Healthy Subjects
Conditions
Keywords
Non-randomized, Verapamil, Itraconazole, Diltiazem, Safety, Tolerability, Pharmacokinetics
Brief summary
This is a phase 1, non-randomized, fixed sequence, 3-period, drug-drug interaction study to assess the pharmacokinetics (PK) of AZD7986 in healthy subjects when administered alone and in combination with multiple doses of verapamil and itraconazole or diltiazem
Detailed description
This study will be an open-label, non-randomised, fixed sequence, 3-period study conducted at a single study centre to assess the PK of AZD7986 in healthy subjects when administered alone and in combination with multiple doses of verapamil and itraconazole or diltiazem. An adaptive design with an interim analysis of the PK data from Periods 1 and 2 will be used to determine which of itraconazole or diltiazem will be administered in combination with AZD7986 in Period 3. Treatments to be administered in a fixed order separated by a washout period: period 1 - single AZD7986 (25 mg) on Day 1 (1 hour before food), washout 7 days period 2 - verapamil (240 mg extended release formulation) daily 1 hour before food (Day 1 to 10) and a single dose of AZD7986 (25 mg) 1 hour before food (Day 5), washout period 14 days period 3 - subject to interim pharmacokinetic analysis of AZD7986 alone compared with AZD7986 and verapamil combined, either itraconazole (200 mg, oral solution formulation 10mg/mL) administered twice on Day 1 and daily on days 2 to 11 (1 hour before food) plus AZD7986 (25mg) single dose on Day 6 (1 hour before food); or diltiazem (360 mg, extended release formulation) on Days 1 to 13 (1 hour before food) plus AZD7986 (25 mg) 1 hour before food on Day 8.
Interventions
DRUGAZD7986
Oral solution, single dose, dilution from concentrate
DRUGVerapamil
Extended release tablet for oral use
DRUGItraconazole
Oral solution
DRUGDiltiazem
Extended release capsule
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 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 55 years (inclusive) with suitable veins for cannulation or repeated venepuncture. 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 follicle-stimulating hormone (FSH) levels in the post menopausal range(\> 40 milli-International unit \[mIU\]/mL). Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation. 4. Have a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive. 5. Provision of signed, written and dated informed consent for optional genetic/biomarker research. 6. Hormone replacement therapy is not allowed for females to exclude any drug drug interaction between the hormone replacement therapy and AZD7986.
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 AZD7986. 4. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, as judged by the investigator. 5. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody. 6. Any clinically significant abnormal findings in vital signs after at least 10 minutes of rest, defined as the following: * Systolic blood pressure \< 100 mmHg or \> 140 mmHg; * Diastolic blood pressure \< 50 mmHg or \> 90 mmHg; or * Pulse rate \< 50 or \> 85 beats per minute. 7. Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12 Lead ECG as considered by the investigator that may interfere with the interpretation of ECG interval measured from the onset of the QRS complex (electrical activity or ventricular contraction on the ECG where Q represents the downward deflection, R represents upward deflection and S represents a downward one) to the end of the T wave corrected for heart rate (QTc) interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy. 8. Prolonged QT interval corrected for heart rate using Fridericia's formula (QTcF) \> 450 ms or shortened QTcF \< 340 ms or family history of long QT syndrome. 9. PR (PQ) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular pre-excitation). 10. PR (PQ) interval prolongation \> 200 ms, intermittent second or third degree atrioventricular (AV) block (Wenckebach block while asleep is not exclusive), or AV dissociation. 11. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS \> 110 ms. Subjects with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation. 12. Known or suspected history of drug abuse, as judged by the investigator. 13. Current smokers or those who have smoked or used nicotine products within the 3 months before screening. 14. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the investigator. 15. Positive screen for drugs of abuse or cotinine at screening or on each admission to the study centre or positive screen for alcohol on each admission to the study unit. 16. 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 AZD7986. 17. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate,) as judged by the investigator. 18. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of AZD7986. 19. Use of any prescribed or non-prescribed medication including antacids and other drugs for gastric acid-related disorders, 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 AZD7986 or longer if the medication has a long half-life. Note: Hormonal replacement therapy is not allowed for females. 20. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening. 21. 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 AZD7986 in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest. Note: Subjects consented and screened, but not dosed in this study or a previous phase I study, are not excluded. 22. Subjects who have previously received AZD7986. 23. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives. 24. 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. 25. Subjects who cannot communicate reliably with the investigator. 26. Subjects who are vegans or have medical dietary restrictions. 27. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order. 28. Subject has increased risk of infection: * History and/or presence of tuberculosis (TB); positive result for interferon gamma release assay (IGRA) (i.e., QuantiFERON TB-Gold), subjects who have resided in regions where tuberculosis and mycosis are endemic during 90 days before screening, or who intend to visit such a region during the duration of the study i.e., deserts areas, Eastern Europe, Central and South America, Africa except Egypt, Russia, Asia, Indonesia. The test may be repeated if the initial test result is indeterminate. * Oral body temperature of \> 37.7°C on Day -1, or as judged by the investigator. * Blood neutrophil count \< 1.7 x109/L (Screening and Day -1 morning sample). * Is in high risk-group for HIV infection within the last 6 months (i.e., men who have had unprotected sex with men, women who have had sex without a condom with men who have sex with men, people who have had sex without a condom with a person who has lived or travelled in Africa, people who inject drugs, people who have had sex without a condom with somebody who has injected drugs, people who have caught another sexually transmitted infection, people who have received a blood transfusion while in Africa, Eastern Europe, the countries of the former Soviet Union, Asia or Central and Southern America). * Other latent or chronic infections (e.g., recurrent sinusitis, genital or ocular herpes, urinary tract infection) or at risk of infection (surgery, trauma, or significant infection) within 90 days of screening, or history of skin abscesses within 90 days of screening. * Clinically significant lower respiratory tract infection not resolved within 4 weeks prior to screening, as determined by the investigator. * Subjects with active malignancy or neoplastic disease in the previous 5 years other than superficial basal cell carcinoma. * Disease history suggesting abnormal immune function. * Subjects who have received live or live-attenuated vaccine in the 4 weeks prior to dosing. * High-sensitivity C-reactive protein above upper limit of laboratory reference range at screening and on Day -1. 29. Subjects with a history or signs of current gingivitis/periodontitis or a history or current hyperkeratosis of palms and soles will be excluded. (Due to the fact that many subjects lacking functional DPP1 enzyme have been described to have periodontitis and palmoplantar hyperkeratosis.) 30. Subjects with total urinary protein/urine creatinine ratio outside the normal range. 31. Drugs affecting CYP3A4 should be refrained from use for 3 weeks prior to study commencement and thereafter until study completion. In addition, the following is considered a criterion for the exclusion from the optional genetic component of the study: 32. History of bone marrow transplant 33. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection. 34. Hypersensitivity to the verapamil or to any of the excipients. 35. History of serious cardiac events such as myocardial infarction. 36. History of sino-atrial block; sick sinus syndrome; chronic or uncompensated heart failure (including left ventricular heart failure). 37. History of atrial flutter, atrial fibrillation or Wolff-Parkinson-White syndrome. 38. Known hypersensitivity to diltiazem or to any of the excipients. 39. Known hypersensitivity to itraconazole or to any of the excipients. 40. Elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-t]). | Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose | To assess the effect of Verapamil and Itraconazole on the PK of AZD7986. |
| Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax). | Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose | To assess the effect of Verapamil and Itraconazole on the PK of AZD7986. |
| Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC). | Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose | To assess the effect of verapamil and itraconazole on the PK of AZD7986. |
| Pharmacokinetics (PK) of AZD7986 by Assessment of Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz). | Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose | To assess the effect of Verapamil and Itraconazole on the PK of AZD7986. |
| Pharmacokinetics (PK) of AZD7986 by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax) | Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose | To assess the effect of Verapamil and Itraconazole on the PK of AZD7986. |
| Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F). | Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose | To assess the effect of Verapamil and Itraconazole on the PK of AZD7986. |
| Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F). | Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose | To assess the effect of Verapamil and Itraconazole on the PK of AZD7986. |
| Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC [0 - τ]) of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. | Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose | To assess the area under the plasma concentration-time curve from time over the dosing interval tau (24 hours) of Verapamil, itraconazole and OH-itraconazole (a metabolite of Itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole. |
| Assessment of the Tmax of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. | Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose | To assess the time to reach maximum observed concentration of Verapamil, Itraconazole and OH-itraconazole (a metabolite of itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole. |
Countries
United Kingdom
Participant flow
Recruitment details
This study was conducted at PAREXEL Early Phase Clinical Unit - London
Pre-assignment details
Fifteen healthy male subjects were enrolled in the study to assess the pharmacokinetics (PK) of AZD7986 when administered alone (Treatment Period 1) and in combination with multiple doses of verapamil (Treatment Period 2) and itraconazole (Treatment Period 3).
Participants by arm
| Arm | Count |
|---|---|
| All Participants All 15 participants who were enrolled in the study and who received at least a single dose of the study drug in three treatment periods in a fixed sequence and were separated by a washout period. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 33 Years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 15 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 | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 15 | 7 / 15 | 5 / 15 | 3 / 15 | 6 / 15 | 11 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC [0 - τ]) of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole.
To assess the area under the plasma concentration-time curve from time over the dosing interval tau (24 hours) of Verapamil, itraconazole and OH-itraconazole (a metabolite of Itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole.
Time frame: Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7986 | Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC [0 - τ]) of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. | 2178 h*nmol/L | Geometric Coefficient of Variation 44.7 |
| AZD7986 + Verapamil | Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC [0 - τ]) of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. | 18090 h*nmol/L | Geometric Coefficient of Variation 22.6 |
| AZD7986 + Itraconazole | Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC [0 - τ]) of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. | 31390 h*nmol/L | Geometric Coefficient of Variation 19.8 |
Primary
Assessment of the Tmax of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole.
To assess the time to reach maximum observed concentration of Verapamil, Itraconazole and OH-itraconazole (a metabolite of itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole.
Time frame: Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD7986 | Assessment of the Tmax of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. | 4.00 hours |
| AZD7986 + Verapamil | Assessment of the Tmax of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. | 1.50 hours |
| AZD7986 + Itraconazole | Assessment of the Tmax of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. | 5.00 hours |
Primary
Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC).
To assess the effect of verapamil and itraconazole on the PK of AZD7986.
Time frame: Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7986 | Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC). | 6697 h*nmol/L | Geometric Coefficient of Variation 44.8 |
| AZD7986 + Verapamil | Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC). | 8857 h*nmol/L | Geometric Coefficient of Variation 43.3 |
| AZD7986 + Itraconazole | Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC). | 7615 h*nmol/L | Geometric Coefficient of Variation 35.1 |
Comparison: The study was sized for Cmax primarily and not AUC. A two-sided 90% confidence interval for the ratio of AUC between the two treatments groups was used to determine equivalence.90% CI: [121.78, 143.64]ANOVA
Comparison: The study was sized for Cmax primarily and not AUC. A two-sided 90% confidence interval for the ratio of AUC between the two treatments groups was used to determine equivalence.90% CI: [104.69, 123.49]ANOVA
Primary
Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax).
To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time frame: Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7986 | Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax). | 385.8 nmol/L | Geometric Coefficient of Variation 27.4 |
| AZD7986 + Verapamil | Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax). | 591.9 nmol/L | Geometric Coefficient of Variation 27.1 |
| AZD7986 + Itraconazole | Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax). | 234.1 nmol/L | Geometric Coefficient of Variation 39 |
Comparison: The study was designed based on a test for bioequivalence. Using an estimated standard deviation for Cmax of AZD7986 of less than or equal to 0.202, 12 evaluable subjects were deemed needed to achieve a power of 90%, at an assumed ratio of 0.95, to show that a two-sided 90% confidence interval for the ratio of Cmax between 2 treatments (AZD7986 and AZD7986+ Verapamil/Itraconazole) would be contained within the (0.8;1.25) equivalence limit. 3 extra subjects were added to compensate for dropout.90% CI: [136.16, 172.83]ANOVA
Comparison: The study was designed based on a test for bioequivalence. Using an estimated standard deviation for Cmax of AZD7986 of less than or equal to 0.202, 12 evaluable subjects were deemed needed to achieve a power of 90%, at an assumed ratio of 0.95, to show that a two-sided 90% confidence interval for the ratio of Cmax between 2 treatments (AZD7986 and AZD7986+ Verapamil/Itraconazole) would be contained within the (0.8;1.25) equivalence limit. 3 extra subjects were added to compensate for dropout.90% CI: [53.84, 68.34]ANOVA
Primary
Pharmacokinetics (PK) of AZD7986 by Assessment of Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz).
To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time frame: Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD7986 | Pharmacokinetics (PK) of AZD7986 by Assessment of Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz). | 23.35 hours | Standard Deviation 5.731 |
| AZD7986 + Verapamil | Pharmacokinetics (PK) of AZD7986 by Assessment of Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz). | 20.36 hours | Standard Deviation 4.812 |
| AZD7986 + Itraconazole | Pharmacokinetics (PK) of AZD7986 by Assessment of Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz). | 27.89 hours | Standard Deviation 5.407 |
Primary
Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F).
To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time frame: Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD7986 | Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F). | 9.807 L/h | Standard Deviation 5.267 |
| AZD7986 + Verapamil | Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F). | 7.359 L/h | Standard Deviation 3.765 |
| AZD7986 + Itraconazole | Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F). | 8.308 L/h | Standard Deviation 3.452 |
Primary
Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F).
To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time frame: Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD7986 | Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F). | 297.1 Litres | Standard Deviation 83.48 |
| AZD7986 + Verapamil | Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F). | 194.6 Litres | Standard Deviation 41.68 |
| AZD7986 + Itraconazole | Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F). | 317.8 Litres | Standard Deviation 89.06 |
Primary
Pharmacokinetics (PK) of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-t]).
To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time frame: Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7986 | Pharmacokinetics (PK) of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-t]). | 6545 h*nmol/L | Geometric Coefficient of Variation 44.8 |
| AZD7986 + Verapamil | Pharmacokinetics (PK) of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-t]). | 8739 h*nmol/L | Geometric Coefficient of Variation 43.5 |
| AZD7986 + Itraconazole | Pharmacokinetics (PK) of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-t]). | 7361 h*nmol/L | Geometric Coefficient of Variation 34.4 |
Comparison: The study was sized for Cmax primarily and not AUC (0-t). A two-sided 90% confidence interval for the ratio of AUC (0-t) between the two treatments groups was used to determine equivalence.90% CI: [122.7, 145.29]ANOVA
Comparison: The study was sized for Cmax primarily and not AUC (0-t). A two-sided 90% confidence interval for the ratio of AUC (0-t) between the two treatments groups was used to determine equivalence.90% CI: [103.34, 122.37]ANOVA
Primary
Pharmacokinetics (PK) of AZD7986 by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax)
To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time frame: Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD7986 | Pharmacokinetics (PK) of AZD7986 by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax) | 0.75 hours |
| AZD7986 + Verapamil | Pharmacokinetics (PK) of AZD7986 by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax) | 1.50 hours |
| AZD7986 + Itraconazole | Pharmacokinetics (PK) of AZD7986 by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax) | 1.50 hours |