Influence of Fedratinib on the Pharmacokinetics of the Transporter Probe Substrates Digoxin, Rosuvastatin, and Metformin

NCT04231435 | Completed Phase 1 FDA Drug

• 2 other identifiers: FEDR-CP-003U1111-1245-6233
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This is a nonrandomized, fixed-sequence, open-label study to evaluate the effect of a single dose of fedratinib on the PK, safety, and tolerability of single doses of digoxin, rosuvastatin, and metformin in healthy subjects. The subjects will participate as follows:

• Screening phase
• Treatment phase (includes baseline)
• Follow-up telephone call Subjects will be screened for eligibility during the screening phase. Subjects who meet all inclusion criteria and none of the exclusion criteria will return to the clinical site on Day -1 for protocol-specified assessments, and will be domiciled at the clinical site from Day -1 through the morning of Day 22. During the study, blood samples will be collected at prespecified times for PK and PD. Urine samples will be collected at prespecified times for urinary PK evaluation of metformin. Subject safety will be monitored throughout the study.

Conditions

Healthy Volunteers

Keywords

Healthy Adult Subjects; Fedratinib; Drug Interactions; Transporters

Outcome Measures

Primary Outcomes (4)

• Pharmacokinetic - Cmax (Digoxin, Rosuvastatin and Metformin

  Maximum observed plasma concentration

  96 hours

• Pharmacokinetic - AUC (Digoxin, Rosuvastatin and Metformin

  Area under the curve

  96 hours

• Pharmacokinetic - CLr

  Renal Clearance

  48 hours

• Analysis of Glucose AUC after OGTT using linear trapezoidal method

  Area under the curve

  3 hours

Secondary Outcomes (1)

• Adverse Events (AEs)

  From the time the ICF is signed until study completion and up to 30 days after the last dose of IP

Study Arms (1)

Treatment Administration

EXPERIMENTAL

All subjects will receive the following oral doses of IP following an overnight fast in the fixed-sequence below: * Day 1 (Period 1): 1 × 0.25-mg digoxin tablet, 1 × 10-mg rosuvastatin tablet, and 1 × 1000-mg metformin tablet. * Day 7 (Period 2): 6 × 100-mg fedratinib capsules PLUS (after approximately 1 hour from the time of fedratinib administration) 1 × 0.25 mg digoxin tablet, 1 × 10-mg rosuvastatin tablet, and 1 × 1000-mg metformin tablet.

Drug: Fedratinib; Drug: Digoxin; Drug: Rosuvastatin; Drug: Metformin

Interventions

Fedratinib DRUG

Oral

Treatment Administration

Digoxin DRUG

Oral

Treatment Administration

Rosuvastatin DRUG

Oral

Treatment Administration

Metformin DRUG

Oral

Treatment Administration

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must satisfy the following criteria to be enrolled in the study:
• Subject must understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted.
• Subject must be willing and able to communicate with the Investigator and adhere to the study visit schedule and other protocol requirements.
• Subject is male or female of any race ≥ 18 to ≤ 65 years of age at the time of signing the ICF.
• Female subjects NOT of childbearing potential must:
• a. Have been surgically sterilized (hysterectomy or bilateral oophorectomy; proper documentation required) at least 6 months before Screening, or postmenopausal (defined as 24 consecutive months without menses before Screening, with a follicle-stimulating hormone \[FSH\] level in the post-menopausal range according to the laboratory used at Screening).
• Females of childbearing potential (FCBP1) must:
• Have a negative pregnancy test as verified by the investigator at Screening and Baseline (prior to starting study treatment). She must agree to ongoing pregnancy testing during the course of the study, as applicable, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
• Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis, as applicable, and source documented) or agree to use, and be able to comply with, any one of the following highly effective contraception methods without interruption, beginning at least 14 days prior to starting investigational product (IP), during the study treatment, and for at least 30 days after the last dose of IP. - Intrauterine device (IUD; non-hormonal only); tubal ligation; or a partner with a vasectomy. The chosen form of birth control must be effective by the time the subject receives the first dose of IP.
• Male subjects must:
• a. Practice true abstinence from heterosexual contact (which must be reviewed on a monthly basis, as applicable, and source documented) or agree to use a barrier method of birth control (condoms not made from natural \[animal\] membrane \[latex condoms are recommended\]) during sexual contact with a pregnant female or FCBP while receiving study treatment, and for at least 30 days after the last dose of IP, even if he has undergone a successful vasectomy.
• Must have a body mass index (BMI) ≥ 18 and ≤ 33 kg/m2 at screening.
• Must be healthy, as determined by the Investigator on the basis of medical history, physical examination (PE), clinical laboratory test results, vital signs, and 12-lead electrocardiogram (ECG) at screening and check-in (Day -1), as applicable:
• Aspartate aminotransferase (AST), ALT, and total bilirubin must be at or below the upper limit of the reference range on or before check-in (Day -1). Other clinical laboratory results must be either within normal range or deemed not clinically significant by the Investigator. Any out of range lab tests may be repeated up to 1 time during Screening and up to 1 time at check-in per Investigator discretion to confirm eligibility.
• Must be afebrile (febrile is defined as ≥ 38°C or 100.3°F).

You may not qualify if:

• The presence of any of the following will exclude a subject from enrollment:
• History (within 3 years prior to Screening) of any clinically significant neurological, GI, hepatic, renal, respiratory, cardiovascular, metabolic, endocrine, hematological, dermatological, psychological, or other major disorders as determined by the Investigator.
• Any condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk if he or she were to participate in the study or confounds the ability to interpret data from the study (congenital nonhemolytic hyperbilirubinemia \[eg, Gilbert's syndrome\] is not acceptable).
• Subject has prior history of Wernicke's Encephalopathy (WE).
• Subject has thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard.
• Subject has an estimated glomerular filtration rate (GFR) of \<90 mL/min/1.73 m2 based on the 4-variable Modification of Diet in Renal Disease (MDRD) equation.
• Use of any prescribed systemic or topical medication, including vaccines, within 30 days of the first dose administration (with the exception of any palonosetron administered for purposes of this study).
• Use of any nonprescribed systemic or topical medication (including vitamin/mineral supplements and herbal medicines) within 14 days of the first dose administration (with the exception of acetaminophen up to 2 grams/day for no more than 3 consecutive days to treat minor illness or headache \[per Investigator judgment\]).
• Use of any metabolic enzyme or relevant transporter inhibitors or inducers that would affect the relevant drugs within 30 days of the first dose administration unless determined by the Investigator that there will be no impact on the study integrity or subject safety.
• Exposure to an investigational drug (new chemical entity) within 30 days preceding the first dose administration or 5 half-lives of that investigational drug, if known (whichever is longer).
• Presence of any surgical or medical conditions possibly affecting drug absorption, distribution, metabolism, and excretion (eg, bariatric procedure, cholecystectomy).
• Appendectomy is acceptable.
• Donated blood or plasma within 8 weeks before the first dose administration.
• History of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual \[DSM\]) within 2 years before dosing or positive drug screening test reflecting consumption of illicit drugs.
• History of alcohol abuse (as defined by the current version of the DSM) within 2 years before dosing or positive alcohol screen.

Sponsors & Collaborators

• Celgene: lead
• Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation: collaborator

Study Sites (1)

PPD Phase 1 Clinic

Austin, Texas, 78744, United States

Location

Related Publications (1)

• Ogasawara K, Wood-Horrall RN, Thomas M, Thomas M, Liu L, Liu M, Xue Y, Surapaneni S, Carayannopoulos LN, Zhou S, Palmisano M, Krishna G. Impact of fedratinib on the pharmacokinetics of transporter probe substrates using a cocktail approach. Cancer Chemother Pharmacol. 2021 Dec;88(6):941-952. doi: 10.1007/s00280-021-04346-7. Epub 2021 Sep 3.

  PMID: 34477937 DERIVED

MeSH Terms

Interventions

fedratinib; Digoxin; Rosuvastatin Calcium; Metformin

Intervention Hierarchy (Ancestors)

Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates; Sulfonamides; Amides; Organic Chemicals; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Biguanides; Guanidines; Amidines

Study Officials

• Leon Carayannopolous, M.D.

  Celgene

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: January 14, 2020
• First Posted: January 18, 2020
• Study Start: December 18, 2019
• Primary Completion: February 19, 2020
• Study Completion: February 21, 2020
• Last Updated: May 21, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: See Plan Description
• Access Criteria: See Plan Description

Locations

US (1)