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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Hepatic impaired | Experimental | Participants with moderate hepatic impairment who will receive a single oral dose of pexidartinib. |
|
| Healthy controls | Experimental | Sex-, age-, and weight-matched healthy participants who will receive a single oral dose of pexidartinib. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pexidartinib | Drug | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis. | 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) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Time of Maximum Plasma Concentration (Tmax) is defined as the time of maximum observed plasma concentration and was calculated using non-compartmental analysis. | 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) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | 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. | 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 ) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis. | 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 |
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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:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Study Leader | Daiichi Sankyo | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Pharmacology of Miami, LLC. | Miami | Florida | 33014-3616 | United States | ||
| Orlando Clinical Research Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35247274 | Derived | Zahir H, Greenberg J, Hsu C, Marbury TC, Lasseter KC, Xu LA, Tap WD, Healey JH, Stacchiotti S, LaCreta F. Effect of Mild and Moderate Hepatic Impairment (Defined by Child-Pugh Classification and National Cancer Institute Organ Dysfunction Working Group Criteria) on Pexidartinib Pharmacokinetics. J Clin Pharmacol. 2022 Aug;62(8):992-1005. doi: 10.1002/jcph.2042. Epub 2022 Mar 31. |
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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/
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.
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.
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A total of 16 participants who met all inclusion criteria and no exclusion criteria were enrolled from 07 Jan 2020 to 02 Oct 2020 at 2 clinics in the United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | Normal HF | Healthy matched participants with normal hepatic function (HF) who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10 hours(h) before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. |
| FG001 | Moderate HI | Participants with moderate HI who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10 hours(h) before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. Moderate hepatic impairment (HI) was assessed by National Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Baseline characteristics were assessed using the Safety Analysis Set.
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| ID | Title | Description |
|---|---|---|
| BG000 | Normal HF | Healthy matched participants with normal HF who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10h before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. |
| BG001 | Moderate HI |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maximum Plasma Concentration (Cmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. | Posted | Mean | Standard Deviation | ng/mL | 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 |
|
Adverse events were collected from the date of signing the informed consent form up to 30 days after last dose, up to 10 months.
Adverse events were defined as any untoward, unfavorable, unintended medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All-cause mortality includes all deaths that occurred during the study and within the 30 days after the last dose of the study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Normal HF | Healthy matched participants with normal HF who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10h before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Conjunctival haemorrhage | Eye disorders | MedDRA 23.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Contact for Clinical Trial Information | Daiichi Sanyko, Inc. | 908-992-6400 | CTRinfo@dsi.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 10, 2019 | May 5, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000070779 | Giant Cell Tumor of Tendon Sheath |
| ID | Term |
|---|---|
| D005870 | Giant Cell Tumors |
| D009372 | Neoplasms, Connective Tissue |
| D018204 | Neoplasms, Connective and Soft Tissue |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| C000600259 | pexidartinib |
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| 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) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Elimination Rate Constant (Kel) is defined as elimination rate constant and was calculated using non-compartmental analysis. | 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) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis. | 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) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis. | 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) Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | 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. | 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) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis. | 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) of of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | 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. | 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) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Subjects Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis. | 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 |
| 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 | 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. | 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 |
| Percentage of Plasma Protein Binding of Pexidartinib and ZAAD-1006a Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | 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. | 2.5 and 24 hours post-dose |
| 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 | 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. | Post-dose and up to 30 days |
| Orlando |
| Florida |
| 32809 |
| United States |
Participants with moderate HI who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10h before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. Moderate hepatic impairment (HI) was assessed by National Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG). |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Weight | Mean | Standard Deviation | kilogram |
|
| OG001 | Moderate HI | Participants with moderate HI who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10h before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. Moderate hepatic impairment (HI) was assessed by National Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG). |
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| Primary | Time of Maximum Plasma Concentration (Tmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Time of Maximum Plasma Concentration (Tmax) is defined as the time of maximum observed plasma concentration and was calculated using non-compartmental analysis. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. | Posted | Median | Full Range | hours | 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 |
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| Primary | 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 | 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. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. | Posted | Mean | Standard Deviation | ng•h/mL | 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 |
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| Primary | 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 | 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. | The pharmacokinetic parameter of Area Under the Plasma Concentration-Time Curve up to Infinity was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis. | Posted | Mean | Standard Deviation | ng•h/mL | 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 |
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| Primary | Elimination Rate Constant (Kel) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Elimination Rate Constant (Kel) is defined as elimination rate constant and was calculated using non-compartmental analysis. | The pharmacokinetic parameter of Elimination Rate Constant was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.. | Posted | Mean | Standard Deviation | fraction per hour | 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 |
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| Primary | Terminal Elimination Half-Life (t1/2) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis. | The pharmacokinetic parameter of Terminal Elimination Half-Life was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis. | Posted | Mean | Standard Deviation | hours | 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 |
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| Primary | Total Apparent Clearance (CL/F) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis. | The pharmacokinetic parameter of Total Apparent Clearance was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis. | Posted | Mean | Standard Deviation | liters per hour | 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 |
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| Primary | Volume of Distribution in the Terminal Phase (Vz/F) Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | 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. | The pharmacokinetic parameter of Volume of Distribution in the Terminal Phase was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis. | Posted | Mean | Standard Deviation | liters | 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 |
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| Secondary | Maximum Plasma Concentration (Cmax) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. | Posted | Mean | Standard Deviation | ng/mL | 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 |
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| Secondary | Maximum Plasma Concentration (Tmax) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. | Posted | Mean | Full Range | hours | 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 |
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| Secondary | 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 | 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. | Pharmacokinetic parameters were assessed using the Pharmacokinetic Analysis Set. | Posted | Mean | Standard Deviation | ng•h/mL | 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 |
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| Secondary | 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 | Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. | Posted | Mean | Standard Deviation | hours | 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 |
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| Secondary | 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 | 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. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. | Posted | Mean | Standard Deviation | ratio | 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 |
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| Secondary | Percentage of Plasma Protein Binding of Pexidartinib and ZAAD-1006a Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants | 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. | The pharmacokinetic parameter of Percentage of Plasma Protein Binding was assessed using the Pharmacokinetic Analysis Set. Only those participants with data available at the specified timepoints were analyzed. | Posted | Mean | Standard Deviation | percentage of protein binding | 2.5 and 24 hours post-dose |
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| Secondary | 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 | 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. | TEAEs were assessed using the Safety Analysis Set. | Posted | Count of Participants | Participants | Post-dose and up to 30 days |
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|
|
| 0 |
| 8 |
| 0 |
| 8 |
| 1 |
| 8 |
| EG001 | Moderate HI | Participants with moderate HI who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10h before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. Moderate hepatic impairment (HI) was assessed by National Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG). | 0 | 8 | 0 | 8 | 2 | 8 |
| Gastrointestinal disorders | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
|
Not provided
Not provided
| D009369 | Neoplasms |
| D013585 | Synovitis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D052256 | Tendinopathy |
| D009135 | Muscular Diseases |
| Pexidartinib at 24hrs post-dose |
|
|
| ZAAD-1006a at 2.5hrs post-dose |
|
|
| ZAAD-1006a at 24hrs post-dose |
|
|
| Gastrointestinal Disorders (Dyspepsia) |
|
| Nervous System Disorders (Headache) |
|