Bioavailability of Belumosudil (KD025) in Healthy Male Subjects

A 3-way, Crossover, Randomized, Open-label Study in Healthy Subjects Comparing the Bioavailability of Belumosudil (KD025) Tablets in Fed and Fasted States and Relative Bioavailability of Tablets and Capsules in the Fed State

Phase 1 bioavailability study to evaluate the pharmacokinetics (PK) and tolerability/safety of the belumosudil tablet formulation in the fasted and fed states and compared to the belumosudil capsule formulation in the fed state.

Study Overview

• Status: Completed
• Conditions: Bioavailability
• Intervention / Treatment: Drug: Belumosudil Tablet; Drug: Belumosudil Capsule

Detailed Description

This is a Phase 1, 3-way, crossover, randomized, open-label study in healthy subjects designed to compare the bioavailability of belumosudil (previously known as KD025) tablet formulation administered in the fed and fasted states and to assess the relative bioavailability of belumosudil tablet and capsule formulations in the fed state.

The primary objective of the study is to determine the PK parameters of belumosudil tablet formulation in the fed and fasted states.

The secondary objectives of the study are: (1) to assess the relative bioavailability of a tablet (test) to capsule (reference formulation of belumosudil; (2) to assess and compare the variability in the maximum concentration (Cmax) and area under the concentration-time curve (AUC) for belumosudil treatments (belumosudil 200 mg tablet in the fasting state, belumosudil 200 mg tablet in the fed state, and belumosudil as two 100 mg capsules in the fed state); and (3) to provide additional safety and tolerability information for belumosudil.

This is a single-center, open-label, randomized, single-dose, 3-period, 3-way, crossover study in healthy subjects.

In each of 3 study periods, each subject receives 1 of the following single-dose treatments:

• Regimen A: Belumosudil 200 mg tablet in the fasted state
• Regimen B: Belumosudil 200 mg tablet in the fed state
• Regimen C: Belumosudil 200 mg as two 100-mg capsules in the fed state

Subjects are randomized to receive 1 dose of investigational product (IP; belumosudil tablet or capsule) in the morning of Day 1 in a randomized manner following an overnight fast or a high-fat breakfast. Administration is performed on Day 1 with an appropriate interval between subjects based on logistical requirements. Start time is determined based on logistics.

Subjects undergo a screening visit in the 21 days preceding first dose. Subjects are admitted to the clinical unit on the evening prior to dosing (Day -1), remain on site until 24 hours post-dose, and return to the clinic at 36 and 48 hours post-dose for PK assessments.

There is a minimum washout period of 6 days between each dose administration. All other meals are standardized for each of the in-clinic phases of the 3 treatment periods. Each period follows the same study design.

The randomized cohorts for the 3-periods were as follows:

• Cohort ABC: Regimen A (Period 1); Regimen B (Period 2); Regimen C (Period 3)
• Cohort BCA: Regimen B (Period 1); Regimen C (Period 2); Regimen A (Period 3)
• Cohort CAB: Regimen C (Period 1); Regimen A (Period 2); Regimen B (Period 3)

A follow-up call is made 3 to 5 days after the final dose of IP.

Planned enrollment is 24 subjects to insure there are 20 evaluable subjects. A subject is considered evaluable if (s)he completes treatment with fasted and fed tablet formulations (Regimens A and B) without major protocol deviations.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Ruddington Nottingham, United Kingdom, NG116JS
    • Quotient Clinical Limited

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

To be eligible for study entry subjects has to satisfy all of the following criteria:

1. Healthy males
2. Aged 18 to 55 years of age
3. Good state of health (mentally and physically) as indicated by a comprehensive clinical assessment (detailed medical history and a complete physical examination), ECG, and laboratory investigations (hematology, coagulation, clinical chemistry and urinalysis)
4. Body mass index 18.0-30.0 kg/m^2, or if outside the range, considered not clinically significant by the Investigator
5. Willing and able to communicate and participate in the whole study
6. Provide written informed consent
7. Agree to use an adequate method of contraception for up to 90 days post discharge

Exclusion Criteria

Subjects are excluded from the study if one of more of the following statements is applicable:

1. Participated in a clinical research study within the previous 3 months
2. Study site employees, or immediate family members of a study site or sponsor employee
3. Had been previously enrolled in this study
4. History of any drug or alcohol abuse in the past 2 years
5. Regular alcohol consumption > 21 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
6. Current smokers and those who had smoked within the last 12 months. A breath carbon monoxide (CO) reading of greater than 10 ppm at screening
7. Did not have suitable veins for multiple venepunctures/cannulation as assessed by the Investigator at screening
8. Clinically significant abnormal biochemistry, hematology, coagulation, or urinalysis as judged by the Investigator
9. Positive drugs of abuse test result or alcohol breath test
10. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody (Ab) or human immunodeficiency virus (HIV) results
11. History of any clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal (GI) disease that may have compromised the subject's safety or interfered with the objectives of the study as judged by the investigator

12. Subject had a history or presence of any of the following:

    • Active GI disease requiring therapy
    • Hepatic disease and/or alanine aminotransaminase (ALT) or aspartate aminotransaminase (AST) > 1.5 × upper limit of normal (ULN) at screening
    • Renal disease and/or serum creatinine > 1.5 × ULN at screening
    • Other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs
13. QT interval corrected using Fridericia's formula (QTcF) > 450 msec at the screening or admission ECG
14. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients
15. Known sensitivity to ROCK2 inhibitor agents or to any of the constituents of the belumosudil formulation
16. Presence or history of clinically significant allergy requiring treatment, as judged by the Investigator. Hayfever is permitted unless it is active.
17. Donation or loss of > 400 mL of blood within the previous 3 months
18. Taking or had taken any prescribed or over-the-counter drug (other than 4 g per day paracetamol) or herbal remedies in the 14 days before IP administration
19. Fails to satisfy the Investigator's discretion of fitness to participate or for any other reason

Additional Restrictions

1. Abstain from alcohol during the 24 h prior to each admission until discharge from the clinic in each study period
2. Not to drink liquids or eat food containing grapefruit, cranberry, caffeine, or other xanthines from 24 hours prior to each admission until 48 hours post-dose
3. Refrain from eating food containing any seeds (e.g., poppy) for 48 hours before the screening visit and then from 48 h prior to each admission until discharge from the clinic for each study period
4. Not to take part in any unaccustomed strenuous exercise from 72 hours prior to the screening visit and then from 72 hours prior to admission until discharge from the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regimen A; Single-dose belumosudil 200 mg tablet in the fasted state	Drug: Belumosudil Tablet; Other Names: Rezurock (brand); SLx-2119
Experimental: Regimen B; Single-dose belumosudil 200 mg tablet in the fed state	Drug: Belumosudil Tablet; Other Names: Rezurock (brand); SLx-2119
Experimental: Regimen C; Single-dose belumosudil capsules (administered as two 100-mg capsules) in the fed state	Drug: Belumosudil Capsule; Other Names: Rezurock (brand); SLx-2119

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics: Cmax of Dosing Regimen A (Tablets--Fasting) vs. Dosing Regimen B (Tablets--Fed) for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose	Maximum concentration (Cmax) of parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) at 48 hours after dosing	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose
Pharmacokinetics: AUCs of Dosing Regimen A (Tablets--Fasting) vs. Dosing Regimen B (Tablets--Fed) for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose	Area under concentration-time curve from zero to last dose of belumosudil 200 mg tablets (AUC[0-last]) and from zero to infinity (AUC[0-inf]) for Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) at 48 hours after dosing	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics: Cmax for the Relative Bioavailability of Regimen B/Regimen A and Regimen B/Regimen C by Ratio of the Adjusted Geometric Means at 48 Hours Post-dose	Analysis of the maximum concentration (Cmax) of the relative bioavailability of Regimen B (belumosudil 200 mg tablet-fed) vs. Regimen A (belumosudil 200 mg tablet-fasting) and for Regimen B vs. Regimen C (belumosudil 200 mg capsule-fed) utilizing the Ratio of the Adjusted Geometric Means at 48 hours after dosing	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose
Pharmacokinetics: AUCs for the Relative Bioavailability of Regimen B/Regimen A and Regimen B/Regimen C by Ratio of the Adjusted Geometric Means at 48 Hours Post-dose	Analysis of the area under concentration-time curve for zero to infinity (AUC[0-inf]), and zero to last dose (AUC[0-last]) of the relative bioavailability of Regimen B (belumosudil 200 mg tablet-fed) vs. Regimen A (belumosudil 200 mg tablet-fasting) and for Regimen B vs. Regimen C (belumosudil 200 mg capsule-fed) utilizing the Ratio of the Adjusted Geometric Means at 48 hours after dosing	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose
Pharmacokinetics: Cmax of Dosing Regimen A (Tablets--Fasting) vs. Dosing Regimen B (Tablets--Fed) vs. Dosing Regimen C (Capsules--Fed) for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose	Maximum concentration (Cmax) of parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) compared to a single dose of belumosudil 200 mg capsule (two 100-mg capsules) to subjects who are fed (Regimen C) at 48 hours after dosing	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose
Pharmacokinetics: AUCs of Regimen A (Tablet--Fasting) vs. Dosing Regimen B (Tablet--Fed) vs. Dosing Regimen C (Capsule--Fed) for KD025, KD025m1, and KD025m2 for Belumosudil 200 mg at 48 Hours Post-dose	Area under concentration curve from zero to last dose (AUC[0-last]) and from zero to infinity (AUC[0-inf]) for parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) compared to administering a single dose of 200 mg capsule (two 100-mg capsules) to subjects who are fed at 48 hours after dosing	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose
Pharmacokinetics: Lambda-z for Regimens A, B, and C for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose	Slope of the regression line passing through the apparent elimination phase in a concentration-time plot (Lambda-z) for Regimen A, Regimen B, and Regimen C for for the parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) at 48 hours after dosing	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose
Pharmacokinetics: t(1/2), MRT(0-last), and MRT(0-inf) for Regimens A, B, and C for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose	Apparent elimination half-life (t[1/2]), mean residence time from zero to last dose (MRT[0-last]), and MRT for zero to infinity (MRT[0-inf]) for Regimen A, Regimen B, and Regimen C for for the parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) at 48 hours after dosing	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose
Safety: Number of Subjects With TEAEs and SAEs	Number of subjects with treatment-emergent adverse events (TEAEs), severity and relationship to belumosudil, serious adverse events (SAEs), TEAEs leading to withdrawal from study, and deaths. Treatment-emergent adverse events (TEAEs) are AEs that are not present before the first dose of IMP or that are present before the first dose of IMP but worsen in intensity during exposure to IMP. Severity: mild = 1; moderate = 2; severe = 3; life-threatening = 4; and death = 5. Related to belumosudil defined as possibly related, probably related, and related.	Approximately 1 month
Safety: Total Number of Participants With TEAEs, Related TEAEs, Leading to Withdrawal, Severe, Serious, Leading to Death	Total number of subjects who had treatment-emergent adverse events (TEAEs), TEAEs related to belumosudil, TEAEs leading to withdrawal of subject, severe TEAEs, serious TEAE (SAE), and TEAEs leading to death. Treatment-emergent adverse events (TEAEs) are AEs that are not present before the first dose of IMP or that are present before the first dose of IMP but worsen in intensity during exposure to IMP. Severity: mild = 1; moderate = 2; severe = 3; life-threatening = 4; and death = 5. Related to belumosudil defined as possibly related, probably related, and related.	Approximately 1 month

Collaborators and Investigators

• Sponsor: Kadmon Corporation, LLC
• Collaborators: Quotient Clinical

Publications and helpful links

General Publications

• Schueller O, McDermott J, Evans P, Lohmer L, Alabanza A, Patel J. Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects. Clin Pharmacol Drug Dev. 2022 Jul;11(7):807-814. doi: 10.1002/cpdd.1083. Epub 2022 Mar 2.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): October 12, 2015
• Study Completion (Actual): October 12, 2015

Study Registration Dates

• First Submitted: September 1, 2015
• First Submitted That Met QC Criteria: September 21, 2015
• First Posted (Estimate): September 23, 2015

Study Record Updates

• Last Update Posted (Actual): May 25, 2022
• Last Update Submitted That Met QC Criteria: May 9, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Belumosudil
• Other Study ID Numbers: KD025-106; 2015-002832-42 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No