Drug-drug Interaction, Autoimmune Diseases, Fibrotic Disease
Conditions
Brief summary
This is a single-center, 2-part, non-randomized, open-label study of the drug-drug interactions of belumosudil (KD025) with itraconazole, rifampicin, rabeprazole, and omeprazole in healthy male subjects.
Detailed description
Part 1: The primary objective of Part 1 of this study is to determine the effect of itraconazole, rifampicin, and rabeprazole on the pharmacokinetics of once daily (QD) orally administered belumosudil in healthy male subjects. Part 1 consists of 4 periods. In each study period, subjects will receive a single dose of belumosudil, in the fed state. Additionally, in order to assess the effects of inhibition and induction of CYP3A4 and the elevation of gastric pH on belumosudil exposure, subjects will receive multiple doses of perpetrator drugs in Periods 2 to 4; a strong CYP3A4 inhibitor, itraconazole, in Period 2; a proton pump inhibitor, rabeprazole, in Period 3; and a strong CYP3A4 inducer, rifampicin, in Period 4. Subjects will receive a total of 4 single oral dosses of investigative product (IP), 200 mg belumosudil QD, in the fed state over 4 periods (each lasting 3 days with a minimum washout of 2, 8, and 4 days following completion of Periods 1, 2, and 3, respectively). Subjects also will receive 9 single oral doses of itraconazole 200 mg (QD over 9 days) in Period 2; 7 single oral doses of rabeprazole 20 mg (BID over 3 days followed by QD on 1 day) in Period 3; and 9 single doses of rifampicin 600 mg (QD over 9 days) in Period 4. A follow-up visit will take place 3 to 5 days post-final discharge. Part 2: The primary objective of Part 2 of this study is to determine the effect of omeprazole on the PK of a single-day twice daily (BID; every 12 hours \[Q12h\]) dose of belumosudil administered orally, in healthy male subjects. Part 2 consists of 2 periods. In Period 1, subjects will receive a single dose of belumosudil, in the fed state. In Period 2, in order to assess the effects of inhibition and induction of CYP3A4 and the elevation of gastric pH on belumosudil exposure, subjects will receive multiple doses of a proton pump inhibitor, omeprazole. Subjects will receive a total of 4 single oral doses of IP (200 mg belumosudil, BID \[Q12h\] on 2 occasions) in the fed state over 2 periods (each lasting 3 days with a minimum washout of 2 days between dosing in Period 1 and the start of dosing with non-IP in Period 2). Subjects will also receive 4 single oral doses of omeprazole 20 mg (QD over 4 days) in Period 2. A follow-up visit will take place 3 to 5 days post-final discharge.
Interventions
DRUGRabeprazole
Perpetrator drug
DRUGRifampicin
Perpetrator drug
DRUGItraconazole
Perpetrator drug
DRUGBelumosudil
Development candidate
DRUGOmeprazole
Perpetrator drug
Sponsors
Quotient Sciences
Kadmon Corporation, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Two-Part, Non-Randomised
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males 2. Age 18 to 55 years 3. Good state of health (mentally and physically) as indicated by a comprehensive clinical assessment (detailed medical history and a complete physical examination), electrocardiogram (ECG) and laboratory investigations (hematology, clinical chemistry, and urinalysis) 4. Body weight ≥50 kg 5. Body mass index of 18.0 to 32.0 kg/m\^2 or, if outside the range, considered not clinically significant by the investigator 6. Must be willing and able to communicate and participate in the whole study 7. Must provide written informed consent 8. Must adhere to the contraception requirements
Exclusion criteria
1. Subjects who had previously participated in any other investigational study drug trial in which receipt of an IP occurred within 90 days prior to dosing. (Subjects who had previously received belumosudil in Part 1 at least 90 days prior to dosing in Part 2 were eligible to participate.) 2. Subjects who are study site employees, or immediate family members of a study site or sponsor employee 3. Subjects with pregnant partners 4. History of any drug or alcohol abuse in the past 2 years 5. Regular alcohol consumption in males \>21 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type) 6. Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission 7. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months 8. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening 9. Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator 10. Positive drugs of abuse test result at screening and admission 11. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results 12. Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of \<80 mL/min using the Cockcroft-Gault equation 13. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator 14. Subject has a history or presence of any of the following: * Active gastrointestinal disease requiring therapy * Hepatic disease and/or alanine aminotransaminase (ALT) or aspartate aminotransaminase (AST) \> ULN * Renal disease and/or serum creatinine \> ULN * Other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs 15. Subjects with a history of cholecystectomy or gall stones 16. Subject has QT interval corrected using Fridericia's formula (QTcF) intervals \>450 msec at screening or admission 17. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients; including intolerance to itraconazole, rabeprazole, and rifampicin 18. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active 19. Donation or loss of greater than 400 mL of blood within the previous 3 months 20. Subjects who are taking, or have 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. 21. Failure to satisfy the investigator of fitness to participate for any other reason Subjects Agreed to the Following Restrictions During the Duration of the Study: 1. No alcohol during the 24-hour period prior to screening and the 24-hour period prior to admission in Period 1, and 24 hours prior to commencing non-IP treatment in Part 1, Periods 2 to 4 and Part 2, Period 2, until discharge for each treatment period. 2. No food or drinks containing grapefruit or cranberry from 24 hours prior to admission in Period 1, and 24 hours prior to commencing non-IP treatment in Part 1 Periods 2 to 4 and Part 2 Period 2, until discharge for each treatment period. 3. No food or drinks containing caffeine or other xanthines from 24 hours prior to admission until discharge for each treatment period. 4. No food containing poppy seeds for 48 hours prior to screening and for 24 hours prior to admission until discharge for each treatment period. 5. No unaccustomed or strenuous exercise from the 72-hour period before the screening visit and then from 24 hours prior to admission until discharge for each treatment period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 | Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose | Maximum concentration (Cmax) of the parent drug, KD025, Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) for belumosudil alone, belumosudil + itraconazole, belumosudil + rabeprazole, and belumosudil + rifampicin at 0 to 48 hours post-dose |
| Pharmacokinetics: Cmax of KD025m1 in Part 1 | Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose | Maximum concentration (Cmax) of Metabolite 1 (KD025m1) for belumosudil alone and for belumosudil + rifampicin up to 48 hours post-dose |
| Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22,24,36, and 48 hours post-dose | Maximum concentration (Cmax) of the parent drug (KD025), for Metabolite 1 (KD025m1), and for Metabolite 2 (KD025m2), for belumosudil alone and for belumosudil + omeprazole up to 48 hours post-dose |
| Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | Part 1: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose; Part 2: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22,24,36, and 48 hours post-dose | Area under concentration-time curve from zero hours to infinity (AUC\[0-inf\]) and from zero hours to 24 hours post-dose (AUC\[0-24)) for the parent drug KD025, and Metabolite 2, KD025m2, for subjects up to 48 hours each for Part 1 and for Part 2 |
| Pharmacokinetics: AUC(0-24) of KD025m1 for Part 1 and for Part 2 | Part 1: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12, and 24 hours post-dose; Part 2: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22, and 24 hours post-dose | Area under concentration-time curve from zero hours to 24 hours post-dose (AUC\[0-24\]) for Metabolite 1, KD025m1, for subjects in Part 1 and for subjects in Part 2 |
Countries
United Kingdom
Participant flow
Recruitment details
This was a single centre, non-randomised, open label, two-part study. Part 1 of the study was a 4-period sequential dose study in healthy male subjects. The estimated duration from screening to discharge from the study was approximately 10 weeks. Part 2 of the study was a 2-period sequential dose study in healthy males. The estimated duration from screening to discharge from the study was approximately 7 weeks.
Participants by arm
| Arm | Count |
|---|---|
| All Subjects Part 1: KD025 QD Dosing Period 1: 200 mg KD025 QD alone; Period 2: 200 mg KD025 QD with Itraconazole; Period 3: 200 mg KD025 QD with Rabeprazole; Period 4: 200 mg KD025 QD with Rifampicin | 35 |
| All Subjects in Part 2: KD025 BID Dosing Period 1: 200 mg KD025 BID alone; Period 2: 200 mg KD025 BID with Omeprazole | 38 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 1 Period 3 | Protocol Violation | 1 | 0 |
| Part 1 Period 3 | Withdrawal by Subject | 2 | 0 |
| Part 1 Period 4 | Physician Decision | 1 | 0 |
| Part 1 Period 4 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | All Subjects Part 1: KD025 QD Dosing | All Subjects in Part 2: KD025 BID Dosing | Total |
|---|---|---|---|
| Age, Continuous | 37.0 years STANDARD_DEVIATION 11.8 | 32.6 years STANDARD_DEVIATION 10.6 | 34.7 years STANDARD_DEVIATION 11.4 |
| BMI (body mass index) | 26.81 kg/m^2 STANDARD_DEVIATION 3 | 25.94 kg/m^2 STANDARD_DEVIATION 3.36 | 26.36 kg/m^2 STANDARD_DEVIATION 3.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 28 Participants | 35 Participants | 63 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 35 Participants | 38 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 | 0 / 33 | 0 / 32 | 0 / 38 | 0 / 38 |
| other Total, other adverse events | 6 / 35 | 9 / 35 | 6 / 33 | 8 / 32 | 9 / 38 | 5 / 38 |
| serious Total, serious adverse events | 0 / 35 | 1 / 35 | 0 / 33 | 0 / 32 | 0 / 38 | 0 / 38 |
Outcome results
Primary
Pharmacokinetics: AUC(0-24) of KD025m1 for Part 1 and for Part 2
Area under concentration-time curve from zero hours to 24 hours post-dose (AUC\[0-24\]) for Metabolite 1, KD025m1, for subjects in Part 1 and for subjects in Part 2
Time frame: Part 1: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12, and 24 hours post-dose; Part 2: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22, and 24 hours post-dose
Population: Subjects in Part 1 who received belumosudil alone and belumosudil with rifampicin; Subjects in Part 2 who received belumosudil alone and belumosudil with omeprazole. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: AUC(0-24) of KD025m1 for Part 1 and for Part 2 | 75.6 (ng*h)/mL | Geometric Coefficient of Variation 42.1 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: AUC(0-24) of KD025m1 for Part 1 and for Part 2 | 148 (ng*h)/mL | Geometric Coefficient of Variation 41.9 |
| Part 1, Period 3: Belumosudil + Rabeprazole | Pharmacokinetics: AUC(0-24) of KD025m1 for Part 1 and for Part 2 | 138 (ng*h)/mL | Geometric Coefficient of Variation 91.3 |
| Part 1, Period 4: Belumosudil + Rifampicin | Pharmacokinetics: AUC(0-24) of KD025m1 for Part 1 and for Part 2 | 91.5 (ng*h)/mL | Geometric Coefficient of Variation 76.3 |
Primary
Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2
Area under concentration-time curve from zero hours to infinity (AUC\[0-inf\]) and from zero hours to 24 hours post-dose (AUC\[0-24)) for the parent drug KD025, and Metabolite 2, KD025m2, for subjects up to 48 hours each for Part 1 and for Part 2
Time frame: Part 1: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose; Part 2: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22,24,36, and 48 hours post-dose
Population: Subjects in Part 1 who received belumosudil alone, belumosudil with itraconazole, belumosudil with rabeprazole, and belumosudil with rifampicin; Subjects in Part 2 who received belumosudil alone and belumosudil with omeprazole. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025m2 | 1100 (ng*h)/mL | Geometric Coefficient of Variation 63.7 |
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025 | 8430 (ng*h)/mL | Geometric Coefficient of Variation 30.5 |
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025 | 9080 (ng*h)/mL | Geometric Coefficient of Variation 33.3 |
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025m2 | 1230 (ng*h)/mL | Geometric Coefficient of Variation 69.5 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025 | 10400 (ng*h)/mL | Geometric Coefficient of Variation 35.8 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025 | 11200 (ng*h)/mL | Geometric Coefficient of Variation 38.1 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025m2 | 745 (ng*h)/mL | Geometric Coefficient of Variation 70.7 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025m2 | 843 (ng*h)/mL | Geometric Coefficient of Variation 73.7 |
| Part 1, Period 3: Belumosudil + Rabeprazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025m2 | 110 (ng*h)/mL | Geometric Coefficient of Variation 84 |
| Part 1, Period 3: Belumosudil + Rabeprazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025 | 1680 (ng*h)/mL | Geometric Coefficient of Variation 65.8 |
| Part 1, Period 3: Belumosudil + Rabeprazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025m2 | 174 (ng*h)/mL | Geometric Coefficient of Variation 11.1 |
| Part 1, Period 3: Belumosudil + Rabeprazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025 | 1510 (ng*h)/mL | Geometric Coefficient of Variation 60.7 |
| Part 1, Period 4: Belumosudil + Rifampicin | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025m2 | 396 (ng*h)/mL | Geometric Coefficient of Variation 50.2 |
| Part 1, Period 4: Belumosudil + Rifampicin | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025 | 2500 (ng*h)/mL | Geometric Coefficient of Variation 34.5 |
| Part 1, Period 4: Belumosudil + Rifampicin | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025m2 | 376 (ng*h)/mL | Geometric Coefficient of Variation 56.7 |
| Part 1, Period 4: Belumosudil + Rifampicin | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025 | 2490 (ng*h)/mL | Geometric Coefficient of Variation 34.1 |
| Part 2, Period 1: Belumosudil Only | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025m2 | 1900 (ng*h)/mL | Geometric Coefficient of Variation 90.4 |
| Part 2, Period 1: Belumosudil Only | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025 | 18800 (ng*h)/mL | Geometric Coefficient of Variation 37.1 |
| Part 2, Period 1: Belumosudil Only | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025 | 16800 (ng*h)/mL | Geometric Coefficient of Variation 36.4 |
| Part 2, Period 1: Belumosudil Only | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025m2 | 1950 (ng*h)/mL | Geometric Coefficient of Variation 82.3 |
| Part 2, Period 2: Belumosudil + Omeprazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025m2 | 767 (ng*h)/mL | Geometric Coefficient of Variation 115.3 |
| Part 2, Period 2: Belumosudil + Omeprazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025 | 9880 (ng*h)/mL | Geometric Coefficient of Variation 59.2 |
| Part 2, Period 2: Belumosudil + Omeprazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-inf): KD025m2 | 1110 (ng*h)/mL | Geometric Coefficient of Variation 30.3 |
| Part 2, Period 2: Belumosudil + Omeprazole | Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 | AUC(0-24): KD025 | 7970 (ng*h)/mL | Geometric Coefficient of Variation 58.9 |
Primary
Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1
Maximum concentration (Cmax) of the parent drug, KD025, Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) for belumosudil alone, belumosudil + itraconazole, belumosudil + rabeprazole, and belumosudil + rifampicin at 0 to 48 hours post-dose
Time frame: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose
Population: Subject in Part 1 who received belumosudil alone, belumosudil with itraconazole, belumosudil with rabeprazole, and belumosudil with rifampicin. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 | Parent Drug KD025 | 1770 ng/mL | Geometric Coefficient of Variation 31.3 |
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 | KD025m2 | 337 ng/mL | Geometric Coefficient of Variation 54.7 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 | Parent Drug KD025 | 2130 ng/mL | Geometric Coefficient of Variation 31 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 | KD025m2 | 221 ng/mL | Geometric Coefficient of Variation 60.8 |
| Part 1, Period 3: Belumosudil + Rabeprazole | Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 | Parent Drug KD025 | 227 ng/mL | Geometric Coefficient of Variation 58.4 |
| Part 1, Period 3: Belumosudil + Rabeprazole | Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 | KD025m2 | 23.5 ng/mL | Geometric Coefficient of Variation 70.7 |
| Part 1, Period 4: Belumosudil + Rifampicin | Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 | KD025m2 | 148 ng/mL | Geometric Coefficient of Variation 57.3 |
| Part 1, Period 4: Belumosudil + Rifampicin | Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 | Parent Drug KD025 | 712 ng/mL | Geometric Coefficient of Variation 35 |
Primary
Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2
Maximum concentration (Cmax) of the parent drug (KD025), for Metabolite 1 (KD025m1), and for Metabolite 2 (KD025m2), for belumosudil alone and for belumosudil + omeprazole up to 48 hours post-dose
Time frame: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22,24,36, and 48 hours post-dose
Population: Subjects in Part 2 who received belumosudil alone and belumosudil with omeprazole. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--1st Dose: KD025m1 | 23.8 ng/mL | Geometric Coefficient of Variation 39.6 |
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--2nd Dose: KD025m2 | 257 ng/mL | Geometric Coefficient of Variation 83.9 |
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--2nd Dose: KD025m1 | 23.6 ng/mL | Geometric Coefficient of Variation 46.4 |
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--2nd dose: KD025 | 1760 ng/mL | Geometric Coefficient of Variation 37 |
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--1st Dose: KD025m2 | 282 ng/mL | Geometric Coefficient of Variation 75.6 |
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--1st dose: KD025 | 1790 ng/mL | Geometric Coefficient of Variation 34.5 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--2nd Dose: KD025m2 | 115 ng/mL | Geometric Coefficient of Variation 121.8 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--1st dose: KD025 | 575 ng/mL | Geometric Coefficient of Variation 145.7 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--2nd dose: KD025 | 903 ng/mL | Geometric Coefficient of Variation 63.8 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--1st Dose: KD025m1 | 18.0 ng/mL | Geometric Coefficient of Variation 54.6 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--2nd Dose: KD025m1 | 18.9 ng/mL | Geometric Coefficient of Variation 48.7 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 | Cmax--1st Dose: KD025m2 | 72.3 ng/mL | Geometric Coefficient of Variation 166.8 |
Primary
Pharmacokinetics: Cmax of KD025m1 in Part 1
Maximum concentration (Cmax) of Metabolite 1 (KD025m1) for belumosudil alone and for belumosudil + rifampicin up to 48 hours post-dose
Time frame: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose
Population: Subjects in Part 1 who received belumosudil alone and belumosudil with rifampicin. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1, Period 1: Belumosudil Alone | Pharmacokinetics: Cmax of KD025m1 in Part 1 | 23.2 ng/mL | Geometric Coefficient of Variation 40 |
| Part 1, Period 2: Belumosudil + Itraconazole | Pharmacokinetics: Cmax of KD025m1 in Part 1 | 52.5 ng/mL | Geometric Coefficient of Variation 34 |