A Study to Determine the Effects of PF-04965842 on Midazolam PK in Healthy Volunteers

Masking: None (Open Label)
Primary Purpose: Other

• Drug: PF-04965842
  
  orally bioavailable small molecule that selectively inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site.
  Other Name: JAK1 Inhibitor
• Drug: Midazolam
  
  substrate which undergoes extensive metabolism by CYP3A4 and CYP3A5 and acts as a sensitive probe for evaluating drug interaction with respect to these isoenzymes

• Sequence 1
  
  In Sequence 1, Period 1, subjects will be dosed with a single administration of midazolam 2 mg oral solution on Day 1. Midazolam PK will then be assessed over the next 24 hours (hr). Period 1 will be immediately followed by Period 2 with no washout, in which subjects will be dosed with 200 mg PF-04965842 orally once daily (QD) for 7 days. Midazolam 2 mg oral solution will be administered on the morning of Day 2 and Day 7 within 5 minutes after PF-04965842 dosing. Midazolam PK will be assessed for 24 hr following dosing.
  Interventions:
  

  • Drug: PF-04965842
  • Drug: Midazolam
• Sequence 2
  
  In Sequence 2, Period 1, subjects will be dosed with 200 mg PF-04965842 orally QD for 7 days. Midazolam 2 mg oral solution will be administered on the morning of Day 2 and Day 7 within 5 minutes after PF-04965842 dosing. Midazolam PK will be assessed for 24 hr following dosing. Subjects will then undergo a washout period of at least 7 days. In Period 2 subjects will be dosed with a single administration of midazolam 2 mg oral solution on Day 1. Midazolam PK will then be assessed over the next 24 hr.
  Interventions:
  

  • Drug: PF-04965842
  • Drug: Midazolam

Inclusion Criteria:

• Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures
• Healthy female subjects and/or male subjects who, at the time of screening, are between the ages of 18 and 55 years, inclusive
• Female subjects with child-bearing potential must not be intending to become pregnant, currently pregnant, or lactating. Conditions apply: negative pregnancy test, effective method of contraception
• Non-childbearing potential must meet at least 1 of the following criteria: documented hysterectomy and/or bilateral oophorectomy, ovarian failure, achieved postmenopausal status confirmed with FSH
• Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs)

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, GI, CV, hepatic, psych, neurological, or allergic disease (including drug allergies, but excluding seasonal)
• Evidence or history of clinically significant dermatological condition (eg, contact dermatitis or psoriasis) or visible rash present during physical examination
• Subjects, who according to the product label for midazolam, would be at increased risk if dosed with midazolam
• Self-reported history or risk factors for QT prolongation or torsades de pointes, congenital deafness, family history of sudden death, and family history of long QT syndrome
• Any condition possibly affecting drug absorption (eg, gastrectomy)
• A positive urine drug test
• History of regular alcohol consumption exceeding 14 for female or 21 for male drinks/week (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months of 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)
• Following at least 5 minutes of supine rest, screening supine systolic BP <90 mm Hg or >=140 mm Hg, or screening supine diastolic BP <50 mm Hg or >=90 mm Hg. Any criteria met, BP should be repeated
• Screening supine 12-lead ECG demonstrating: QTcF >450 msec or QRS interval >120 msec. If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated
• AST/SGOT or ALT/SGPT >=1.5 × ULN. Total bilirubin level >1× ULN; subjects with a hx of Gilbert's syndrome must have direct bilirubin <= ULN Known relevant history of elevated liver function tests (LFTs)
• History of tuberculosis (TB) (active or latent) or inadequately treated TB infection. 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 baseline
• History of disseminated herpes zoster, or disseminated herpes simplex, or recurrent localized dermatomal herpes zoster
• History of sensitivity to heparin or heparin-induced thrombocytopenia
• Pregnant or breastfeeding female; fertile male and WOCBP unwilling to use a highly effective method of contraception through study duration and for at least 28 days after the last dose
• Use of medications and dietary supplements within 7 days or 5 half-lives prior to first dose, acetaminophen/paracetamol <=1 g/day exception. Herbal supplements and hormonal methods of contraception
• Use of tobacco- or nicotine- containing products in excess of the equivalent of 5 cigarettes per day
• Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to first dose of investigational product
• History of hypersensitivity to midazolam or any other bezodiazapine
• History of HIV, hepatitis B or C; positive testing for HIV, HepBsAg, HepBcAb or HCVAb. As an exception, a positive HepBsAb as a result of subject vaccination is permissible
• Unwilling or unable to comply with the criteria in the Lifestyle Requirements section of this protocol
• Investigator site staff members and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members
• Other medical or psych condition including active suicidal ideation/ behavior or lab abnormality that the investigator deems inappropriate for this study or may interfere with study results
• Have any malignancies or have a history of 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
• Subjects at significant risk of suicidal or violent behavior