only healthy volunteers
Conditions
Interventions
Group 1: Ritonavir 100 mg p.o. b.i.d. for 5 days.
Cocktail of 25 µg Rivaroxaban, 25 µg Apixaban und 50µg Edoxaban per os before and at the fifth day of ritonavir intake.
10 µg Midazolam, 50 µg Yohimbi
Sponsors
Universitätsklinikum Heidelberg
Eligibility
Sex/Gender
All
Age
18 Years to 60 Years
Inclusion criteria
Inclusion criteria: 1. Age 18-60 years (y) inclusive at the time of consent, 2. Men or women of child-bearing potential who are willing to use contraception as detailed for each arm or women not of child-bearing potential (WNCBP), or individuals who are convincingly sexually abstinent, hormonal contraceptives (except uterine devices) are not allowed as pregnancy prevention method, 3. Understanding, ability, and willingness to fully comply with trial interventions and restrictions, 4. Ability to provide written, personally signed and dated informed consent to participate in the trial, in accordance with the International Councilon Harmonization (ICH) Good Clinical Practice (GCP) Guideline E6, and applicable regulations, prior to any trial-related interventions, and 5. Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2) immunity as defined by pertinent national regulations. This currently includes a completed SARS-CoV2 vaccination status or a history of confirmed prior COVID disease within 6 months, or COVID disease > 6 months plus subsequent vaccination. Pertinent current national rules for definition of SARS-CoV2 immunity will be followed and may change during the trial.
Exclusion criteria
Exclusion criteria: At the time of SCR: 1. Clinically significant or relevant abnormalities in medical history, physical examination, and laboratory evaluation as assessed by the investigator, 2. Any medical disorder that may require treatment or make the participant unlikely to fully complete the trial, or any condition that presents undue risk from the IMPs or trial interventions, 3. Clinically relevant ongoing or clinically relevant history of physical or psychiatric illness as judged by the investigator, 4. Pregnancy or breast feeding, 5. Any acute or chronic illness or clinically relevant finding known or expected to modify absorption, distribution, metabolism, or excretion of the investigated drugs, 6. Any known history of severe allergic or anaphylactic reactions to drugs or any other clinically significant allergies, 7. Any known allergies to the IMP ritonavir or midazolam, 8. Relevant past or current hepatic dysfunction 9. History of benzodiazepine dependence 10. Past or current myasthenia gravis, severe respiratory insufficiency or sleep apnea syndrome 11. Clinically relevant findings in any of the following investigations at SCR. Minor deviations from the normal range can be acceptable, if judged by the investigator to be of no clinical relevance for this trial • Hemoglobin (Hb) upper limit of normal (ULN) x 1.2, In case of suspected Gilbert’s disease: non-fasting total bilirubin = ULN x 1.2 and fasting total bilirubin = ULN x 1.5 are acceptable. • Alanine aminotransferase (ALT) > ULN x 1.1, • Aspartate aminotransferase (AST) > ULN x 1.2, • Creatine kinase (CK) not within normal limits (Volunteers with CK elevations between ULN and ULN x 3 may be included if troponin T is negative), if CK is elevated after physical activity a reassessment of CK is allowed, and • Thyroid stimulating hormone (TSH) not within normal limits. 12. A positive result in the drug screen test at SCR, 13. A positive human immunodeficiency virus (HIV) antibody screen (HIV) or hepatitis B (HBV) or hepatitis C (HCV) antibody screen, 14. A prior SARS-CoV2 vaccination within < 2 weeks before the baseline visit or any plans to get vaccinated during the expected trial duration trial, 15. Any intake of substances (prescription medication, over-thecounter medicine, or herbal preparations with active ingredients) known to inhibit drug metabolizing enzymes or transport enzymes within a period of less than 5 times the respective elimination halflife (t1/2) with regard to the expected date of first dose of IMP (except hormonal contraception, iodine, and levothyroxine), 16. Any intake of substances (prescription medication, over-thecounter medicine, or herbal preparations with active ingredients) known to induce drug metabolizing enzymes or transport enzymes within a period of 14 days with regard to the expected date of first dose of IMP, 17. Consumption of grapefruit within 7 d prior to the expected date of first dose of IMP and expected noncompliance to refrain from grapefruit intake until the last visit of this trial. Minor intake of grapefruit may be accepted, if judged by the investigator to have no impact on metabolism, 18. Unable to refrain from smoking during study days, 19. Pathologic alcohol consumption, 20. Use of an IMP within 30 d prior to the expected date of receiving the first dose of IMP or active enrolment in another drug or vaccine clinical trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Geometric mean ratios of AUC0-24h and Cmax of victim drugs before, during, and after short-term low-dose therapy with ritonavir: • Arm A: 25 µg apixaban, 50 µg edoxaban, 25 µg rivaroxaban • Arm B: 10 mg atorvastatin • Arm C: 10 mg rosuvastatin. | — |
Secondary
| Measure | Time frame |
|---|---|
| Geometric mean ratios of AUC0-8 of victim drugs before, during, and after short-term low-dose therapy with ritonavir • Standard non-compartmental PK parameters of all victim drugs • Frequency, severity, seriousness, relatedness, expectedness, and outcome of adverse events under trial medication. Additional secondary endpoints only for Arm A • AUC2-4 of midazolam microdose before, during, and after a short-term low-dose therapy with ritonavir, • AUC0.5-4h of a 50 µg yohimbine microdose before, during, and after a short-term low-dose therapy with ritonavir, • Hydroxylation index at 3 h of a 100 µg omeprazole microdose before, during a short-term low-dose therapy with ritonavir (100 mg p.o. b.i.d.), and thereafter | — |
Countries
Germany
Outcome results
None listed