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

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04223635
• Collaborator: (none)
• Enrollment: 16
• Locations: 2
• Arms: 2
• Actual Duration (Months): 8.8
• Patients Per Site: 8
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Jan 7, 2020
• Actual Primary Completion Date: Oct 2, 2020
• Actual Study Completion Date: Oct 2, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Maximum Plasma Concentration (Cmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Pharmacology of Miami, LLC.	Miami	Florida	United States	33014-3616
2	Orlando Clinical Research Center	Orlando	Florida	United States	32809

Sponsors and Collaborators

• Daiichi Sankyo, Inc.

Investigators

• Study Director: Clinical Study Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 10, 2019

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT04223635
• Other Study ID Numbers: PL3397-A-U129
• First Posted: Jan 10, 2020
• Last Update Posted: Jun 22, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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: Liver Diseases

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Period Title: Overall Study
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Normal HF	Moderate HI	Total
Arm/Group Description	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.	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).	Total of all reporting groups
Overall Participants	8	8	16
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	6 75%	7 87.5%	13 81.3%
>=65 years	2 25%	1 12.5%	3 18.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.1 (6.69)	59.4 (4.34)	58.8 (5.48)
Sex: Female, Male (Count of Participants)
Female	3 37.5%	3 37.5%	6 37.5%
Male	5 62.5%	5 62.5%	10 62.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 25%	1 12.5%	3 18.8%
White	6 75%	7 87.5%	13 81.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Weight (kilogram) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram]	86.30 (13.49)	78.13 (14.83)	82.21 (14.33)

Outcome Measures

1. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants
Description	Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
Mean (Standard Deviation) [ng/mL]	1420 (738)	1250 (556)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal HF, Moderate HI
	Comments
	Type of Statistical Test	Other
	Comments	Least squares (LS) means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% Confidence Interval (CIs) for the ratio (%) of GMS were presented.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric LS Mean
	Estimated Value	92.60
	Confidence Interval	(2-Sided) 90%; 54.38 to 157.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, moderate HI represents the numerator and normal HF represents the denominator.

2. Primary Outcome

Title	Time of Maximum Plasma Concentration (Tmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants
Description	Time of Maximum Plasma Concentration (Tmax) is defined as the time of maximum observed plasma concentration and was calculated using non-compartmental analysis.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
Median (Full Range) [hours]	1.9	2.5

3. Primary Outcome

Title	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
Description	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.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
Mean (Standard Deviation) [ng•h/mL]	26500 (12200)	38600 (16200)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal HF, Moderate HI
	Comments
	Type of Statistical Test	Other
	Comments	Least squares means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% CIs for the ratio (%) of GMS were presented.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Least Square Mean
	Estimated Value	147.17
	Confidence Interval	(2-Sided) 90%; 95.39 to 227.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, moderate HI represents the numerator and normal HF represents the denominator.

4. Primary Outcome

Title	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
Description	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.
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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	7
Mean (Standard Deviation) [ng•h/mL]	27300 (12400)	38900 (17600)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal HF, Moderate HI
	Comments
	Type of Statistical Test	Other
	Comments	Least squares means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% CIs for the ratio (%) of GMS were presented.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric Least Square Mean
	Estimated Value	142.87
	Confidence Interval	(2-Sided) 90%; 91.21 to 223.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, moderate HI represents the numerator and normal HF represents the denominator.

5. Primary Outcome

Title	Elimination Rate Constant (Kel) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants
Description	Elimination Rate Constant (Kel) is defined as elimination rate constant and was calculated using non-compartmental analysis.
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

Outcome Measure Data

Analysis Population Description

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..

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	7
Mean (Standard Deviation) [fraction per hour]	0.02294 (0.002072)	0.019784 (0.0042775)

6. Primary Outcome

Title	Terminal Elimination Half-Life (t1/2) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants
Description	Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis.
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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	7
Mean (Standard Deviation) [hours]	30.4 (2.58)	36.5 (8.05)

7. Primary Outcome

Title	Total Apparent Clearance (CL/F) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants
Description	Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis.
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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	7
Mean (Standard Deviation) [liters per hour]	9.046 (5.1294)	6.270 (3.2935)

8. Primary Outcome

Title	Volume of Distribution in the Terminal Phase (Vz/F) Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants
Description	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.
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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	7
Mean (Standard Deviation) [liters]	391.6 (205.29)	343.0 (238.12)

9. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants
Description	Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
Mean (Standard Deviation) [ng/mL]	1720 (950)	1250 (766)

10. Secondary Outcome

Title	Maximum Plasma Concentration (Tmax) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants
Description	Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
Mean (Full Range) [hours]	3.0	10.0

11. Secondary Outcome

Title	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
Description	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.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
AUCinf	43700 (29300)	78100 (38300)
AUClast	42700 (28800)	72700 (36900)

12. Secondary Outcome

Title	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
Description	Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
Mean (Standard Deviation) [hours]	28.9 (4.03)	37.9 (14.5)

13. Secondary Outcome

Title	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
Description	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.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
MPR AUCinf	1.08 (0.273)	1.27 (0.405)
MPR AUClast	1.09 (0.275)	1.30 (0.373)

14. Secondary Outcome

Title	Percentage of Plasma Protein Binding of Pexidartinib and ZAAD-1006a Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants
Description	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.
Time Frame	2.5 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
Pexidartinib at 2.5hrs post-dose	99.9727 (0.00365)	99.9695 (0.00454)
Pexidartinib at 24hrs post-dose	99.9703 (0.00765)	99.9664 (0.00815)
ZAAD-1006a at 2.5hrs post-dose	99.8605 (0.01056)	99.8570 (0.03238)
ZAAD-1006a at 24hrs post-dose	99.8631 (0.02055)	99.8534 (0.03868)

15. Secondary Outcome

Title	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
Description	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.
Time Frame	Post-dose and up to 30 days

Outcome Measure Data

Analysis Population Description

TEAEs were assessed using the Safety Analysis Set.

Arm/Group Title	Normal HF	Moderate HI
Arm/Group Description	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.	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).
Measure Participants	8	8
Any TEAEs	1 12.5%	2 25%
Eye Disorders (Conjunctival haemorrhage)	0 0%	1 12.5%
Gastrointestinal Disorders (Dyspepsia)	0 0%	1 12.5%
Nervous System Disorders (Headache)	1 12.5%	0 0%

Adverse Events

Time Frame	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 Event Reporting Description	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.
Arm/Group Title	Normal HF		Moderate HI
Arm/Group Description	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.		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).
All Cause Mortality
	Normal HF		Moderate HI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Serious Adverse Events
	Normal HF		Moderate HI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Normal HF		Moderate HI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)		2/8 (25%)
Eye disorders
Conjunctival haemorrhage	0/8 (0%)		1/8 (12.5%)
Gastrointestinal disorders
Gastrointestinal disorders	0/8 (0%)		1/8 (12.5%)
Nervous system disorders
Headache	1/8 (12.5%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.