Pharmacokinetics (PK) Drug Interaction Study of Milademetan and Itraconazole or Posaconazole in Healthy Participants

Early Phase 1

Completed

• Conditions: Pharmacokinetics
• Interventions: Drug: Milademetan; Drug: Posaconazole; Drug: Itraconazole

• Registration Number: NCT03614455
• Lead Sponsor: Daiichi Sankyo

Brief Summary

This will be an open-label, randomized, 3-treatment, 2-period, 2-sequence study in healthy subjects to evaluate the single-dose PK of milademetan when given as monotherapy and when administered with steady-state levels of the strong CYP3A4 inhibitors itraconazole or posaconazole.

The duration of the study for each individual subject will be approximately 49 days from the start of Screening through Study Discharge. Subjects will remain in-house for up to 23 days, including 22 overnight stays.

Detailed Description

Not available

Study Timeline

• Study Start: 2018-07-13
• Study First Submitted: 2018-07-30
• Study First Submitted QC: 2018-07-30
• Study First Posted: 2018-08-03
• Primary Completion: 2018-10-01
• Study Completion: 2018-10-01
• Status Verified: 2018-11
• Last Update Submitted: 2019-02-08
• Last Update Posted: 2019-02-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 36

Inclusion Criteria

• Has negative urine test for drugs of abuse, alcohol and tobacco
• If female, is surgically sterile or postmenopausal
• If male, agrees to protocol-defined contraceptive methods
• Has adequate hematologic, hepatic, and renal function as defined by the protocol
• Is able and willing to follow all study procedures
• Has provided a signed informed consent

Exclusion Criteria

• Is female who is pregnant or breastfeeding

• Is unable to swallow oral medication

• Is unable to follow study procedures

• Has creatinine clearance < 90 mL/min at screening

• Is taking or has taken any medications or therapies outside of protocol-defined parameters

• Has history of or a known allergic reaction to azole antifungal agents

• Has any disease or condition that, per protocol or in the opinion of the investigator, might affect:

  1. safety and well-being of the participant or offspring
  2. safety of study staff

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Milademetan alone (A)	Milademetan	During Period 1, participants receive a single 100 mg milademetan oral dose on Study Day 1, with PK sampling to 168 hours post-dose (during the following 7-day washout period)
Milademetan with posaconazole (AC)	Posaconazole	During Period 2, participants receive 200 mg posaconazole three times daily (TID) on Study Days 8 through 20, along with a single 100 mg milademetan dose on Day 14
Milademetan with itraconazole (AB)	Itraconazole	During Period 2, participants receive itraconazole, 200 mg twice daily (BID) on Study day 8 and 200 mg once daily (QD) on Study Days 9 through 20, along with a single 100 mg milademetan dose on Day 14
Milademetan with itraconazole (AB)	Milademetan	During Period 2, participants receive itraconazole, 200 mg twice daily (BID) on Study day 8 and 200 mg once daily (QD) on Study Days 9 through 20, along with a single 100 mg milademetan dose on Day 14
Milademetan with posaconazole (AC)	Milademetan	During Period 2, participants receive 200 mg posaconazole three times daily (TID) on Study Days 8 through 20, along with a single 100 mg milademetan dose on Day 14

Primary Outcome Measures

Name	Time	Method
Maximum plasma concentration (Cmax) of milademetan	pre-dose and then at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose	Categories: alone (A), in sequence AB, in sequence AC
Area under the plasma concentration-time curve extrapolated to infinity (AUCinf) of milademetan	within 168 hours postdose	Categories: alone (A), in sequence AB, in sequence AC

Secondary Outcome Measures

Name	Time	Method
Apparent volume of distribution (Vz/F)	within 168 hours postdose	Categories: alone (A), in sequence AB, in sequence AC
Time to reach maximum plasma concentration (Tmax) of milademetan	pre-dose and then at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose	Categories: alone (A), in sequence AB, in sequence AC
Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0-t) for milademetan	within 168 hours postdose	Categories: alone (A), in sequence AB, in sequence AC
Terminal elimination half-life (t½) of milademetan	within 168 hours postdose	Categories: alone (A), in sequence AB, in sequence AC
Apparent total body clearance (CL/F) of milademetan	within 168 hours postdose	Categories: alone (A), in sequence AB, in sequence AC

Trial Locations

Locations (1)

Covance Clinical Research Unit, Inc.; 🇺🇸 Dallas, Texas, United States