treatment Period 2 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 1.09 Hours | Standard Deviation 0.17 |
| Treatment Period 2 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 1.11 Hours | Standard Deviation 0.15 |
| Treatment Period 2 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 1.06 Hours | Standard Deviation 0.15 |
| Treatment Period 3 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 2.02 Hours | Standard Deviation 1.84 |
| Treatment Period 3 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 1.51 Hours | Standard Deviation 0.68 |
| Treatment Period 3 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 1.54 Hours | Standard Deviation 0.7 |
| Treatment Period 4 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 1.56 Hours | Standard Deviation 0.36 |
| Treatment Period 4 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 1.42 Hours | Standard Deviation 0.36 |
| Treatment Period 4 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 1.57 Hours | Standard Deviation 0.47 |
| Treatment Period 5 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 1.28 Hours | Standard Deviation 0.28 |
| Treatment Period 5 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 1.36 Hours | Standard Deviation 0.31 |
| Treatment Period 5 | Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 1.23 Hours | Standard Deviation 0.26 |
Secondary
Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period.
To evaluate metabolite to parent ratios (MRAUC0-t, MRCmax, MRAUC) at each treatment period.
Time frame: Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: The PK analysis set consisted of all subjects in the safety analysis set for whom at least 1 of the primary PK parameters for AZD9496 could be calculated for at least Treatment Period 2 and 1 other treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data. Data not available for all participants.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRAUC(0-t) | 0.122 Ratio | Geometric Coefficient of Variation 48.12 |
| Treatment Period 1 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRAUC(0-t) | 0.013 Ratio | Geometric Coefficient of Variation 33.81 |
| Treatment Period 1 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRCmax | 0.017 Ratio | Geometric Coefficient of Variation 30.16 |
| Treatment Period 1 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRCmax | 0.159 Ratio | Geometric Coefficient of Variation 37.68 |
| Treatment Period 2 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRCmax | 0.019 Ratio | Geometric Coefficient of Variation 21.01 |
| Treatment Period 2 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRAUC(0-t) | 0.163 Ratio | Geometric Coefficient of Variation 30.75 |
| Treatment Period 2 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRAUC | 0.173 Ratio | Geometric Coefficient of Variation 21.11 |
| Treatment Period 2 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRAUC(0-t) | 0.019 Ratio | Geometric Coefficient of Variation 22.07 |
| Treatment Period 2 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRAUC | 0.020 Ratio | Geometric Coefficient of Variation 14.91 |
| Treatment Period 2 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRCmax | 0.165 Ratio | Geometric Coefficient of Variation 25.97 |
| Treatment Period 3 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRAUC(0-t) | 0.016 Ratio | Geometric Coefficient of Variation 23.06 |
| Treatment Period 3 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRCmax | 0.018 Ratio | Geometric Coefficient of Variation 31.23 |
| Treatment Period 3 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRCmax | 0.170 Ratio | Geometric Coefficient of Variation 30.68 |
| Treatment Period 3 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRAUC | 0.018 Ratio | Geometric Coefficient of Variation 10.9 |
| Treatment Period 3 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRAUC(0-t) | 0.165 Ratio | Geometric Coefficient of Variation 33.49 |
| Treatment Period 3 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRAUC | 0.172 Ratio | Geometric Coefficient of Variation 7.81 |
| Treatment Period 4 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRCmax | 0.158 Ratio | Geometric Coefficient of Variation 36.29 |
| Treatment Period 4 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRAUC(0-t) | 0.150 Ratio | Geometric Coefficient of Variation 41.38 |
| Treatment Period 4 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRAUC(0-t) | 0.015 Ratio | Geometric Coefficient of Variation 32.71 |
| Treatment Period 4 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRCmax | 0.017 Ratio | Geometric Coefficient of Variation 33.79 |
| Treatment Period 5 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRCmax | 0.022 Ratio | Geometric Coefficient of Variation 20.22 |
| Treatment Period 5 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRCmax | 0.179 Ratio | Geometric Coefficient of Variation 27.25 |
| Treatment Period 5 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRAUC | 0.193 Ratio | Geometric Coefficient of Variation 39.07 |
| Treatment Period 5 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRAUC(0-t) | 0.020 Ratio | Geometric Coefficient of Variation 21.32 |
| Treatment Period 5 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M3 - MRAUC(0-t) | 0.177 Ratio | Geometric Coefficient of Variation 30.28 |
| Treatment Period 5 | Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period. | M5 - MRAUC | 0.021 Ratio | Geometric Coefficient of Variation 26.57 |
Secondary
Pharmacokinetics: Apparent Oral Clearance (CL/F) of AZD9496 and Its Metabolites at Each Treatment Period
Time frame: Day 1, Day 2, Day 3 and Day 4
Population: Too few data points available. CL/F not calculated for M3 and M5. Where less than 3 participants contribute data, the PK parameter was not calculated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: Apparent Oral Clearance (CL/F) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | NA L/h | — |
| Treatment Period 2 | Pharmacokinetics: Apparent Oral Clearance (CL/F) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 80.8 L/h | Standard Deviation 39.8 |
| Treatment Period 3 | Pharmacokinetics: Apparent Oral Clearance (CL/F) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 107.0 L/h | Standard Deviation 32.7 |
| Treatment Period 4 | Pharmacokinetics: Apparent Oral Clearance (CL/F) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 167.5 L/h | Standard Deviation 30.1 |
| Treatment Period 5 | Pharmacokinetics: Apparent Oral Clearance (CL/F) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 110.0 L/h | Standard Deviation 26.7 |
Secondary
Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period
Time frame: Day 1, Day 2, Day 3, Day 4
Population: Too few data points available and so λz not calculated for all participants. Where less than 3 participants contribute data, the PK parameter was not calculated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | NA T-1 | — |
| Treatment Period 1 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | M5 | 0.618 T-1 | Geometric Coefficient of Variation 38.36 |
| Treatment Period 1 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | M3 | NA T-1 | — |
| Treatment Period 2 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | M3 | 0.537 T-1 | Geometric Coefficient of Variation 29.69 |
| Treatment Period 2 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 0.3132 T-1 | Geometric Coefficient of Variation 58.96 |
| Treatment Period 2 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | M5 | 0.426 T-1 | Geometric Coefficient of Variation 55.48 |
| Treatment Period 3 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | M3 | 0.422 T-1 | Geometric Coefficient of Variation 88.14 |
| Treatment Period 3 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 0.1236 T-1 | Geometric Coefficient of Variation 183.17 |
| Treatment Period 3 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | M5 | 0.526 T-1 | Geometric Coefficient of Variation 41.77 |
| Treatment Period 4 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 0.0459 T-1 | Geometric Coefficient of Variation 31.05 |
| Treatment Period 4 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | M3 | 0.380 T-1 | Geometric Coefficient of Variation 34.17 |
| Treatment Period 5 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | M3 | 0.230 T-1 | Geometric Coefficient of Variation 75.62 |
| Treatment Period 5 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 0.0777 T-1 | Geometric Coefficient of Variation 46.67 |
| Treatment Period 5 | Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period | M5 | 0.154 T-1 | Geometric Coefficient of Variation 65.2 |
Secondary
Pharmacokinetics: Apparent Volume of Distribution (Vss/F) of AZD9496 and Its Metabolites at Each Treatment Period
Time frame: Day 1, Day 2, Day 3 and Day 4
Population: Too few data points available. Data not calculated for Vss/F for M3 and M5 .
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 2 | Pharmacokinetics: Apparent Volume of Distribution (Vss/F) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 277.5 L | Standard Deviation 127.3 |
| Treatment Period 3 | Pharmacokinetics: Apparent Volume of Distribution (Vss/F) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 1291 L | Standard Deviation 1097 |
| Treatment Period 4 | Pharmacokinetics: Apparent Volume of Distribution (Vss/F) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 3495 L | Standard Deviation 1532 |
| Treatment Period 5 | Pharmacokinetics: Apparent Volume of Distribution (Vss/F) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 920.7 L | Standard Deviation 392.1 |
Secondary
Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable. Data not available for all participants. Where less than 3 participants contribute data, the PK parameter was not calculated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-12 Hours | 256.2 ng*h/mL | Geometric Coefficient of Variation 65.67 |
| Treatment Period 1 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-24 Hours | 299.9 ng*h/mL | Geometric Coefficient of Variation 60.13 |
| Treatment Period 1 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-12 Hours | 63.02 ng*h/mL | Geometric Coefficient of Variation 72.17 |
| Treatment Period 1 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-24 Hours | 73.26 ng*h/mL | Geometric Coefficient of Variation 71.57 |
| Treatment Period 1 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-12 Hours | 6.162 ng*h/mL | Geometric Coefficient of Variation 78.95 |
| Treatment Period 1 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-24 Hours | 7.417 ng*h/mL | Geometric Coefficient of Variation 65.09 |
| Treatment Period 2 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-12 Hours | 37.83 ng*h/mL | Geometric Coefficient of Variation 33.76 |
| Treatment Period 2 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-24 Hours | NA ng*h/mL | — |
| Treatment Period 2 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-12 Hours | 1194 ng*h/mL | Geometric Coefficient of Variation 51.83 |
| Treatment Period 2 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-12 Hours | 377.3 ng*h/mL | Geometric Coefficient of Variation 23.86 |
| Treatment Period 2 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-24 Hours | NA ng*h/mL | — |
| Treatment Period 2 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-24 Hours | 1306 ng*h/mL | Geometric Coefficient of Variation 44.9 |
| Treatment Period 3 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-24 Hours | 114.9 ng*h/mL | Geometric Coefficient of Variation 47.43 |
| Treatment Period 3 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-12 Hours | 8.646 ng*h/mL | Geometric Coefficient of Variation 74.31 |
| Treatment Period 3 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-12 Hours | 515.3 ng*h/mL | Geometric Coefficient of Variation 57.4 |
| Treatment Period 3 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-12 Hours | 91.52 ng*h/mL | Geometric Coefficient of Variation 57.32 |
| Treatment Period 3 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-24 Hours | 614.8 ng*h/mL | Geometric Coefficient of Variation 49.08 |
| Treatment Period 3 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-24 Hours | 10.09 ng*h/mL | Geometric Coefficient of Variation 60.5 |
| Treatment Period 4 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-24 Hours | 91.49 ng*h/mL | Geometric Coefficient of Variation 32.74 |
| Treatment Period 4 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-24 Hours | 411.7 ng*h/mL | Geometric Coefficient of Variation 28 |
| Treatment Period 4 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-12 Hours | 62.41 ng*h/mL | Geometric Coefficient of Variation 33.9 |
| Treatment Period 4 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-24 Hours | 8.32 ng*h/mL | Geometric Coefficient of Variation 27.76 |
| Treatment Period 4 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-12 Hours | 5.953 ng*h/mL | Geometric Coefficient of Variation 31.78 |
| Treatment Period 4 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-12 Hours | 326.3 ng*h/mL | Geometric Coefficient of Variation 36.18 |
| Treatment Period 5 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-12 Hours | 40.2 ng*h/mL | Geometric Coefficient of Variation 49.71 |
| Treatment Period 5 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-12 Hours | 391.6 ng*h/mL | Geometric Coefficient of Variation 46.7 |
| Treatment Period 5 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-24 Hours | 2130 ng*h/mL | Geometric Coefficient of Variation 36.83 |
| Treatment Period 5 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M5 AUC 0-24 Hours | 46.57 ng*h/mL | Geometric Coefficient of Variation 49.04 |
| Treatment Period 5 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | M3 AUC 0-24 Hours | 490.4 ng*h/mL | Geometric Coefficient of Variation 47.82 |
| Treatment Period 5 | Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 AUC 0-12 Hours | 1920 ng*h/mL | Geometric Coefficient of Variation 38.5 |
Secondary
Pharmacokinetics: Mean Residence Time (MRT) of AZD9496 and Its Metabolites at Each Treatment Period
Time frame: Day 1, Day 2, Day 3, Day 4
Population: Data points not available for all participants. MRT not calculated for M3 and M5 metabolites. Where less than 3 participants contribute data, the PK parameter was not calculated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: Mean Residence Time (MRT) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | NA Hours | — |
| Treatment Period 2 | Pharmacokinetics: Mean Residence Time (MRT) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 3.122 Hours | Geometric Coefficient of Variation 23.77 |
| Treatment Period 3 | Pharmacokinetics: Mean Residence Time (MRT) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 8.992 Hours | Geometric Coefficient of Variation 107.76 |
| Treatment Period 4 | Pharmacokinetics: Mean Residence Time (MRT) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 19.73 Hours | Geometric Coefficient of Variation 52.63 |
| Treatment Period 5 | Pharmacokinetics: Mean Residence Time (MRT) of AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 7.939 Hours | Geometric Coefficient of Variation 29.73 |
Secondary
Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable. Data not available for all participants. Where less than 3 participants contribute data, the PK parameter was not calculated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period 1 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | NA Hours | — |
| Treatment Period 1 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | NA Hours | — |
| Treatment Period 1 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 1.18 Hours | Standard Deviation 0.47 |
| Treatment Period 2 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 1.34 Hours | Standard Deviation 0.39 |
| Treatment Period 2 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 2.59 Hours | Standard Deviation 1.75 |
| Treatment Period 2 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 1.89 Hours | Standard Deviation 1.35 |
| Treatment Period 3 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 2.19 Hours | Standard Deviation 2.13 |
| Treatment Period 3 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 8.95 Hours | Standard Deviation 7.55 |
| Treatment Period 3 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 1.41 Hours | Standard Deviation 0.55 |
| Treatment Period 4 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 15.66 Hours | Standard Deviation 4.47 |
| Treatment Period 4 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 1.89 Hours | Standard Deviation 0.57 |
| Treatment Period 5 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | M3 | 3.69 Hours | Standard Deviation 2.7 |
| Treatment Period 5 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | AZD9496 | 9.65 Hours | Standard Deviation 3.96 |
| Treatment Period 5 | Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period | M5 | 5.06 Hours | Standard Deviation 2.25 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period.
To evaluate time to reach maximum observed plasma concentration (Tmax) for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period
Population: The PK analysis set consisted of all subjects in the safety analysis set for whom at least 1 of the primary PK parameters for AZD9496 could be calculated for at least Treatment Period 2 and 1 other treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment Period 1 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 4.25 Hours |
| Treatment Period 1 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 4.50 Hours |
| Treatment Period 1 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 4.50 Hours |
| Treatment Period 2 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 2.50 Hours |
| Treatment Period 2 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 2.25 Hours |
| Treatment Period 2 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 2.50 Hours |
| Treatment Period 3 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 3.77 Hours |
| Treatment Period 3 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 3.52 Hours |
| Treatment Period 3 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 4.00 Hours |
| Treatment Period 4 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 4.25 Hours |
| Treatment Period 4 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 4.99 Hours |
| Treatment Period 4 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 5.00 Hours |
| Treatment Period 5 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M3 | 4.26 Hours |
| Treatment Period 5 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | AZD9496 | 4.25 Hours |
| Treatment Period 5 | Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period. | M5 | 4.51 Hours |