Drug-drug Interaction Between Belumosudil, Itraconazole, Rifampicin, Rabeprazole, and Omeprazole in Healthy Volunteers

Phase 1

Completed

• Conditions: Drug-drug Interaction; Autoimmune Diseases; Fibrotic Disease
• Interventions: Drug: Belumosudil; Drug: Itraconazole; Drug: Rabeprazole; Drug: Rifampicin; Drug: Omeprazole

• Registration Number: NCT03530995
• Lead Sponsor: Kadmon Corporation, LLC

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.

Study Timeline

• Study Start: 2018-04-09
• Study First Submitted: 2018-04-13
• Study First Submitted QC: 2018-05-09
• Study First Posted: 2018-05-21
• Primary Completion: 2019-02-08
• Study Completion: 2019-02-08
• Results First Submitted: 2021-08-13
• Results First Submitted QC: 2021-08-13
• Results First Posted: 2021-09-13
• Status Verified: 2022-05
• Last Update Submitted: 2022-05-09
• Last Update Posted: 2022-05-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 73

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1, Period 3	Belumosudil	Drug: Rabeprazole. Subjects will receive rabeprazole 20 mg BID on Day 1 through Day 3. Drug: Belumosudil. Subjects will receive belumosudil 200 mg + rabeprazole 20 mg QD on Day 4.
Part 1, Period 1	Belumosudil	Drug: Belumosudil. Subjects will receive belumosudil 200 mg single dose on Day 1
Part 1, Period 2	Belumosudil	Drug: Itraconazole. Subjects will receive itraconazole 200 mg QD on Day 1 through Day 7. Drug: Belumosudil. Subjects will receive belumosudil 200 mg + itraconazole 200 mg QD on Day 8 Subjects will receive itraconazole 200 mg QD on Day 9
Part 1, Period 2	Itraconazole	Drug: Itraconazole. Subjects will receive itraconazole 200 mg QD on Day 1 through Day 7. Drug: Belumosudil. Subjects will receive belumosudil 200 mg + itraconazole 200 mg QD on Day 8 Subjects will receive itraconazole 200 mg QD on Day 9
Part 1, Period 3	Rabeprazole	Drug: Rabeprazole. Subjects will receive rabeprazole 20 mg BID on Day 1 through Day 3. Drug: Belumosudil. Subjects will receive belumosudil 200 mg + rabeprazole 20 mg QD on Day 4.
Part 1, Period 4	Rifampicin	Drug: Rifampicin. Subjects will receive rifampicin 600 mg QD on Day 1 through Day 9. Drug: Belumosudil. Subjects will receive belumosudil 200 mg on Day 10.
Part 1, Period 4	Belumosudil	Drug: Rifampicin. Subjects will receive rifampicin 600 mg QD on Day 1 through Day 9. Drug: Belumosudil. Subjects will receive belumosudil 200 mg on Day 10.
Part 2, Period 1	Belumosudil	Drug: Belumosudil. Subjects will receive belumosudil 200 mg BID on Day 1.
Part 2, Period 2	Belumosudil	Drug: Omeprazole. Subjects will receive omeprazole 20 mg QD on Day 1 through Day 3. Drug: Belumosudil. Subjects will receive belumosudil 200 mg BID + omeprazole 20 mg QD on Day 4.
Part 2, Period 2	Omeprazole	Drug: Omeprazole. Subjects will receive omeprazole 20 mg QD on Day 1 through Day 3. Drug: Belumosudil. Subjects will receive belumosudil 200 mg BID + omeprazole 20 mg QD on Day 4.

Primary Outcome Measures

Name	Time	Method
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
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: 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: 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 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

Trial Locations

Locations (1)

Quotient Sciences Ltd; 🇬🇧 Ruddington, Nottingham, United Kingdom