A Drug-Drug Interaction Study of CYP3A4 Inhibition and Pan-CYP Induction on APX001

NCT ID: NCT04166669

Last Updated: 2024-05-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-12
• Study Completion Date: 2020-03-03

Brief Summary

This is a Phase 1, open-label study to evaluate the drug-drug interaction potential of a strong CYP3A4 inhibitor (itraconazole) and a pan-CYP inducer (rifampin) on APX001 in two parallel groups of healthy subjects.

Conditions

Fungal Infection

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1

Drugs: APX001, itraconazole

Group Type: EXPERIMENTAL

APX001

Intervention Type: DRUG

Cohort 1 Day 1: APX001 500 mg IV BID over a 3-hour infusion; Day 18: APX001 500 mg IV BID over a 3-hour infusion. Cohort 2 Day 1: APX001 1000 mg IV BID over a 3-hour infusion; Day 24: APX001 1000 mg IV BID over a 3-hour infusion.

Itraconazole

Intervention Type: DRUG

Cohort 1 Days 15-30: itraconazole 200 mg oral solution QD.

Cohort 2

Drugs: APX001, rifampin

Group Type: EXPERIMENTAL

APX001

Intervention Type: DRUG

Cohort 1 Day 1: APX001 500 mg IV BID over a 3-hour infusion; Day 18: APX001 500 mg IV BID over a 3-hour infusion. Cohort 2 Day 1: APX001 1000 mg IV BID over a 3-hour infusion; Day 24: APX001 1000 mg IV BID over a 3-hour infusion.

Rifampin

Intervention Type: DRUG

Cohort 2 Days 15-33: rifampin 600 mg oral QD.

Interventions

APX001

Cohort 1 Day 1: APX001 500 mg IV BID over a 3-hour infusion; Day 18: APX001 500 mg IV BID over a 3-hour infusion. Cohort 2 Day 1: APX001 1000 mg IV BID over a 3-hour infusion; Day 24: APX001 1000 mg IV BID over a 3-hour infusion.

Intervention Type: DRUG

Itraconazole

Cohort 1 Days 15-30: itraconazole 200 mg oral solution QD.

Intervention Type: DRUG

Rifampin

Cohort 2 Days 15-33: rifampin 600 mg oral QD.

Intervention Type: DRUG

Other Intervention Names

Fosmanogepix; Sporanox; Rifampicin

Eligibility Criteria

Inclusion Criteria

• Women must be postmenopausal or surgically sterile, or
• Women of childbearing potential must agree to avoid pregnancy during the study and to use contraception, or abstinence, at least 2 weeks before the start of study drug administration until 3 months after the last dose of study drug.
• Male subjects must agree to use barrier contraception, or commit to abstinence, from first Admission to the clinic until 3 months after the last dose of study drug.
• Body mass index (BMI): 18.0 to 32.0 kg/m sq, inclusive
• Weight: >= 50 kg
• Screening hematology, clinical chemistry, coagulation, and urinalysis consistent with overall good health
• Able to understand and comply with the requirements of the study, willing to return for all clinic visits, including confinement periods, and complete all study-related procedures Willing and able to provide written informed consent.

Exclusion Criteria

• Having any uncontrolled or active major systemic disease including, but not limited to: cardiovascular, pulmonary, ,gastrointestinal, metabolic, urogenital, neurological, immunological, psychiatric, or neoplastic disorder with metastatic potential.
• History or presence of malignancy within the past year. Subjects who have been successfully treated with no recurrence of basal cell carcinoma of the skin or carcinoma in-situ of the cervix may be enrolled.
• Active acute or chronic infection, including, but not limited to: upper airway infection, urinary tract infection, or skin infection within 30 days preceding entry into the study.
• Significant and/or acute illness within 5 days prior to the first study drug administration that may impact safety assessments, in the opinion of the Investigator.
• Participation in an investigational drug study within 60 days prior to the first study drug administration in the current study. Participation in more than 3 other drug studies in the 10 months prior to the first study drug administration in the current study.
• Use of any prescription medication within 14 days prior to the planned first study drug administration and throughout the study (excluding female contraception).
• Use of any non-prescription or over-the-counter medications within 7 days prior to the planned first study drug administration and throughout the study. This includes all vitamins, other herbal supplements, or remedies.
• Taking any drug or herbal CYP3A modulator (e.g. erythromycin; St. John's Wort) within 4 weeks (or 5 half-lives, whichever is longer) or any other nutrients known to modulate CYP3A activity (e.g. grapefruit juice; Seville orange) within 2 weeks prior to the first Admission.
• History of tobacco or any nicotine-containing product or device use within the past 3 months prior to the planned first study drug administration
• History of alcohol or substance abuse based on Investigator's judgment, within the past 12 months prior to the planned first study drug administration
• Concurrent social conditions (e.g. drugs-of-abuse, alcohol use of more than 24 units per week) that may potentially interfere with the subject's compliance with the protocol
• History of clinically significant allergic drug reactions
• Clinically significant physical examination, vital signs, laboratory safety test, or electrocardiogram (ECG) abnormalities
• Donation or loss of more than 100 mL of blood within 60 days prior to the first study drug administration. Donation or loss of more than 1.5 liters of blood (for male subjects) or more than 1.0 liter of blood (for female subjects) in the 10 months prior to the first study drug administration in the current study.
• Positive results on any of the following screening laboratory tests: serum pregnancy test, urine alcohol test, urine drugs-of-abuse (including cotinine), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, and human immunodeficiency virus (HIV) antibody.
• Prior exposure to APX001
• Known allergy to corn or corn products or any inactive components of the study drug
• Known hypersensitivity to culprit drugs (itraconazole or rifampin).

• Diagnosis or suspected of having porphyria or having first-degree relatives diagnosed or suspected of having porphyria.
• Unwilling not to use contact lenses for the duration of rifampin dosing (Day 15 to Day 33 for Cohort 2) until 7 days after the last dose of rifampin (subjects in Cohort 2 may resume wearing contact lenses on Day 40).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Basilea Pharmaceutica

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marc Engelhardt

Role: STUDY_DIRECTOR

Basilea Pharmaceutica International Ltd, Allschwil

Locations

PRA Health Sciences (PRA) - Early Development Services (EDS)

Groningen, , Netherlands

PRA-EDS

Groningen, , Netherlands

Countries

Netherlands

References

Hodges MR, van Marle S, Kramer WG, Ople E, Tawadrous M, Jakate A. Phase 1 drug-drug interaction study to assess the effect of CYP3A4 inhibition and pan-CYP induction on the pharmacokinetics and safety of fosmanogepix in healthy participants. Antimicrob Agents Chemother. 2024 Jun 5;68(6):e0165023. doi: 10.1128/aac.01650-23. Epub 2024 May 17.

Reference Type: DERIVED

PMID: 38757982 (View on PubMed)

Other Identifiers

C4791007

Identifier Type: OTHER

Identifier Source: secondary_id

APX001-107

Identifier Type: -

Identifier Source: org_study_id