A Study to Determine the Effects of PF-04965842 on the Pharmacokinetics of Oral Contraceptive Steroids in Healthy Female Subjects
A Study to Determine the Effects of PF-04965842 on the Pharmacokinetics of Oral Contraceptive Steroids in Healthy Female Subjects
This is a Phase 1, randomized, 2 way crossover, open-label study of the effect of
 multiple-dose PF 04965842 on single-dose OC PK in healthy female subjects. Subjects will be
 randomized to 1 of 2 treatment sequences. A total of 16 healthy female subjects (8 in each
 treatment sequence) will be enrolled in the study. Each treatment sequence will consist of 2
 periods.
In Treatment Sequence 1, Period 1 Day 1, subjects will be dosed with a single administration
 of OC in the form of 1 PORTIA (ethyinyl estradiol [EE] and levonorgestrel [LN]) or equivalent
 tablet, orally. OC (EE and LN) PK will then be assessed at pre dose and over 48 hours after
 OC dosing. Period 1 will be immediately followed by Period 2 with no washout. The 48 hours
 post-OC dose PK sample for Period 1 must be collected prior to receiving the first dose of PF
 04965842 in Period 2. In Period 2, subjects will be dosed with 200 mg PF 04965842 PO QD for 9
 days followed by administration of a single dose of OC oral tablet immediately after
 administration of a 200 mg dose of PF-04965842 on the morning of Day 10. OC PK in Period 2
 will be assessed at pre dose and over 48 hours after OC dosing. Dosing with 200 mg PF
 04965842 PO QD will continue until Day 11.

 In Treatment Sequence 2, Period 1, subjects will be dosed with 200 mg PF 04965842 PO QD for 9
 days followed by administration of a single dose of OC oral tablet immediately after
 administration of a 200 mg dose of PF-04965842 on the morning of Day 10. OC PK will be
 assessed at pre dose and over 48 hours following OC dosing. Dosing with 200 mg PF 04965842 PO
 QD will continue until Day 11. Subjects will then undergo a washout period of at least 10
 days (Day -1 of Period 2 starts 10 days after Day 12 of Period 1). In Period 2 subjects will
 be dosed with a single OC administration on Day 1. OC PK will then be assessed at pre dose
 and over 48 hours after OC dose.
Inclusion Criteria:

 -  Healthy female subjects of both childbearing and non-childbearing potential who, at
 the time of Screening, are between the ages of 18 and 55 years, inclusive. Healthy is
 defined as no clinically relevant abnormalities identified by a detailed medical
 history, full physical examination, including blood pressure (BP) and pulse rate
 measurement, 12 lead ECG, or clinical laboratory tests.

 Female subjects of non-childbearing potential must meet at least 1 of the following
 criteria:

 1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at
 least 12 consecutive months with no alternative pathological or physiological cause; a
 serum follicle stimulating hormone (FSH) level confirming the postmenopausal state;

 2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;

 3. Have medically confirmed ovarian failure. All other female subjects (including female
 subjects with tubal ligations) are considered to be of childbearing potential.

 -  Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110
 lb).

 -  Evidence of a personally signed and dated informed consent document indicating
 that the subject has been informed of all pertinent aspects of the study.

 -  Subjects who are willing and able to comply with all scheduled visits, treatment
 plan, laboratory tests, and other study procedures.

 Exclusion Criteria:

 -  Evidence or history of clinically significant hematological, renal, endocrine,
 pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological,
 gynecologic or allergic disease (including drug allergies, but excluding untreated,
 asymptomatic, seasonal allergies at the time of dosing).

 -  Evidence of acute exacerbation of dermatological condition (eg, AD or psoriasis) or
 visible rash present during physical examination.

 -  Subjects, who according to the product label for OC, would be at increased risk if
 dosed with OC.

 Based on PORTIA product label, combination OCs should not be used in women with any of the
 following conditions:

 1. Thrombophlebitis or thromboembolic disorders.

 2. A past history of deep-vein thrombophlebitis or thromboembolic disorders.

 3. Cerebral-vascular or coronary artery disease.

 4. Thrombogenic valvulopathies.

 5. Thrombogenic rhythm disorders.

 6. Diabetes mellitus with vascular involvement.

 7. Uncontrolled hypertension.

 8. Known or suspected carcinoma of the breast.

 9. Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia.

 10. Undiagnosed abnormal genital bleeding.

 11. Cholestatic jaundice of pregnancy or jaundice with prior pill use.

 12. Hepatic adenomas or carcinomas, or active liver disease, as long as liver function has
 not returned to normal.

 13. Known or suspected pregnancy.

 14. Hypersensitivity to any of the components of Portia (LN and EE tablets).

 15. Are receiving Hepatitis C drug combinations containing
 ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for
 alanine aminotransferase (ALT) elevations.

 -  Any condition possibly affecting drug absorption (eg, gastrectomy).

 -  A positive urine drug test.

 -  History of regular alcohol consumption exceeding 7 drinks/week for female
 subjects (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or
 1.5 ounces [45 mL] of hard liquor) within 6 months before Screening.

 -  Treatment with an investigational drug within 30 days (or as determined by the
 local requirement) or 5 half lives preceding the first dose of investigational
 product (whichever is longer).

 -  Screening supine systolic BP <90 mm Hg or 140 mm Hg following at least 5 minutes
 of supine rest or Screening supine diastolic BP <50 mm Hg or 90 mm Hg following
 at least 5 minutes of supine rest.

 If a subject meets any of these criteria, the BP should be repeated 2 more times and the
 average of the 3 BP values should be used to determine the subject's eligibility.

 -  Screening supine 12 lead ECG demonstrating a corrected QT (QTc) interval >450 msec or
 a QRS interval >120 msec. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG
 should be repeated 2 more times and the average of the 3 QTc or QRS values should be
 used to determine the subject's eligibility.

 -  Subjects with ANY of the following abnormalities in clinical laboratory tests at
 Screening, as assessed by the study specific laboratory and confirmed by a single
 repeat test, if deemed necessary:

 -  Aspartate aminotransferase (AST) or ALT level >= 1.5 × upper limit of normal
 (ULN);

 -  Total bilirubin (TBili) level > 1 × ULN;

 -  Use of CYP2C19 inhibitors (eg, fluconazole, fluoxetine, fluvoxamine, ticlopidine
 omeprazole, voriconazole, cimetidine, esomeprazole, and felbamate) or inducers (eg,
 rifampin, ritonavir, efavirenz, enzalutamide, phenytoin, and St. John's Wort) within
 28 days or 5 half-lives (whichever is longer) prior to dosing.

 -  Use of CYP2C9 inhibitors (eg, amiodarone, felbamate, fluconazole, miconazole,
 piperine, diosmin, disulfiram, fluvastatin, fluvoxamine, voriconazole, efavirenz,
 isoniazid) or inducers (eg, aprepitant, carbamazepine, enzalutamide, rifampin,
 ritonavir, nevirapine, phenobarbital, and St. John's Wort) within 28 days or 5
 half-lives (whichever is longer) prior to dosing.

 -  Use of CYP3A4 inhibitors (eg, ketoconazole, ciprofloxacin, diltiazem) or other
 inducers (eg, phenytoin, carbamazepine) within 28 days or 5 half-lives (whichever is
 longer) prior to dosing.

 -  Known relevant history of elevated liver function tests (LFTs).

 -  History of active or latent or inadequately treated tuberculosis (TB) infection, or a
 positive QuantiFERON-TB Gold test.

 -  Any history of chronic infections, any history of recurrent infections, any history of
 latent infections, or any acute infection within 2 weeks of Screening.

 -  History of disseminated herpes zoster, or disseminated herpes simplex, or
 recurrent localized dermatomal herpes zoster.

 -  History of systemic infection requiring hospitalization, parenteral antimicrobial
 therapy, or considered clinically significant by the investigator within 6 months
 prior to Screening.

 -  History of receiving a live vaccine within 6 weeks prior to the first dose of
 investigational product, or is expected to receive a live vaccine within 6 weeks after
 the last dose of investigational product.

 -  Have a known immunodeficiency disorder or a first-degree relative with a hereditary
 immunodeficiency.

 -  History or evidence of any malignancies with the exception of adequately treated or
 excised non-metastatic basal cell or squamous cell cancer of the skin, or cervical
 carcinoma in situ.

 -  Use of prescription or nonprescription drugs and dietary supplements within 7 days or
 5 half lives (whichever is longer) prior to the first dose of investigational product.
 As an exception, acetaminophen/paracetamol may be used at doses of <= 1 g/day. Limited
 use of nonprescription medications that are not believed to affect subject safety or
 the overall results of the study may be permitted on a case by case basis following
 approval by the sponsor.

 Herbal supplements and hormonal methods of contraception (including oral and transdermal
 contraceptives, injectable progesterone, progestin subdermal implants, progesterone
 releasing intrauterine devices [IUDs], vaginal ring, and postcoital contraceptive methods)
 and hormone replacement therapy must have been discontinued at least 28 days prior to the
 first dose of investigational product.

 Use of hormone based intravaginal creams (i.e., Estrace) for treatment of vaginal dryness,
 itching, or burning due to menopause and/or vulvovaginal atrophy Depo Provera must have
 been discontinued at least 6 months prior to the first dose of investigational product.

 -  Use of tobacco- or nicotine-containing products within 3 months of Screening or a
 positive urine cotinine at Screening.

 -  Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more
 within 60 days prior to dosing.

 -  History of sensitivity to heparin or heparin-induced thrombocytopenia.

 -  History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; positive
 testing for HIV, hepatitis B surface antigen (HepBsAg), hepatitis B core antibody
 (HepBcAb), or hepatitis C antibody (HCVAb).

 A positive hepatitis B surface antibody (HepBsAb) finding as a result of subject
 vaccination is permissible.

 -  A current or past medical history of conditions associated with thrombocytopenia,
 coagulopathy, or platelet dysfunction.

 -  Unwilling or unable to comply with the criteria in the Lifestyle Requirements section
 of this protocol.

 -  Unwillingness to use an additional form of contraception for the duration of the study
 and for the specified time after follow-up.

 -  History of discontinued use of OCs for medical reasons.

 -  Pregnant female subjects; breastfeeding female subjects; females of childbearing
 potential who do not agree to use an acceptable method of nonhormonal contraception.

 -  Subjects who are investigator site staff members directly involved in the conduct of
 the study and their family members, site staff members otherwise supervised by the
 investigator, or subjects who are Pfizer employees, including their family members,
 directly involved in the conduct of the study.

 -  Other acute or chronic medical or psychiatric condition including recent (within the
 past year) or active suicidal ideation or behavior or laboratory abnormality that may
 increase the risk associated with study participation or investigational product
 administration or may interfere with the interpretation of study results and, in the
 judgment of the investigator, would make the subject inappropriate for entry into this
 study.