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

Biological Availability Clinical Trial

Official title:

Open-label, Randomized, Fixed Sequence Cross-over Study With Five Parallel Treatment Arms and Three Treatment Periods to Quantify the Drug-drug Interactions of Two Rifampicin Dose Strengths on Four Progestins and a Fixed Progestin-ethinylestradiol Combination Compared With Midazolam in Healthy Post-menopausal Women

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03353857
• Other study ID #: 19604
• Secondary ID: 2017-002792-26
• Status: Completed
• Phase: Phase 1
• Start date: November 29, 2017
• Est. completion date: February 19, 2019

Study information

• Verified date: April 2020
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: February 19, 2019
• Est. primary completion date: July 4, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 45 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Biological Availability

Intervention

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

Locations

Country	Name	City	State
Germany	CRS Clinical-Research-Services Mannheim GmbH	Mannheim	Baden-Württemberg
Germany	CRS Clinical-Research-Services Mönchengladbach GmbH	Mönchengladbach	Nordrhein-Westfalen

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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

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