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

NCT03353857 | Completed Phase 1

• 2 other identifiers: 196042017-002792-26
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 2

Brief Summary

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

Conditions

Biological Availability

Outcome Measures

Primary Outcomes (14)

• Area under the plasma concentration time curve from zero to infinity (AUC) of levonorgestrel in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Maximum plasma concentration (Cmax) of levonorgestrel in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Area under the plasma concentration time curve from zero to infinity (AUC) of norethindrone in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Maximum plasma concentration (Cmax) of norethindrone in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Area under the plasma concentration time curve from zero to infinity (AUC) of etonogestrel in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Maximum plasma concentration (Cmax) of etonogestrel in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Area under the plasma concentration time curve from zero to infinity (AUC) of dienogest in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Maximum plasma concentration (Cmax) of dienogest in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Area under the plasma concentration time curve from zero to infinity (AUC) of drospirenone (+EE) in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Maximum plasma concentration (Cmax) of drospirenone (+EE) in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Area under the plasma concentration time curve from zero to infinity (AUC) of ethinylestradiol (+DRSP) in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Maximum plasma concentration (Cmax) of ethinylestradiol (+DRSP) in the presence of MDZ (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Area under the plasma concentration time curve from zero to infinity (AUC) of midazolam in combination with the hormonal contraceptive only (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

• Maximum plasma concentration (Cmax) of midazolam in combination with the hormonal contraceptive only (without RIF) and in combination with 10 mg/d and 600 mg/d RIF

  Over 7 days in Period 1 (no RIF) and 4 days in treatment Periods 2 and 3

Study Arms (5)

levonorgestrel

EXPERIMENTAL

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.

Drug: levonorgestrel/ Microlut; Drug: Midazolam/ Midazolam-ratiopharm; Drug: Rifampicin

norethindrone

EXPERIMENTAL

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.

Drug: Norethindrone/ Noriday; Drug: Midazolam/ Midazolam-ratiopharm; Drug: Rifampicin

desogestrel

EXPERIMENTAL

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.

Drug: Desogestrel/ Cerazette; Drug: Midazolam/ Midazolam-ratiopharm; Drug: Rifampicin

dienogest

EXPERIMENTAL

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.

Drug: Dienogest/ Visanne; Drug: Midazolam/ Midazolam-ratiopharm; Drug: Rifampicin

Drospirenone/ ethinylestradiol

EXPERIMENTAL

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.

Drug: Drospirenone, Ethinylestradiol/ Yasmin; Drug: Midazolam/ Midazolam-ratiopharm; Drug: Rifampicin

Interventions

levonorgestrel/ Microlut DRUG

In Period 1, 0.03 mg single dose administered as 1x0.03 mg tablet on Study Day 1, In Period 2, 0.03 mg single dose administered as 1x0.03 mg tablet on Study Day 15 In Period 3, 0.03 mg single dose administered as 1x0.03 mg tablet at Study Day 26

levonorgestrel

Norethindrone/ Noriday DRUG

In Period 1, 0.35 mg single dose administered as 1x0.35 mg tablet on Study Day 1, In Period 2, 0.35 mg single dose administered as 1x0.35 mg tablet on Study Day 15 In Period 3, 0.35 mg single dose administered as 1x0.35 mg tablet at Study Day 26

norethindrone

Desogestrel/ Cerazette DRUG

In Period 1, 0.075 mg single dose administered as 1x0.075 mg tablet on Study Day 1, In Period 2, 0.075 mg single dose administered as 1x0.075 mg tablet on Study Day 15 In Period 3, 0.075 mg single dose administered as 1x0.075 mg tablet at Study Day 26

desogestrel

Dienogest/ Visanne DRUG

In Period 1, 2 mg single dose administered as 1x2 mg tablet on Study Day 1, In Period 2, 2 mg single dose administered as 1x2 mg tablet on Study Day 15 In Period 3, 2 mg single dose administered as 1x2 mg tablet at Study Day 26

dienogest

Drospirenone, Ethinylestradiol/ Yasmin DRUG

In Period 1, 3 mg drospirenone, 0.03 mg ethinylestradiol single dose administered as 1x3mg drospirenone, 0.03 mg ethinylestradiol tablet on Study Day 1, In Period 2, 3 mg drospirenone, 0.03 mg ethinylestradiol single dose administered as 1x3mg drospirenone, 0.03 mg ethinylestradiol tablet on Study Day 15, In Period 3, 3 mg drospirenone, 0.03 mg ethinylestradiol single dose administered as 1x3mg drospirenone, 0.03 mg ethinylestradiol tablet on Study Day 26,

Drospirenone/ ethinylestradiol

Midazolam/ Midazolam-ratiopharm DRUG

In Period 1, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 1, In Period 2, 1 mg single dose administered as 1x0.5 ml oral solution on Study Day 15 In Period 3, 1 mg single dose administered as 1x0.5 ml oral solution at Study Day 26

Drospirenone/ ethinylestradiol; desogestrel; dienogest; levonorgestrel; norethindrone

Rifampicin DRUG

In period 2, 10 mg (suspension, 0.5 ml) for 11 days at 10 mg/day In period 3, 600 mg (film-coated tablets) for 11 days at 600 mg/day

Drospirenone/ ethinylestradiol; desogestrel; dienogest; levonorgestrel; norethindrone

Eligibility Criteria

• Age: 45 Years - 70 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Bayer: lead

Study Sites (2)

CRS Clinical-Research-Services Mannheim GmbH

Mannheim, Baden-Wurttemberg, 68167, Germany

Location

CRS Clinical-Research-Services Mönchengladbach GmbH

Mönchengladbach, North Rhine-Westphalia, 41061, Germany

Location

Related Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.
• Click here to find results for studies related to Bayer Healthcare products.

MeSH Terms

Interventions

Levonorgestrel; Norethindrone; Desogestrel; dienogest; drospirenone; Ethinyl Estradiol; drospirenone and ethinyl estradiol combination; Midazolam; Rifampin

Intervention Hierarchy (Ancestors)

Norgestrel; Norpregnenes; Norpregnanes; Norsteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Norpregnatrienes; Estrogenic Steroids, Alkylated; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2017
• First Posted: November 27, 2017
• Study Start: November 29, 2017
• Primary Completion: July 4, 2018
• Study Completion: February 19, 2019
• Last Updated: April 15, 2020

Record last verified: 2020-04

Locations

DE (2)