Drug-drug Interaction Between Rifampicin and Progestins/Ethinylestradiol and Midazolam

Bayer

Status and phase: Completed; Phase 1

Conditions: Biological Availability

Treatments: Drug: Midazolam/ Midazolam-ratiopharm; Drug: levonorgestrel/ Microlut; Drug: Desogestrel/ Cerazette; Drug: Norethindrone/ Noriday; Drug: Dienogest/ Visanne; Drug: Rifampicin; Drug: Drospirenone, Ethinylestradiol/ Yasmin

Study type: Interventional

Funder types: Industry

Identifiers

NCT03353857

19604

2017-002792-26 (EudraCT Number)

Details and patient eligibility

About

Quantify the effect of a probe CYP3A4 inducer (Rifampicin) on the pharmacokinetics of levonorgestrel, norethindrone, desogestrel, dienogest, drospirenone,estradiol and midazolam

Enrollment: 68 patients

Sex: Female

Ages: 45 to 70 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Healthy female subject based on a complete medical history, physical examination, ECG, and clinical laboratory tests

• Age: 45 to 70 years (inclusive) at the first screening visit

• Minimum body weight 50 kg with Body mass index (BMI) above or equal to 18.5 kg/m², and below or equal to 30 kg/m² at the first screening visit

• Postmenopausal state, revealed indicated by either:

  • medical history, if applicable (natural menopause at least 12 months prior to first study drug administration, for women younger than 60 years confirmed by follicle stimulating hormone (FSH) >40 IU/L AND estradiol ≤ 20 pg/mL; or
  • surgical menopause by bilateral ovariectomy at least 3 months prior to first study drug administration)

Exclusion criteria

• Relevant diseases within the last 4 weeks prior to the first study drug administration, i.e. any disease requiring treatment by a health-care provider
• Febrile illness within 1 week before the first study drug administration
• Known severe allergies, non-allergic drug reactions, or multiple drug allergies
• Presence or history of thrombosis, thrombophlebitis, thromboembolic diseases of veins and/or arteries, e.g. deep vein thrombosis, stroke, myocardial infarction, pulmonary embolism, transient ischemic attack, angina pectoris
• Presence or history of conditions that increase the risk of thromboembolic diseases, e.g. disturbances of the coagulation system, thromboembolic diseases in close relatives at age ≤50 years], valvular heart disease, atrial fibrillation, cardiac dysfunction)
• Presence, history, or suspected presence of malignant tumors or tumors of the liver and pituitary
• Presence or history of liver disease e.g. disturbances of the bilirubin excretion (Dubin-Johnson and Rotor syndromes), cholecystectomy ; cholestasis, idiopathic icterus or pruritus during a previous pregnancy or estrogen-progestogen treatment
• Relevant kidney diseases or renal injury associated with multisystem diseases/disorders, e.g. glomerulonephritis systemic lupus erythematous, diabetic nephropathy. A history of a single episode of uncomplicated nephrolithiasis does not prevent participation
• Known metabolic disorder, e.g. diabetes mellitus, severe hypertriglyceridemia
• Migraine with neurologic symptoms
• Clinically significant depression, current or in the last year
• Known current thyroid disorders which require treatment. Subjects with an euthyroid struma who do not need any treatment can participate.
• Chronic respiratory insufficiency
• History of porphyria
• Contraindications for midazolam, e.g. myasthenia gravis, and sleep apnea

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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68 participants in 5 patient groups

levonorgestrel

Experimental group

Description:

levonorgestrel and midazolam will be administered on Day 1, Day 15 and Day 26. rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.

Treatment:

Drug: Rifampicin

Drug: Midazolam/ Midazolam-ratiopharm

Drug: levonorgestrel/ Microlut

norethindrone

Experimental group

Description:

norethindrone and midazolam will be administered on Day 1, Day 15 and Day 26. rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.

Treatment:

Drug: Rifampicin

Drug: Norethindrone/ Noriday

Drug: Midazolam/ Midazolam-ratiopharm

desogestrel

Experimental group

Description:

desogestrel and midazolam will be administered on Day 1, Day 15 and Day 26. rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.

Treatment:

Drug: Rifampicin

Drug: Desogestrel/ Cerazette

Drug: Midazolam/ Midazolam-ratiopharm

dienogest

Experimental group

Description:

dienogest and midazolam will be administered on Day 1, Day 15 and Day 26. rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.

Treatment:

Drug: Rifampicin

Drug: Dienogest/ Visanne

Drug: Midazolam/ Midazolam-ratiopharm

Drospirenone/ ethinylestradiol

Experimental group

Description:

drospirenone/ethinylestradiol and midazolam will be administered on Day 1, Day 15 and Day 26. rifampicin (10 mg/day) will be administered on Day 8 to Day 18 and rifampicin (600 mg/day) on Day 19 to Day 29.

Treatment:

Drug: Rifampicin

Drug: Drospirenone, Ethinylestradiol/ Yasmin

Drug: Midazolam/ Midazolam-ratiopharm