Effect of Tipranavir and Ritonavir on the Pharmacokinetic Characteristics of Norethindrone-Ethinyl Estradiol in Healthy Female Adult Volunteers

A Single Centre, Open-label, Randomized, Parallel Group, Multiple Dose Comparison of the Effect of TPV 750 mg and RTV 200 mg or TPV 500 mg and RTV 100 mg, Administered Twice Daily, on the Pharmacokinetic Characteristics of Norethindrone-Ethinyl Estradiol (Ortho®-1/35 ) Administered as a Single Dose, in Healthy Female Adult Volunteers.

Study to characterize the effects of two dose combinations of Tipranavir (TPV)/Ritonavir (RTV) (TPV 750 mg/RTV 200 mg and TPV 500 mg/RTV 100 mg), administered twice-daily, on the pharmacokinetics of Norethindrone-Ethinyl Estradiol (NET/EE) 1 mg/ 0.035 mg administered as a single dose.

Study Overview

• Status: Terminated
• Conditions: Healthy
• Intervention / Treatment: Drug: Tipranavir low dose; Drug: Ritonavir high dose; Drug: Ritonavir low dose; Drug: Tipranavir high dose; Drug: Norethindrone-Ethinyl Estradiol

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Female subjects between 18 and 50 years of age inclusive
2. A Body Mass Index (BMI) between 18 and 29 kg/m2
3. Signed informed consent prior to trial participation
4. Ability to swallow numerous large capsules without difficulty
5. Acceptable laboratory values that indicate adequate baseline organ function are required at the time of screening. Laboratory values are considered to be acceptable if severity is less than or equal to Grade 1, based on the AIDS Clinical Trials Group Grading Scale. All abnormal laboratory values greater than Grade 1 are subject to approval by the trial clinical monitor.
6. Acceptable medical history, physical examination and ECG, and chest X-ray (if not conducted within the last 12 months) are required prior to entering the treatment phase of the study
7. Willingness to abstain from alcohol for 48 hours prior to Study Day 0 and abstain from alcohol for the duration of the study. In addition, red wine must not have been ingested within 5 days prior to Day 0 (Visit 2)
8. Willingness to abstain from ingesting grapefruit, grapefruit juice, or products containing grapefruit juice, within 10 days before Day 0, Visit 2 and for the duration of the study
9. Willingness to abstain from ingesting Seville oranges, garlic supplements, St. John's Wort, Milk Thistle, or methylxanthine-containing drinks or food (coffee, tea, cola, energy drinks, chocolate, etc) within 5 days of Day 0, Visit 2 and for the duration of the study
10. Willingness to abstain from over the counter herbal medications for the duration of the study
11. Reasonable probability for completion of the study

Exclusion Criteria:

1. Female subjects who are of reproductive potential who:

   • Have positive serum beta-human chorionic gonadotropin at Visit 1, or on Day 0 or Day 1
   • Have not been using a barrier contraceptive method for at least 3 months prior to Visit 3 (Day 1)
   • Are not willing to use a reliable method of double-barrier contraception (such as diaphragm with spermicidal cream/jelly or condoms with spermicidal foam), during the trial and 30 days after completion/termination
   • Are breast-feeding
2. Participation in another trial with an investigational medicine within 30 days prior to Day 0 (Visit 2)
3. Use of any medication listed in the protocol within 30 days prior to Day 0 (Visit 2)
4. Use of any other pharmacological contraceptive (including oral, patch or injectable contraceptives) for 1 month prior to study initiation and for the duration of the study
5. Administration of antibiotics within 10 days prior to Day 0 (Visit 2) or during the trial
6. History of central nervous system (CNS), gastrointestinal, hepatic, or renal disorders within the past sixty (60) days. Subjects will be excluded for these disorders greater than sixty days if, in the opinion of the investigator, the subject does not qualify as a healthy volunteer
7. History of thrombotic disease
8. History of migraine headache
9. Have serological evidence of hepatitis B or C virus
10. Have serological evidence of exposure to HIV
11. Recent history of alcohol or substance abuse (within 6 months of study period)
12. Cigarette smoking (greater than 10 cigarettes per day)
13. Blood or plasma donations within 30 days prior to Day 0 (Visit 2) or during the trial.
14. Subjects with a seated systolic blood pressure either <100 mm Hg or >150 mm Hg; resting heart rate either <50 beats/min or >90 beats/min. For subjects with a resting heart rate below 50, due to a high fitness level, the investigator may discuss exclusion with the medical monitor on a case-by-case basis
15. Subjects with a history of any illness or allergy that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering Tipranavir, Ritonavir or NET/EE to the subject
16. Subjects who have had an acute illness within 2 weeks prior to Day 0 (Visit 2)
17. Subjects who are currently taking any over-the-counter drug within 7 days prior to Day 0,(Visit 2) or who are currently taking any prescription drug that, in the opinion of the investigator in consultation with the clinical monitor, might interfere with either the absorption, distribution or metabolism of the test substances
18. Known hypersensitivity to TPV, RTV, or NET/EE
19. Inability to comply with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TPV/RTV low dose	Drug: Tipranavir low dose; Drug: Ritonavir low dose; Other Names: Norvir-SEC®; Drug: Norethindrone-Ethinyl Estradiol; Other Names: Ortho®-1/35
Experimental: TPV/RTV high dose	Drug: Ritonavir high dose; Other Names: Norvir-SEC®; Drug: Tipranavir high dose; Drug: Norethindrone-Ethinyl Estradiol; Other Names: Ortho®-1/35

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area under plasma concentration time curve	up to day 17
Maximum plasma concentration of the analyte	up to day 17
Drug concentration of the analyte in plasma at 12 hours after administration	up to day 17

Secondary Outcome Measures

Outcome Measure	Time Frame
Oral clearance of the analyte	up to day 17
Time of maximum concentration of the analyte	up to day 17
Apparent terminal half life of the analyte	up to day 17
Number of subjects with adverse events	up to 45 days
Number of subject with clinically relevant changes in laboratory parameters	up to 17 days

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: May 1, 2002
• Primary Completion (Actual): June 1, 2002

Study Registration Dates

• First Submitted: September 18, 2014
• First Submitted That Met QC Criteria: September 18, 2014
• First Posted (Estimate): September 19, 2014

Study Record Updates

• Last Update Posted (Estimate): September 19, 2014
• Last Update Submitted That Met QC Criteria: September 18, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Estrogens; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; HIV Protease Inhibitors; Viral Protease Inhibitors; Contraceptives, Oral, Hormonal; Ritonavir; Estradiol; Ethinyl Estradiol; Tipranavir; Norethindrone; Norethindrone Acetate; Norinyl
• Other Study ID Numbers: 1182.22