PK of Pacritinib in Patients With Mild, Moderate, Severe Renal Impairment and ESRD Compared to Healthy Subjects

NCT02807077 | Completed Phase 1

• 1 other identifier: PAC105
• Study Type: interventional
• Target: 40
• Locations: 3 countries
• Sites: 3

Brief Summary

This is a Phase 1 open label, single dose, 5 parallel-group study in which a single 400 mg dose of pacritinib will be administered orally to patients with renal impairment (mild, moderate, severe, and patients with ESRD requiring hemodialysis) and sex-, age- and weight-matched healthy subjects.Patients with ESRD will receive a single 400 mg dose of pacritinib during 2 different treatment periods: Dialysis and Inter-Dialysis. The primary objective of the study is to evaluate the pharmacokinetics and safety of pacritinib in renal impairment.

Conditions

Myelofibrosis

Keywords

Healthy subjects

Outcome Measures

Primary Outcomes (7)

• The maximum plasma concentration (Cmax)

  The following pharmacokinetic parameters of pacritinib and major human metabolites were assessed following 400 mg single-dose administration of pacritinib capsule in patients with renal impairment and matched healthy subjects

  Plasma: 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, and 168 hrs post-dose. Urine- 0-168 hr interval

• The time to reach maximum plasma concentration (tmax)

  The following pharmacokinetic parameters of pacritinib and major human metabolites were assessed following 400 mg single-dose administration of pacritinib capsule in patients with renal impairment and matched healthy subjects

  Plasma: 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, and 168 hrs post-dose. Urine- 0-168 hr interval

• The area under the plasma concentration-time curve from time zero to time of the last measured concentration above the limit of quantification (AUC0-t).

  The following pharmacokinetic parameters of pacritinib and major human metabolites were assessed following 400 mg single-dose administration of pacritinib capsule in patients with renal impairment and matched healthy subjects

  Plasma: 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, and 168 hrs post-dose. Urine- 0-168 hr interval

• The area under the plasma concentration-time curve from zero to infinity (AUC0-∞)

  The following pharmacokinetic parameters of pacritinib and major human metabolites were assessed following 400 mg single-dose administration of pacritinib capsule in patients with renal impairment and matched healthy subjects

  Plasma: 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, and 168 hrs post-dose. Urine- 0-168 hr interval

• The apparent terminal elimination rate constant (λZ) and the respective apparent terminal elimination half-life (t½)

  The following pharmacokinetic parameters of pacritinib and major human metabolites were assessed following 400 mg single-dose administration of pacritinib capsule in patients with renal impairment and matched healthy subjects

  Plasma: 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, and 168 hrs post-dose. Urine- 0-168 hr interval

• The apparent volume of distribution (Vd)

  The following pharmacokinetic parameters of pacritinib and major human metabolites were assessed following 400 mg single-dose administration of pacritinib capsule in patients with renal impairment and matched healthy subjects

  Plasma: 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, and 168 hrs post-dose. Urine- 0-168 hr interval

• The apparent total body clearance (CL/F)

  The following pharmacokinetic parameters of pacritinib and major human metabolites were assessed following 400 mg single-dose administration of pacritinib capsule in patients with renal impairment and matched healthy subjects

  Plasma: 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, and 168 hrs post-dose. Urine- 0-168 hr interval

Secondary Outcomes (1)

• Incidence of Treatment emergent Adverse Events

  Day 1 to Day 8

Study Arms (5)

Subjects with mild renal impairment

EXPERIMENTAL

Group 1, will consist of patients each with mild, moderate, or severe renal disease, respectively, based on their estimated glomerular filtration rate (eGFR, calculated by the Modification of Diet in Renal Disease \[MDRD\] study equation). Each of these patients will receive a single 400 mg dose of pacritinib.

Drug: Pacritinib

Subjects with moderate renal impairment

EXPERIMENTAL

Group 2, will consist of patients each with mild, moderate, or severe renal disease, respectively, based on their estimated glomerular filtration rate (eGFR, calculated by the Modification of Diet in Renal Disease \[MDRD\] study equation). Each of these patients will receive a single 400 mg dose of pacritinib.

Drug: Pacritinib

Subjects with severe renal impairment

EXPERIMENTAL

Group 3, will consist of patients each with mild, moderate, or severe renal disease, respectively, based on their estimated glomerular filtration rate (eGFR, calculated by the Modification of Diet in Renal Disease \[MDRD\] study equation). Each of these patients will receive a single 400 mg dose of pacritinib.

Drug: Pacritinib

Subjects with ESRD

EXPERIMENTAL

Group 4, will consist of patients with ESRD requiring hemodialysis who have been on a stable dialysis regimen for at least 6 months. In this cohort only, patients will participate in 2 treatment periods, Dialysis and Inter-Dialysis, separated by a 14-day period between pacritinib administration. In the Dialysis Treatment Period, a single 400 mg dose of pacritinib will be administered 4 hours prior to each patient's normally scheduled hemodialysis. In the Inter-Dialysis Treatment Period, a single 400 mg dose of pacritinib will be administered immediately after the end of the patient's normally scheduled hemodialysis session.

Drug: Pacritinib

Healthy subjects

EXPERIMENTAL

Group 5, will consist of 8 healthy subjects enrolled to match the sex-, age-, and weight of the patients with mild, moderate, and severe renal impairment and patients with ESRD enrolled in the study. Healthy subjects will be administered a single 400 mg dose of pacritinib.

Drug: Pacritinib

Interventions

Pacritinib DRUG

Group 1, 2, 3, and 5 will be administered single oral 400-mg dose of pacritinib. Subjects in the Group 4 received a single 400-mg dose of pacritinib during two different treatment periods: Dialysis and Inter-Dialysis

Healthy subjects; Subjects with ESRD; Subjects with mild renal impairment; Subjects with moderate renal impairment; Subjects with severe renal impairment

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All Study Participants
• Male and/or female participants aged 18 to 85 years (inclusive)
• 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
• Body mass index (BMI) 18-33kg/m2 (inclusive) at Screening
• 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
• Negative hepatitis panel (including hepatitis B surface antigen \[HBsAg\] and hepatitis C virus antibody \[anti HCV\]) and negative human immunodeficiency virus (HIV) antibody screens
• 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
• 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

You may not qualify if:

• 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:
• Pregnant or lactating female
• Renal transplant at any time
• Liver cirrhosis or a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody test result
• History of immunodeficiency diseases, including a positive HIV antibody test result
• Acute renal failure
• History of chronic or recurrent urinary tract infection active within the past 30 days
• History of pelvic irradiation within the past 30 days
• Alcohol related hepatic disease
• 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
• 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

Sponsors & Collaborators

• CTI BioPharma: lead
• SGS S.A.: collaborator

Study Sites (3)

APEX GmbH

Munich, D-81241, Germany

Location

Republican Clinical Hospital

Chisinau, MD-2025, Moldova

Location

Carol Davila Nephrology Hospital Bucharest

Bucharest, Romania

Location

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Igor Codreanu, MD

  Republican Clinical Hospital

  PRINCIPAL INVESTIGATOR

• Gernot Klein, MD

  APEX GmbH

  PRINCIPAL INVESTIGATOR

• Mircea N Penescu, MD

  Carol Davila Nephrology Hospital Bucharest

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 3, 2016
• First Posted: June 21, 2016
• Study Start: November 1, 2014
• Primary Completion: July 1, 2015
• Study Completion: July 1, 2015
• Last Updated: October 22, 2018

Record last verified: 2018-10

Locations

DE (1); MO (1); RO (1)