Clinical trial NCT03530995: Drug-drug Interaction Between Belumosudil, Itraconazole, Rifampicin, Rabeprazole, and Omeprazole in Healthy Volunteers
Official title: A 2-Part, Non-randomized, Open-label Study to Evaluate the Effect of Itraconazole, Rifampicin, Rabeprazole, and Omeprazole on the Pharmacokinetics of Belumosudil (KD025)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Drug-drug Interaction
Autoimmune Diseases
Fibrotic Disease
Lead sponsor: Kadmon Corporation, LLC
Sponsor class: INDUSTRY
Collaborators: name: Quotient Sciences
First posted: 2018-05-21
Enrollment: 73
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Two-Part, Non-Randomised
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1
timeFrame: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose
measure: Pharmacokinetics: Cmax of KD025m1 in Part 1
timeFrame: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose
measure: Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2
timeFrame: 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
measure: Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2
timeFrame: 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
measure: Pharmacokinetics: AUC(0-24) of KD025m1 for Part 1 and for Part 2
timeFrame: 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
Secondary outcomes:
Other outcomes:
Locations:
city: Ruddington
country: United Kingdom
facility: Quotient Sciences Ltd
state: Nottingham
Study officials:
References:
citation: Schueller O, Willson A, Singh N, Lohmer L, Alabanza A, Patel J. A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors. Clin Pharmacol Drug Dev. 2022 Jul;11(7):795-806. doi: 10.1002/cpdd.1082. Epub 2022 Mar 1.