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Study of Pexidartinib in Participants With Moderate Hepatic Impairment Compared With Healthy Participants

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ClinicalTrials.gov Identifier: NCT04223635
Recruitment Status : Completed
First Posted : January 10, 2020
Results First Posted : June 7, 2021
Last Update Posted : June 22, 2021
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Brief Summary:
The pharmacokinetics of a single dose of pexidartinib was investigated in participants with impaired hepatic function and compared with healthy control participants with normal hepatic function.

Condition or disease Intervention/treatment Phase
Moderate Hepatic Impairment Drug: Pexidartinib Early Phase 1

Detailed Description:

Pexidartinib is an orally administered tyrosine kinase inhibitor, currently approved in the US for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

The primary objective of this study is to determine the plasma pharmacokinetics (PK) of pexidartinib after a single oral dose of 200 mg in participants with moderate hepatic impairment (HI) as defined by National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria compared to the healthy controls participants with normal hepatic function.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An Open-label, Single-dose Study to Assess the Pharmacokinetics of Pexidartinib in Subjects With Moderate Hepatic Impairment Compared to Healthy Subjects
Actual Study Start Date : January 7, 2020
Actual Primary Completion Date : October 2, 2020
Actual Study Completion Date : October 2, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Hepatic impaired
Participants with moderate hepatic impairment who will receive a single oral dose of pexidartinib.
Drug: Pexidartinib
Single, 200-mg capsule will be administered orally on Day 1 with 240 mL of water, following an overnight fast of at least 10 hours.

Experimental: Healthy controls
Sex-, age-, and weight-matched healthy participants who will receive a single oral dose of pexidartinib.
Drug: Pexidartinib
Single, 200-mg capsule will be administered orally on Day 1 with 240 mL of water, following an overnight fast of at least 10 hours.




Primary Outcome Measures :
  1. Maximum Plasma Concentration (Cmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.

  2. Time of Maximum Plasma Concentration (Tmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Time of Maximum Plasma Concentration (Tmax) is defined as the time of maximum observed plasma concentration and was calculated using non-compartmental analysis.

  3. Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method and was calculated using non-compartmental analysis.

  4. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf ) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf ) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and was calculated using non-compartmental analysis.

  5. Elimination Rate Constant (Kel) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Elimination Rate Constant (Kel) is defined as elimination rate constant and was calculated using non-compartmental analysis.

  6. Terminal Elimination Half-Life (t1/2) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis.

  7. Total Apparent Clearance (CL/F) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis.

  8. Volume of Distribution in the Terminal Phase (Vz/F) Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Volume of Distribution in the Terminal Phase (Vz/F) is defined as volume of distribution in the terminal phase and was calculated using non-compartmental analysis.


Secondary Outcome Measures :
  1. Maximum Plasma Concentration (Cmax) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.

  2. Maximum Plasma Concentration (Tmax) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis.

  3. Area Under the Concentration-Time Curve (AUCinf) of of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Area Under the Concentration-Time Curve (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. AUCinf and AUClast are reported and were calculated using non-compartmental analysis.

  4. Terminal Elimination Half-Life (t1/2) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Subjects Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis.

  5. Metabolite-to-Parent Ratio (MPR) Corrected for Molecular Weight of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Pre-dose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose ]
    AUCinf is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. MPR is defined as a metabolite to parent ratio with metabolite as the numerator and the parent as the denominator. MPR corrected for molecular weight of ZAAD-1006a of AUCinf and AUClast are reported and were calculated using non-compartmental analysis.

  6. Percentage of Plasma Protein Binding of Pexidartinib and ZAAD-1006a Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: 2.5 and 24 hours post-dose ]
    Protein binding (percentage bound) was determined in all participants at 2.5h and 24h post-dose. Plasma was harvested and analyzed for the quantification of pexidartinib using a validated liquid chromatography-tandem mass spectrometry method and the ZAAD-1006a metabolite was analyzed using a qualified liquid chromatography-tandem mass spectrometry assay.

  7. Number of Participants Reporting Treatment-Emergent Adverse Events (TEAE) by System Organ Class and Preferred Term Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [ Time Frame: Post-dose and up to 30 days ]
    A Treatment-Emergent Adverse Event (TEAE) is defined as any event not present prior to the initiation of the drug treatment or any event already present that worsens in either intensity or frequency following exposure to the drug treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

• Screening: Male and female participants, 18 y to 75 years of age, inclusive, with body mass index (BMI) 18 kg/m^2 to 40 kg/m^2, inclusive at Screening.

Participants with hepatic impairment (HI) are required to have:

  • Documented history of chronic liver disease diagnosed by ultrasonography, computed tomography scan, liver biopsy, or magnetic resonance imaging or history of chronic (>6 months) hepatitis B virus or hepatitis C virus infection.
  • Moderate HI as assessed by the National Cancer Institute-Organ Dysfunction Working Group (NCI-ODWG) criteria (total bilirubin [TBIL] >1.5 to 3x upper limit of normal [ULN]) not due to Gilbert's syndrome.
  • Normal or nonclinically relevant findings at physical examination and normal limits or nonclinically relevant deviations in clinical laboratory evaluations, with exception of findings that in the opinion of investigator are consistent with participant's HI.
  • Clinical stability in the opinion of the investigator.
  • Female participants (both, healthy and HI participants) who are of non-childbearing potential must be:

    • Surgically sterile (ie, bilateral tubal ligation or removal of both ovaries and/or uterus at least 6 months prior to dosing, or Essure® with hysterosalpingogram [documentation to confirm tubal occlusion 12 weeks after procedure]).
    • Naturally postmenopausal (spontaneous cessation of menses) for at least 12 consecutive months prior to dosing, confirmed by follicle stimulating hormone (FSH) or estradiol testing.
  • Female participants (both, healthy and HI subjects) who are of childbearing potential must agree to barrier method of contraceptive therapy or refrain from sexual intercourse to prevent pregnancy until 1 month post dose. If the participant is on oral contraceptive, the participant needs to use the barrier method in addition to oral contraceptive. Female participants must refrain from breastfeeding for at least 2 weeks post dose.
  • Male participants (both, healthy and HI subjects) must surgically sterile or agree to use double barrier methods of contraception from Check-in until 1 month after the dose of pexidartinib. Also, male participants must not donate sperm from Check-in until 1 month after pexidartinib administration.

Exclusion Criteria:

  • Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the Screening assessment that could interfere with the objectives of the study or the safety of the participant
  • Participants with primary biliary cirrhosis or primary sclerosing cholangitis
  • Concomitant medication (moderate or strong inhibitor or inducer of CYP3A4 [eg, itraconazole, rifampin], CYP2C9 [eg, fluconazole, carbamazepine] and uridine 5'-diphospho-glucuronosyltransferase (UGT) [eg, probenecid, rifampin]) within 2 weeks before dosing and throughout study
  • History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (with the exception of appendectomy, hernia repair, and/or cholecystectomy)
  • Presence or history of severe adverse reaction to any drug (except penicillin)
  • A positive drugs of abuse screen (unless the drug is medically prescribed by a licensed health care provider) or alcohol breath test at Screening or at Check-in on Day -2 or a participant who will not agree to smoke ≤10 cigarettes or equivalent per day from Screening up to Enrollment, and is unable to be restricted to ≤5 cigarettes per day and for 6 hours post dose during their period of residence in the clinical unit
  • Concomitant use of medications known to affect the elimination of serum creatinine (eg, trimethoprim or cimetidine) and inhibitors of renal tubular secretion (eg, probenecid) within 60 days of Day -2
  • History or presence of an abnormal ECG, which, in the investigator's opinion, is clinically significant and/or a QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥450 milliseconds (ms) and ≥470 ms for healthy male and female participants, respectively, and >500 ms for participants with HI at Screening
  • Consumption of alcohol-within 72 hours prior to Check-in and caffeine-containing beverages within 48 hours prior to Check-in and during confinement
  • Consumption of more than 28 units of alcohol per week for males or 14 units of alcohol per week for females, where 1 unit of alcohol equals one-half pint of beer, 4 ounces (oz) of wine, or 1 oz of spirits, or significant history of alcoholism or drug/chemical abuse within the last 2 years
  • Positive serology for HBsAg and anti-hepatitis C virus (HCV) (healthy participants), hepatitis A virus (HAV) immunoglobulin M, or anti-HIV Type 1 and Type 2 (all participants)
  • Loss of more than 450 mL blood during the 3 months before the trial (eg, as a blood donor)
  • Current enrollment in or have not yet completed at least 30 days or 5 elimination half-lives, whichever is longer, since receiving an investigational device or product, or receipt of other investigational agents within 30 days of pexidartinib

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04223635


Locations
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United States, Florida
Clinical Pharmacology of Miami, LLC.
Miami, Florida, United States, 33014-3616
Orlando Clinical Research Center
Orlando, Florida, United States, 32809
Sponsors and Collaborators
Daiichi Sankyo, Inc.
Investigators
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Study Director: Clinical Study Leader Daiichi Sankyo, Inc.
  Study Documents (Full-Text)

Documents provided by Daiichi Sankyo, Inc.:
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Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT04223635    
Other Study ID Numbers: PL3397-A-U129
First Posted: January 10, 2020    Key Record Dates
Results First Posted: June 7, 2021
Last Update Posted: June 22, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Daiichi Sankyo, Inc.:
Moderate hepatic impaired
Healthy subjects
Pexidartinib
Clinical pharmacology study
Tenosynovial giant cell tumor (TGCT)
Additional relevant MeSH terms:
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Liver Diseases
Digestive System Diseases