Drug-Drug Interaction Study of Pacritinib and CYP450,Transporter Substrates, and CYP450 3A4 in Healthy Male Subjects

NCT05657613 | Completed Phase 1 FDA Drug

• 1 other identifier: PAC109
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1, open-label, fixed-sequence, 2-part DDI study. Subjects will participate in only 1 study part.

Conditions

Drug Interactions

Keywords

Pacritinib; Cytochrome P450 and Transporters

Outcome Measures

Primary Outcomes (6)

• Change in area under curve (AUC) of individual substrates between cocktail alone and cocktail combined with pacritinib administration

  Change in the systemic exposure of digoxin, midazolam omeprazole, rosuvastatin, caffeine and metformin when co-adminstered with pacritinib

  Through study completion, a maximum of 14 days for pacritinib

• Change in maximum plasma concentration (Cmax) of individual substrates between cocktail alone and cocktail combined with pacritinib administration

  To assess the effect of pacritinib on the systemic exposure of digoxin, midazolam, omeprazole, rosuvastatin, caffeine, and metformin

  Through study completion, a maximum of 14 days for pacritinib

• Change in area under curve (AUC) of pacritinib alone and pacritinib + bosentan administration

  To assess the effect of bosentan (CYP450 3A4 inducer) on the systemic exposure of multiple doses of pacritinib

  Through completion, a maximum of 14 days for pacritinib

• Change in Cmax of pacritinib alone and pacritinib + bosentan administration

  To assess the effect of bosentan (CYP450 3A4 inducer) on the peak exposure of multiple doses of pacritinib

  Through study completion, a maximum of 14 days for pacritinib

• Change in AUC of pacritinib alone and pacritinib + fluconazole administration

  To assess the effect of fluconazole (CYP450 3A4 inhibitor) on the systemic exposure of multiple doses of pacritinib

  Through study completion, a maximum of 14 days for pacritinib

• Change in Cmax of pacritinib alone and pacritinib + fluconazole administration

  To assess the effect of fluconazole (CYP450 3A4 inhibitor) on the systemic peak exposure of multiple doses of pacritinib

  Through study completion, a maximum of 14 days for pacritinib

Secondary Outcomes (3)

• Number and severity of adverse events with cocktail substrates in the presence of pacritinib

  Up to 31 days

• Number and severity of adverse events with pacritinib in the presence of CYP450 3A4 inducer

  Up to 31 days

• Number and severity of adverse events with pacritinib in the presence of CYP450 3A4 inhibitor

  Up to 31days

Study Arms (3)

CYP450 Cocktail and Transporter Substrates with Pacritinib

EXPERIMENTAL

This is the first part of the study which is an open-label, single-center, 1-way DDI study designed to assess the effect of pacritinib 200 mg BID at steady state on the systemic exposure of a cocktail of cytochrome P450 (caffeine, midazolam, and omeprazole) and transporter substrates (digoxin, rosuvastatin, and metformin) in 18 healthy male subjects.

Drug: CYP450 Cocktail and Transporter Substrates with Pacritinib

CYP450 3A4 inducer (Bosentan) with Pacritinib

EXPERIMENTAL

The second part of the study comprises of 2 arms. This is the first arm Days 1 through 14: An oral dose of pacritinib 200 mg (2 × 100 mg capsules) BID (approximately 12 hours apart) Days 8 through 14: An oral dose of bosentan 125 mg BID (approximately 12 hours apart) All the doses will be administered with approximately 240 mL of water.

Drug: Part 2 -Group A Bosentan 125 mg (CYP450 3A4 inducer) with Pacritinib

CYP450 3A4 inhibitor (Fluconazole) with Pacritinib

EXPERIMENTAL

This is the second arm of Part 2 of the study: Days 1 through 14: An oral dose of pacritinib 200 mg (2 × 100 mg capsules) BID (approximately 12 hours apart) Days 8 through 14: An oral dose of fluconazole 200 mg QD

Drug: Part 2 Group B - Fluconazole (CYP450 3A4 inhibitor) with Pacritinib

Interventions

CYP450 Cocktail and Transporter Substrates with Pacritinib DRUG

Day 1: Single oral dose of a cocktail of cytochrome P450 substrates (caffeine 100 mg, midazolam 2 mg, omeprazole 20 mg and metformin (transporter) Day 3: Single oral dose of transporter substrates (digoxin 0.25 mg, rosuvastatin 5 mg) Days 8-22: Oral doses of pacritinib 200 mg BID approximately 12 hours apart Day 17: Single oral dose of transporter substrates (digoxin 0.25 mg and rosuvastatin 5 mg) will be coadministered with the AM dose of pacritinib 200 mg. Day 21: Single oral dose of a cocktail of cytochrome P450 substrates (caffeine 100 mg, midazolam 2 mg, and omeprazole 20 mg) along with transporter substrate (metformin 500 mg) will be coadministered with the AM dose of pacritinib 200 mg.

Also known as: Vonjo

CYP450 Cocktail and Transporter Substrates with Pacritinib

Part 2 -Group A Bosentan 125 mg (CYP450 3A4 inducer) with Pacritinib DRUG

Days 1-7: Oral doses of pacritinib 200 mg BID Days 8-14: Oral doses of pacritinib 200 mg BID, coadministered with an oral dose of bosentan 125 mg BID

Also known as: Vonjo

CYP450 3A4 inducer (Bosentan) with Pacritinib

Part 2 Group B - Fluconazole (CYP450 3A4 inhibitor) with Pacritinib DRUG

Days 1-7: Oral doses of pacritinib 200 mg BID Days 8-14: Oral doses of pacritinib 200 mg BID, coadministered with an oral dose of fluconazole 200 mg QD.

Also known as: Vonjo

CYP450 3A4 inhibitor (Fluconazole) with Pacritinib

Eligibility Criteria

• Age: 18 Years - 55 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• The subject is male 18 to 55 years of age, inclusive, at screening.
• The subject has a BMI of 18.0 to 32.0 kg/m2, inclusive, at screening.
• The subject has a normal renal function ≥60 mL/min eGFR.
• The subject is considered by the investigator to be in good general health as determined by medical history review, clinical laboratory test results, vital sign measurements, 12-lead ECG results, and physical examination findings at screening and check-in.
• The male subjects will be sterile, or completely abstain from sexual intercourse, or agree to use, from check-in (Day -1) until 90 days following EOS/ET, one of the following approved methods of contraception: male condom with spermicide or a sterile sexual partner; or use by female sexual partner of an IUD with spermicide, a female condom with spermicide, a contraceptive sponge with spermicide, an intravaginal system, a diaphragm with spermicide, a cervical cap with spermicide, or oral, implantable, transdermal, or injectable contraceptives. The subject will refrain from sperm donation from check-in (Day -1) until 90 days following study completion (Day 31 for Part 1 and Day 24 for Part 2).
• The subject must have adequate venous access for blood draws.
• The subject agrees to comply with all protocol requirements.
• The subject is able to provide written informed consent.
• The subject has a documented result of genotype testing for CYP2C19 \*1/\*1 suggesting normal metabolizers.

You may not qualify if:

• The subject has a history of any clinically significant conditions including the following:
• Asthma treated with oral systemic steroids within the past 6 months
• Diabetes mellitus (types 1 or 2), with the exception of gestational diabetes
• Thyroidectomy or thyroid disease that required medication within the past 12 months
• Serious angioedema episodes within the previous 3 years or requiring medication in the previous 2 years
• Head trauma resulting in a diagnosis of traumatic brain injury other than concussion
• Known clinically relevant history or presence of significant respiratory (eg, interstitial lung disease), GI (eg, GI ulceration, peptic ulceration, GI bleeding, gastroesophageal reflux, or other GI disease affecting gastroesophageal junction), renal, hepatic (eg, known hepatic or biliary abnormalities), hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, metabolic (eg, diabetes) and dermatological or connective tissue disease.
• The subject has a value \>1.5 × ULN for any of the following: prothrombin time, partial thromboplastin time, and international normalized ratio.
• The subject has a seated systolic blood pressure \>160 mm Hg or ≤90 mm Hg and a diastolic blood pressure of \>100 mm Hg or ≤50 mm Hg, inclusive, at screening and check-in unless deemed not clinically significant by the investigator, as approved by the sponsor.
• The subject has a seated pulse rate of \<50 bpm or \>100 bpm and/or an oral body temperature \<35.0°C or \>37.5°C when vital signs are measured at screening and check-in.
• The subject has a clinically significant illness, including viral syndromes, within 3 weeks of dosing.
• The subject has a known clinically significant chronic viral infection (eg, human T-cell lymphotropic virus I or II).
• The subject has a history or clinical manifestation of clinically significant cardiovascular, pulmonary, hepatic (eg, hepatitis), renal, hematologic, gastrointestinal (eg, celiac disease, peptic ulcer, gastroesophageal reflux, inflammatory bowel disease), metabolic, allergic, dermatological, neurological, or psychiatric disorder (as determined by the investigator; appendectomy and cholecystectomy \[within 3 to 6 months\] are not considered to be clinically significant procedures).
• The subject has a history of cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or risk factors for torsades de pointes (eg, heart f failure, hypokalemia).
• The subject has evidence or a history of clinically significant allergic (except for untreated, asymptomatic, seasonal allergies at time of the first dose of study drug), hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or neurological disease. Exceptions to this criterion (eg, stable, mild joint disease unassociated with collagen vascular disease) may be made following discussions with the medical monitor.

Sponsors & Collaborators

• CTI BioPharma: lead
• PPD Development, LP: collaborator

Study Sites (1)

Site 1

Austin, Texas, 78744, United States

Location

MeSH Terms

Interventions

11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene

Study Officials

• Buckley

  CTI BioPharma

  STUDY DIRECTOR

Study Design

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

Model Details: An open-label, fixed-sequence, 2-part drug-drug interaction study of pacritinib in healthy adult males

Study Record Dates

• First Submitted: December 12, 2022
• First Posted: December 20, 2022
• Study Start: January 3, 2023
• Primary Completion: June 8, 2023
• Study Completion: June 8, 2023
• Last Updated: October 17, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)