Healthy
Conditions
Brief summary
The objective of the current study is to investigate if a drug-drug interaction occurs with the administration of omeprazole 80 mg q.d. at steady state on the pharmacokinetics of dipyridamole and the pharmacodynamics of ASA-induced platelet aggregation inhibition (components of Aggrenox®) when administered every 12 hours at steady state.
Detailed description
Purpose:
Interventions
DRUGAggrenox alone
Aggrenox 1 capsule twice daily for 7 days
DRUGAggrenox and omeprazole
Aggrenox 1 capsule twice daily and omeprazole 80mg once daily for 7 days
DRUGOmeprazole alone
omeprazole 80 once daily for 7 days
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (blood pressure(BP), pulse rate (PR)), 12-lead ECG, clinical laboratory tests 2. BMI \>18.5 and BMI \<32 kg/m2 (Body Mass Index)
Exclusion criteria
1. Any finding of the medical examination (including BP, PR and ECG) deviating from normal and of clinical relevance in the opinion of the PI 2. Any evidence of a clinically relevant concomitant disease 3. Clinically significant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, hormonal, or hematologic (including a history of abnormal bruising) disorders in the opinion of the PI 4. Surgery of the gastrointestinal tract that might impair drug absorption 5. Clinically significant diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders 6. History of relevant orthostatic hypotension, fainting spells or blackouts. 7. Chronic or relevant acute infections 8. History of relevant allergy/hypersensitivity (including allergy to study drugs or its excipients, or reactions to related drugs \[e.g., non-steroidal anti-inflammatory drugs\]) 9. Intake of drugs with a long half-life (¿24 hours) within one month, or less than 10 half lives of the respective drug, prior to study drug administration or during the trial 10. Use of drugs which might reasonably influence the results of the trial (including OTC antacids) based on the knowledge at the time of protocol preparation within 14 days prior to administration or during the trial 11. Participation in another trial with an investigational drug within two months prior to administration or during the trial 12. Tobacco use within the 90 days prior to check-in and throughout the study 13. Alcohol abuse within the past 2 years 14. Drug abuse within the past 2 years 15. Blood donation or other significant blood loss within 56 days (inclusive) prior to screening, or plasma donation within 7 days (inclusive) prior to study drug administration, or during the trial 16. Excessive physical activities (within one week prior to first drug administration or during the trial) 17. Any laboratory value outside the reference range that is of clinical relevance in the opinion of the PI; including positive virology, or urine drug screen, or positive fecal occult blood test 18. Inability to comply with dietary regimen of trial site 19. In the opinion of the investigator it would be in the best interest of the subject to be excluded from participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Dipyridamole Maximum Concentration (Cmax) | 7 days | Maximum measured concentration of dipyridamole in plasma |
| Plasma Dipyridamole Area Under Plasma Concentration-time Curve From Zero to 12 Hours (AUC0-12) | 7 days | Area under the concentration time curve of the analyte in plasma from 0 to 12 hours at steady state |
| Inhibition of Platelet Aggregation at 4 Hours Post Dose (IPA4) | 7 days | IPA4 equals the platelet aggregation measured 4 hours post dose divided by the platelet aggregation measured at baseline (multiplied by 100). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Dipyridamole Minimum Concentration (Cmin) | 7 days | Minimum measured concentration of dipyridamole in plasma |
| Inhibition of Platelet Aggregation at 12 Hours Post Dose (IPA12) | 7 days | IPA12 equals the platelet aggregation measured 12 hours post dose divided by the platelet aggregation measured at baseline (multiplied by 100). |
| Percentage Peak-to-trough Fluctuation (%PTF) | 7 days | PTF = 100\*((Cmax-Cmin)/Cavg) where Cavg=(AUC0-12)/12. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (7 Days) | Withdrawal by Subject | 1 | 0 |
| Follow-up Period (14 Days) | Withdrawal by Subject | 0 | 1 |
| Fourth Intervention (7 Days) | Withdrawal by Subject | 1 | 0 |
| Second Intervention (7 Days) | Adverse Event | 0 | 2 |
| Second Intervention (7 Days) | Withdrawal by Subject | 1 | 0 |
| Washout (14 Days) | Lost to Follow-up | 0 | 2 |
| Washout (14 Days) | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 35.3 years |
| Body Mass Index (BMI) | 26.81 kilograms per square meter |
| Ethnicity (NIH/OMB) Hispanic or Latino | 48 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Black / African American | 3 participants |
| Race/Ethnicity, Customized White | 57 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 42 Participants |
| Weight | 75.69 kilograms |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 41 / 56 | 15 / 55 | 17 / 57 | 48 / 57 |
| serious Total, serious adverse events | 0 / 56 | 0 / 55 | 0 / 57 | 0 / 57 |
Outcome results
Primary
Inhibition of Platelet Aggregation at 4 Hours Post Dose (IPA4)
IPA4 equals the platelet aggregation measured 4 hours post dose divided by the platelet aggregation measured at baseline (multiplied by 100).
Time frame: 7 days
Population: The pharmacokinetic data set (PK set) and the pharmacodynamic data set (PD set) include all treated subjects with data that do not have a relevant protocol violation (relevant to PK or PD). No data collected for Omeprazole arm since no platelet inhibition was expected for this treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aggrenox Alone BID | Inhibition of Platelet Aggregation at 4 Hours Post Dose (IPA4) | 97.89 percent of baseline platelet aggregation | Standard Deviation 2.74 |
| Aggrenox BID Plus Omeprazole QD Following Aggrenox Alone | Inhibition of Platelet Aggregation at 4 Hours Post Dose (IPA4) | 96.34 percent of baseline platelet aggregation | Standard Deviation 4.21 |
| Aggrenox BID Plus Omeprazole QD Following Omeprazole Alone | Inhibition of Platelet Aggregation at 4 Hours Post Dose (IPA4) | 97.02 percent of baseline platelet aggregation | Standard Deviation 2.69 |
Comparison: Comparison of Aggrenox + Omeprazole following Omeprazole versus Aggrenox alone90% CI: [98.32, 99.72]
Comparison: Comparison of Aggrenox + Omeprazole following Aggrenox versus Aggrenox alone90% CI: [97.66, 99.18]
Primary
Plasma Dipyridamole Area Under Plasma Concentration-time Curve From Zero to 12 Hours (AUC0-12)
Area under the concentration time curve of the analyte in plasma from 0 to 12 hours at steady state
Time frame: 7 days
Population: The pharmacokinetic data set (PK set) and the pharmacodynamic data set (PD set) include all treated subjects with data that do not have a relevant protocol violation (relevant to PK or PD). No data collected for Omeprazole arm since no plasma dipyridamole was expected for this treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Aggrenox Alone BID | Plasma Dipyridamole Area Under Plasma Concentration-time Curve From Zero to 12 Hours (AUC0-12) | 17100 (nanogram/milliliter)*hours | Geometric Coefficient of Variation 33.7 |
| Aggrenox BID Plus Omeprazole QD Following Aggrenox Alone | Plasma Dipyridamole Area Under Plasma Concentration-time Curve From Zero to 12 Hours (AUC0-12) | 16700 (nanogram/milliliter)*hours | Geometric Coefficient of Variation 28.4 |
| Aggrenox BID Plus Omeprazole QD Following Omeprazole Alone | Plasma Dipyridamole Area Under Plasma Concentration-time Curve From Zero to 12 Hours (AUC0-12) | 16500 (nanogram/milliliter)*hours | Geometric Coefficient of Variation 31.1 |
Comparison: Comparison of Aggrenox + Omeprazole following Omeprazole versus Aggrenox alone90% CI: [90.96, 102.13]
Comparison: Comparison of Aggrenox + Omeprazole following Aggrenox versus Aggrenox alone95% CI: [93.26, 100.95]
Primary
Plasma Dipyridamole Maximum Concentration (Cmax)
Maximum measured concentration of dipyridamole in plasma
Time frame: 7 days
Population: The pharmacokinetic data set (PK set) and the pharmacodynamic data set (PD set) include all treated subjects with data that do not have a relevant protocol violation (relevant to PK or PD). No data collected for Omeprazole arm since no plasma dipyridamole was expected for this treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Aggrenox Alone BID | Plasma Dipyridamole Maximum Concentration (Cmax) | 2750 nanogram/milliliter | Geometric Coefficient of Variation 30.4 |
| Aggrenox BID Plus Omeprazole QD Following Aggrenox Alone | Plasma Dipyridamole Maximum Concentration (Cmax) | 2550 nanogram/milliliter | Geometric Coefficient of Variation 27.5 |
| Aggrenox BID Plus Omeprazole QD Following Omeprazole Alone | Plasma Dipyridamole Maximum Concentration (Cmax) | 2550 nanogram/milliliter | Geometric Coefficient of Variation 29.1 |
Comparison: Comparison of Aggrenox + Omeprazole following Omeprazole versus Aggrenox alone90% CI: [86.95, 97.4]
Comparison: Comparison of Aggrenox + Omeprazole following Aggrenox versus Aggrenox alone90% CI: [87.76, 97.08]
Secondary
Inhibition of Platelet Aggregation at 12 Hours Post Dose (IPA12)
IPA12 equals the platelet aggregation measured 12 hours post dose divided by the platelet aggregation measured at baseline (multiplied by 100).
Time frame: 7 days
Population: The pharmacokinetic data set (PK set) and the pharmacodynamic data set (PD set) include all treated subjects with data that do not have a relevant protocol violation (relevant to PK or PD). No data collected for Omeprazole arm since no platelet inhibition was expected for this treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aggrenox Alone BID | Inhibition of Platelet Aggregation at 12 Hours Post Dose (IPA12) | 98.78 percent of baseline platelet aggregation | Standard Deviation 2.53 |
| Aggrenox BID Plus Omeprazole QD Following Aggrenox Alone | Inhibition of Platelet Aggregation at 12 Hours Post Dose (IPA12) | 97.80 percent of baseline platelet aggregation | Standard Deviation 3 |
| Aggrenox BID Plus Omeprazole QD Following Omeprazole Alone | Inhibition of Platelet Aggregation at 12 Hours Post Dose (IPA12) | 98.11 percent of baseline platelet aggregation | Standard Deviation 2.98 |
Comparison: Comparison of Aggrenox + Omeprazole following Omeprazole versus Aggrenox alone90% CI: [98.8, 99.95]
Comparison: Comparison of Aggrenox + Omeprazole following Aggrenox versus Aggrenox alone90% CI: [98.46, 99.59]
Secondary
Percentage Peak-to-trough Fluctuation (%PTF)
PTF = 100\*((Cmax-Cmin)/Cavg) where Cavg=(AUC0-12)/12.
Time frame: 7 days
Population: The pharmacokinetic data set (PK set) and the pharmacodynamic data set (PD set) include all treated subjects with data that do not have a relevant protocol violation (relevant to PK or PD). No data collected for Omeprazole arm since no plasma dipyridamole was expected for this treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aggrenox Alone BID | Percentage Peak-to-trough Fluctuation (%PTF) | 144 percent of average hourly plasma conc. | Standard Deviation 31.8 |
| Aggrenox BID Plus Omeprazole QD Following Aggrenox Alone | Percentage Peak-to-trough Fluctuation (%PTF) | 132 percent of average hourly plasma conc. | Standard Deviation 41.4 |
| Aggrenox BID Plus Omeprazole QD Following Omeprazole Alone | Percentage Peak-to-trough Fluctuation (%PTF) | 134 percent of average hourly plasma conc. | Standard Deviation 41.2 |
Secondary
Plasma Dipyridamole Minimum Concentration (Cmin)
Minimum measured concentration of dipyridamole in plasma
Time frame: 7 days
Population: The pharmacokinetic data set (PK set) and the pharmacodynamic data set (PD set) include all treated subjects with data that do not have a relevant protocol violation (relevant to PK or PD). No data collected for Omeprazole arm since no plasma dipyridamole was expected for this treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Aggrenox Alone BID | Plasma Dipyridamole Minimum Concentration (Cmin) | 679 nanogram/milliliter | Geometric Coefficient of Variation 47.1 |
| Aggrenox BID Plus Omeprazole QD Following Aggrenox Alone | Plasma Dipyridamole Minimum Concentration (Cmin) | 723 nanogram/milliliter | Geometric Coefficient of Variation 41.8 |
| Aggrenox BID Plus Omeprazole QD Following Omeprazole Alone | Plasma Dipyridamole Minimum Concentration (Cmin) | 713 nanogram/milliliter | Geometric Coefficient of Variation 46.5 |
Comparison: Comparison of Aggrenox + Omeprazole following Omeprazole versus Aggrenox alone90% CI: [97.09, 114.74]
Comparison: Comparison of Aggrenox + Omeprazole following Aggrenox versus Aggrenox alone90% CI: [98.64, 114.09]