Human Absorption, Distribution and Metabolism Study (hAME) [14C]-KD025
Condition: Autoimmune Diseases; Fibrosis
MeSH terms: Autoimmune Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      Human, absorption, metabolism and excretion study of belumosudil (KD025)
    

Detailed description: 
      This is an open-label, 2-part study designed to assess the absolute bioavailability of
      belumosudil (KD025) and to determine the mass balance recovery, metabolite profile, and
      identification of metabolite structures for [14C]-KD025 in healthy male subjects.

      Primary Objectives

        -  To determine the absolute oral bioavailability of KD025 (Part 1)

        -  To determine the mass balance recovery after a single oral dose of [14C]-KD025 (Part 2)

        -  To provide plasma, urine, and fecal samples for metabolite profiling and structural
           identification (Part 2)

      Secondary Objectives

        -  To obtain information regarding the oral PK of total radioactivity, KD025 and its
           metabolites KD025m1 and KD025m2, in plasma

        -  To obtain information regarding the intravenous (IV) pharmacokinetics (PK) of
           [14C]-KD025 in plasma (Part 1)

        -  To determine the routes and rates of elimination of [14C]-KD025 and associated total
           radioactivity (Part 2)

        -  To evaluate the extent of distribution of total radioactivity into blood cells (Part 2)

        -  To assess the qualitative and quantitative metabolic profile of [14C]-KD025 and carry
           out the structural elucidation of the main metabolites in plasma (accounting for ≥ 10%
           of circulating total radioactivity) and in urine and fecal samples accounting for ≥ 10%
           of administered dose (Part 2)

        -  To provide additional safety and tolerability information for belumosudil

      PART 1:

      Part 1 is an open-label, non-randomized single oral dose followed by an IV microtracer
      assessment in 5 healthy male subjects. Subjects receive a single oral dose of belumosudil
      (KD025) 200 mg Tablet (Treatment A), in the fed state following a standard breakfast on the
      morning of Day 1. Subjects then receive an IV dose of 100 μg [14C]-KD025 (a 'microdose')
      containing not more than (NMT) 37 kBq (kilobecquerel; 1000 nanocurie [nCi]) [14C], as a 15
      min IV infusion (Treatment B), beginning 1.75 hours (h) after the oral dose administration
      (Treatment A), i.e., 15 minutes [min] before the expected time of maximum concentration
      [Tmax] 2 h) for the oral dose.

      Planned enrollment is to be 6 subjects to ensure 4 evaluable subjects. An evaluable subject
      for Part 1 will be defined as a subject who had sufficient data for evaluation of the primary
      oral bioavailability objective of the study.

      All subjects are to undergo preliminary screening procedures to determine their eligibility
      for Part 1 and Part 2 at the screening visit (Day -28 to Day -2 of Part 1). Subjects are to
      be admitted to the clinical unit on the evening prior to investigational medicinal product
      (IMP) administration (Day -1 of Part 1) for confirmation of eligibility and baseline
      procedures. Subjects will be dosed on the morning following admission (Day 1 of Part 1).
      Following an overnight fast (approximately 10 h), subjects are to consume a standard
      breakfast and receive a single dose of Belumosudil 200 mg Tablet (Treatment A) 30 min after
      the start of breakfast. At 1 h 45 min (1.75 h) after Treatment A administration, subjects are
      to receive an IV infusion of [14C]-KD025 solution, 100 µg (Treatment B). Subjects are to
      remain resident in the clinic until up to 48 hours post-oral dose (up to Day 3). The minimum
      washout period between dose administrations in Part 1 and 2 is 7 days.

      PART 2:

      Part 2 is an open-label, non-randomized absorption, distribution, metabolism, and elimination
      (ADME) assessment in 5 healthy male subjects. Following a minimum washout period of 7 days,
      subjects who participated in Part 1 of the study are to be admitted to the clinical unit for
      participation in Part 2 of the study. Subjects are to receive a single oral administration of
      [14C]-KD025 200 mg Capsule containing NMT 9.8 MBq (266 µCi) [14C] (Treatment C) in the fed
      state following a standard breakfast on the morning of Day 1.

      A subject in Part 2 will be considered evaluable if they had provided biological samples for
      up to 168 hours after drug administration or demonstrates >90% mass balance recovery, or < 1%
      of the administered dose eliminated in excreta for 2 consecutive days, whichever was sooner.

      Approximately 7 days after subjects are discharged from Part 1 of the study, subjects are to
      be admitted to the clinical unit on the evening of the day prior to IMP administration (Day
      -1 of Part 2) for confirmation of eligibility and baseline procedures.

      Subjects are to be dosed on the morning following admission (Day 1 of Part 2). Following an
      overnight fast (approximately 10 h), subjects consume a standard breakfast and receive a
      single dose of [14C]-KD025 200 mg Capsule (Treatment C) 30 min after the start of breakfast.
      Subjects are to remain in the clinic until up to 168 hours after dosing (up to Day 8 of Part
      2). The plan is for subjects to be released as a group when all subjects had achieved a mass
      balance cumulative recovery of > 90% or if < 1% of the dose administered had been collected
      in urine and feces within 2 separate consecutive 24-hour periods. This may result in the
      subjects being discharged as a group prior to completion of the planned residency period.
      Once the discharge criteria or the planned residency period is achieved, the subjects are to
      undergo discharge assessments; collection of all samples (blood, urine and feces) is stopped.

      If mass balance criteria has not been met by all subjects on Day 8, the residency period for
      the subjects not achieving the release criteria may be extended up to a maximum of 216 h
      post-dose (Day 10 of Part 2). During the additional residency period, only urine and/or feces
      are to be collected. If the criterion is still not met by Day 10, or if additional residency
      not considered appropriate or necessary, then home collections of urine and/or feces may be
      requested at the discretion of the Investigator for individual subjects. To ensure ongoing
      well-being of subjects, a follow-up phone call will take place 5 to 7 days post-discharge
      from the study or after the end of the last collection period.
    

Intervention name(s): Belumosudil 200 mg tablet; [14C]-KD025 at a dose of 100 μg in a 5 mL solution IV microdose; [14C]-KD025 200 mg capsule
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Belumosudil 200 mg tablet, development candidate; test investigational medicinal product; test investigational medicinal product
Other intervention name(s): Rezurock (brand name); KD025; SLx-2119
Intervention MeSH terms: Belumosudil
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Single center, non-randomized, open-label, 2-part study
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: absorption; metabolism; excretion