Clinical trial: PK of Pacritinib in Patients With Mild, Moderate, Severe Renal Impairment and ESRD Compared to Healthy Subjects (NCT02807077)

Eligibility criteria:
Inclusion Criteria:

        All Study Participants

          1. Male and/or female participants aged 18 to 85 years (inclusive)

          2. Male, non-fertile female or female of childbearing potential using a medically
             approved birth control method

               -  Females must be non-pregnant and non-lactating, and females not of childbearing
                  potential must be postmenopausal for at least 1 year or surgically sterile (e.g.,
                  tubal ligation, hysterectomy) for at least 90 days, or agree to use contraception
                  from the time of signing the informed consent or 10 days prior to Check-in (Day
                  -1) until 30 days after Study Completion. One of the following forms of
                  contraception must be used from the time of signing the informed consent or 10
                  days prior to Check-in (Day -1) until 14 days after the final dose
                  administration: non-hormonal intrauterine device (IUD) with spermicide; female
                  condom with spermicide; contraceptive sponge with spermicide; intravaginal system
                  (e.g.,NuvaRing®); diaphragm with spermicide; cervical cap with spermicide; male
                  sexual partner who agrees to use a male condom with spermicide; sterile sexual
                  partner; or abstinence. Oral, implantable, transdermal, or injectable
                  contraceptives may not be used from the time of signing the informed consent or
                  10 days prior to Check-in (Day -1) until 14 days after the final dose
                  administration. For all females, the pregnancy test result must be negative at
                  Screening and Check-in (Day -1)

               -  Males will be sterile, or completely abstain from sexual intercourse, or agree to
                  use, from Check-in (Day -1) until 90 days following Study Completion/ET, one of
                  the following approved methods of contraception: male condom with spermicide;
                  sterile sexual partner; or use by female sexual partner of an IUD with
                  spermicide; a female condom with spermicide; a contraceptive sponge with
                  spermicide; an intravaginal system; a diaphragm with spermicide; a cervical cap
                  with spermicide; or oral, implantable, transdermal, or injectable contraceptives.
                  Participants will refrain from sperm donation from Check-in (Day -1) until 90
                  days following Study Completion

          3. Body mass index (BMI) 18-33kg/m2 (inclusive) at Screening

          4. Negative test for selected drugs of abuse (including alcohol) at Screening and at
             Check-in (Day - 1) for Groups 1-3 and 5. Negative test for selected drugs of abuse
             (including alcohol) is only required at Screening in Group 4

          5. Negative hepatitis panel (including hepatitis B surface antigen [HBsAg] and hepatitis
             C virus antibody [anti HCV]) and negative human immunodeficiency virus (HIV) antibody
             screens

          6. Able to communicate well with the investigator, to understand and comply with the
             requirements of the study. Understand and sign the written informed consent. Legal
             authorized representatives are not permitted

             Patients with Renal Impairment Only

             In addition to the inclusion criteria specified for "All Study Participants" above,
             patients with renal impairment must meet the following criteria:

          7. Have stable renal disease without evidence of progressive renal disease (i.e. no known
             significant change of eGFR for 12 weeks)

               -  mild renal impairment: eGFR 60-89 mL/min/1.73 m2

               -  moderate renal impairment: eGFR 30-59 mL/min/1.73 m2

               -  severe renal impairment: CrCl from eGFR 15-29 mL/min/1.73 m2

               -  ESRD: requiring dialysis and have been on a stable dialysis regimen for at least
                  6 months

             Renal function will be determined from Screening serum creatinine value using the MDRD
             Study equation

          8. Vital signs (after 5 minutes resting measured in the supine position) within the
             following ranges as guidance for the Investigator:

               -  oral body temperature between 35.0-37.8 °C

               -  systolic blood pressure, 95-180 mm Hg

               -  diastolic blood pressure, 55-95 mm Hg

               -  pulse rate, 50-95 bpm

             Blood pressure and pulse will be taken again in a standing position. After 3 minutes
             standing, there shall be no more than a 20 mm Hg drop in systolic or 10 mm Hg drop in
             diastolic blood pressure associated with symptomatic postural hypotension

             Healthy Subjects Only

             In addition to the inclusion criteria specified for "All Study Participants" above,
             healthy subjects must meet the following criteria:

          9. No history or clinical manifestation of clinically significant cardiovascular,
             pulmonary, hepatic, renal, hematologic, gastrointestinal (e.g., celiac disease, peptic
             ulcer, gastro esophageal reflux, inflammatory bowel disease), metabolic, allergic,
             dermatological, neurological, or psychiatric disorder (as determined by the
             Investigator; appendectomy and cholecystectomy are not considered to be clinically
             significant disease)

         10. Normal renal function, eGFR ≥90 mL/min/1.73m2 (determined by Screening serum
             creatinine using the MDRD Study equation)

         11. Matched with all enrolled patients with renal impairment for age classes in the 0-25,
             26-50, 51-75, and 76-100 percentiles of age distribution

         12. Matched with all enrolled patients with renal impairment for weight (BMI) classes in
             the 0-25, 26-50, 51-75, and 76-100 percentiles of BMI distribution

         13. Matched according to the sex distribution of all enrolled patients with renal
             impairment

         14. Vital signs (after 5 minutes resting measured in the supine position) within the
             following ranges as guidance for the Investigator:

               -  oral body temperature between 35.0-37.5 °C

               -  systolic blood pressure, 90-160 mm Hg

               -  diastolic blood pressure, 50-100 mm Hg

               -  pulse rate, 45-90 bpm

        Blood pressure and pulse will be taken again in a standing position. After 3 minutes
        standing, there shall be no more than a 20 mm Hg drop in systolic or 10 mm Hg drop in
        diastolic blood pressure associated with symptomatic postural hypotension

        Exclusion Criteria:

        All Study Participants

        Participants meeting any of the following criteria will be excluded from entry into or
        continuation in the study unless sponsor approval is obtained:

          1. Pregnant or lactating female

          2. Renal transplant at any time

          3. Liver cirrhosis or a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C
             antibody test result

          4. History of immunodeficiency diseases, including a positive HIV antibody test result

          5. Acute renal failure

          6. History of chronic or recurrent urinary tract infection active within the past 30 days

          7. History of pelvic irradiation within the past 30 days

          8. Alcohol related hepatic disease

          9. History of malignancy except the following: cancers determined to be cured or in
             remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers,
             cervical cancer in situ, or resected colonic polyps

         10. Any of the following within the past 6 months:

               -  myocardial infarction (MI) (if the Screening ECG reveals patterns consistent with
                  a MI and the date of the event cannot be determined, then the subject can enter
                  the study at the discretion of the Investigator and/or local medical monitor,
                  with sponsor's permission)

               -  coronary artery bypass surgery or percutaneous coronary intervention

               -  unstable angina or stroke

         11. Past medical history of clinically significant ECG abnormalities, presence of an
             abnormal ECG (which in the Investigator's opinion is clinically significant), QTcF>450
             msec, or has concomitant conditions that increase risk for QTc interval prolongation
             (e.g., heart failure, hypokalemia [defined as serum potassium <3.0mEq/L that is
             persistent and refractory to correction], or family history of long QT interval
             syndrome)

         12. History of significant hypersensitivity, intolerance, or allergy to any drug compound,
             food, or other substance, unless approved by the Investigator

         13. Any medical or surgical conditions that might significantly interfere with the
             gastrointestinal absorption, distribution, metabolism, or excretion of the
             investigational drug. This includes any history of a significant disease of the
             gastrointestinal tract, pancreas, liver, kidneys, and/or blood-forming organs. It does
             not include appendectomy, cholecystectomy, hernia repair, or underlying renal disease
             or abnormalities that occur as a direct result of renal disease in the renal
             impairment patients or abnormalities that occur as a direct result of renal disease

         14. History of drug or alcohol abuse within the last 6 months, or evidence of recent drug
             or alcohol abuse as indicated by laboratory assays conducted during screening or
             baseline evaluations

         15. Heavy use of tobacco- or nicotine-containing products within 6 months prior to
             Check-in (Day -1) and during the entire study, defined as urinary cotinine > 150 ng/mL

         16. Consumption of alcohol- or caffeine-containing foods and beverages for 72 hours prior
             to screening and during the entire study

         17. Consumption of grapefruit-containing foods and beverages or other potent cytochrome
             P450 (CYP)3A4 inhibitors or inducers for 7 days prior to Check-in (Day -1) and during
             the entire study

         18. Participation in any other investigational study drug trial in which receipt of an
             investigational study drug occurred within 5 half-lives or 30 days prior to Check-in
             (Day -1), whichever is longer, and during the entire study

         19. Use of oral, implantable, injectable, or transdermal contraceptives within 10 days
             prior to Check-in (Day -1) or from the time of signing the informed consent (females
             only) until 14 days after the final dose administration

         20. Use of any over-the-counter, non-prescription medications, vitamins, or minerals
             (except as prescribed by a physician), within 14 days prior to Check-in (Day -1) and
             during the entire study

         21. Use of phytotherapeutic/herbal/plant-derived preparations within 14 days prior to
             Check-in (Day -1) of and during the entire study

         22. Use of potent inducers of CYP3A4 within 30 days of Check-in (Day -1)

         23. Use of potent inhibitors of CYP3A4 within 15 days of Check-in (Day -1)

         24. Poor peripheral venous access

         25. Donation or loss of 400 mL or more of blood or plasma within 8 weeks prior to Check-in
             (Day -1) and through entire study

         26. Receipt of blood products within 2 months prior to Check-in (Day -1)

         27. Any diarrhea or vomiting during the Screening period or at Check-in (Day -1)

         28. Any acute or chronic condition that, in the opinion of the Investigator, would limit
             the subject's ability to complete and/or participate in this clinical study

         29. Any of the following concomitant medications within 30 days of Check-in (Day -1)
             (unless cited otherwise below):

               -  potassium-sparing diuretics e.g. spironolactone, triamterene, amiloride (within
                  14 days of Check-in)

               -  class Ia, Ib and Ic or III anti-arrhythmics

               -  probenecid

               -  any medication that is contraindicated in moderate or severe renally impaired
                  population

               -  any drug with a known and frequent toxicity to a major organ system within 3
                  months of Screening (i.e., cytostatic drugs)

         30. Any of the following (repeated and confirmed) laboratory abnormalities at Screening or
             Check-in:

               -  Clinically significant (as judged by the Investigator in consultation with the
                  Sponsor) laboratory abnormalities except elevated blood urea nitrogen (BUN),
                  elevated serum creatinine, hyperglycemia, and/or glycosuria

               -  Alanine aminotransferase (ALT)>1.5xULN

               -  Aspartate aminotransferase (AST)>1.5xULN

               -  Total bilirubin >1.3x ULN (unless due to Gilbert's Syndrome)

               -  Hemoglobin < 8 g/dL

             Laboratory testing may be repeated once prior to dosing (to rule out any possible
             laboratory error)

         31. Planned surgery during the study period

         32. Subjects who are deemed vulnerable by way of imprisonment, remand or detention

             Patients with Renal Impairment Only

             In addition to the exclusion criteria specified for "All Subjects" above, any patient
             with renal impairment who meets the following criteria will be excluded from entry
             into the study:

         33. Any condition that would compromise patients' safety during study participation

         34. Participants in Groups 1-3: Difficulty voiding or urinary tract obstruction at
             Check-in or undergoing any method of dialysis (hemodialysis, peritoneal dialysis)

         35. Screening physical exam or ECG finding considered of clinical significance by the
             Investigator, or a laboratory evaluation outside of the normal reference range with
             the exception of values that are related to renal impairment

         36. Any significant acute or chronic disease (except renal impairment) which is unstable
             or can interfere with the objectives of the study

         37. Any change in stable dose regimens, either over-the-counter or prescription, for
             chronic medical conditions (e.g. diabetes, dyslipidemia, renal impairment) within 4
             weeks preceding dosing

             Healthy Subjects Only

             In addition to the exclusion criteria specified for "All Study Participants" above,
             any healthy subject who meets the following criteria will be excluded from entry into
             the study:

         38. Any screening or baseline physical exam, EKG, or laboratories outside the normal range
             and deemed clinically significant by the Investigator. Results deemed not clinically
             significant by the Investigator in consultation with the Sponsor are allowable.

         39. Use of any prescription medications and/or products within 14 days prior to Check-in
             (Day -1) and during the entire study

         40. History of renal impairment
No condition on gender to be admitted to the trial.
Accepts Healthy Volunteers
Subject must be at least 18 Years old.
Subject must be at most 85 Years

Patient description (medical language): A 61-year-old man comes to the clinic due to nonproductive cough and progressive dyspnea.  The patient's medical conditions include hypertension, hypercholesteremia and peptic ulcer disease.  He smokes 2 packs of cigarettes daily for the past 30 years.  On examination, there are decreased breath sounds and percussive dullness at the base of the left lung.  Other vital signs are normal. Abdomen is soft without tenderness. CT scan shows a left-sided pleural effusion and nodular thickening of the pleura. The plural fluid was bloody on thoracentesis. Biopsy shows proliferation of epithelioid-type cells with very long microvilli.

Patient description (patient's own words): I am 61 and I had to go to the clinic because I couldn't stop coughing and I experienced some breath shortness. I suffer from hypertension and cholesterol and I also have a stomach ulcer. I should admit that I've been smoking 2 packs of cigarettes every day for the past 30 years. My doctor told me that my breath in my left lung sounds bad. But he told me that my blood pressure, heart rate, breathing rate and temperature are normal. My belly is also normal. However my X-Rays show some liquid on the left side and a mass where the liquid got hard. The scary thing is that the liquid was bloody when they got it out. They did a biopsy and it showed that I have an increase of epithelioid-type cells with very long microvilli.

Does the patient match the trial criteria? 0