A Study to Understand the Effect of Itraconazole on the Levels of a Study Medicine Called ARV-471 in Healthy Adults

Healthy Clinical Trial

Official title:

AN INTERVENTIONAL, PHASE 1, OPEN-LABEL, FIXED SEQUENCE, 2-PERIOD STUDY TO ESTIMATE THE EFFECT OF MULTIPLE DOSES OF ITRACONAZOLE ON THE PHARMACOKINETICS OF SINGLE DOSE ARV-471 IN THE FED CONDITION IN HEALTHY ADULT MALES, AND FEMALES OF NONCHILDBEARING POTENTIAL

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05538312
• Other study ID #: C4891009
• Secondary ID: 2022-003282-38
• Status: Completed
• Phase: Phase 1
• Start date: February 23, 2023
• Est. completion date: May 22, 2023

Study information

• Verified date: June 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to understand if a strong CYP3A4 inhibitor (itraconazole) affects how ARV-471 is processed and eliminated in healthy adults. All participants in this study will receive one dose of ARV-471 alone by mouth in Period 1. In Period 2, everyone will receive itraconazole by mouth once a day for multiple days. Participants will also receive one dose of ARV-471 by mouth. The levels of ARV-471 in Period 1 will be compared to the levels of ARV-471 in Period 2 to determine if the CYP3A4 inhibitor affects how ARV-471 is processed differently in healthy adults.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: May 22, 2023
• Est. primary completion date: May 22, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria

• Healthy male and/or female participants of non-childbearing potential who are overtly healthy as determined by medical evaluation including medical history, physical exam, laboratory tests, vital signs and standard 12-lead ECGs and are between the ages of 18 and 65 years, inclusive at the time of signing the informed consent document.
• Body Mass Index of 17.5 to 30.5 kg/meters squared; and a body weight >50 kg.
• Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
• Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures. Exclusion Criteria
• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
• Pregnant female participants, breastfeeding female participants, female participants of childbearing potential.
• Male participants with partners currently pregnant; male participants who are unwilling or unable to use a highly effective method of contraception.
• Use of prescription or non-prescription medications, including vitamins, herbal and dietary supplements, grapefruit/grapefruit containing products, and Seville orange/Seville orange containing products within 7 days prior to the first dose of study intervention with the exception of: Moderate/potent CYP3A inducers which are prohibited within 14 days plus 5 half-lives (whichever is longer) prior to the first dose of study intervention. Moderate/potent CYP3A inhibitors which are prohibited within 14 days or 5 half lives (whichever is longer) prior to the first dose of study intervention.
• Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).
• A positive urine drug test or alcohol breath test at discretion of investigator.
• Screening supine BP =140 mm Hg (systolic) or =90 mm Hg (diastolic), following at least 5 minutes of supine rest.
• Standard 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
• Aspartate transaminase or alanine aminotransferase level = 1.0 × upper limit of normal.
• Total bilirubin level >1.0 × upper limit of normal; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is = upper limit of normal.
• History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening.
• History of use of tobacco or nicotine-containing products in excess of the equivalent of 5 cigarettes/day or 2 chews of tobacco/day.
• Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing.
• Known hypersensitivity or previous adverse events associated with azole antifungals or any of the formulation components of ARV-471.
• History of sensitivity to heparin or heparin induced thrombocytopenia.
• Estimated glomerular filtration rate <60 mL/min/1.73m2.

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• ARV-471
Participants will receive a single dose of ARV-471 by mouth in Period 1 and Period 2, with a washout period of at least 10 days between doses of ARV-471
• Itraconazole
Participants will receive itraconazole by mouth once a day for 11 days in Period 2.

Locations

Country	Name	City	State
Belgium	Pfizer Clinical Research Unit - Brussels	Brussels	Bruxelles-capitale, Région DE

Sponsors (2)

Lead Sponsor	Collaborator
Pfizer	Arvinas Estrogen Receptor, Inc.

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)] of ARV-471 and ARV-473 (an epimer of ARV-471) when ARV-471 is administered alone	AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).	Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose
Primary	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)] of ARV-471 and ARV-473 (an epimer of ARV-471) when ARV-471 is administered with itraconazole	AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).	Period 2 - Day 5 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose
Primary	Maximum Observed Plasma Concentration (Cmax) of ARV-471 and ARV-473 (an epimer of ARV-471) when ARV-471 is administered alone		Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose
Primary	Maximum Observed Plasma Concentration and ARV-473 (an epimer of ARV-471) when ARV-471 is administered with itraconazole		Period 2 - Day 5 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose
Secondary	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of ARV-471 and ARV-473 (an epimer of ARV-471) when ARV-471 is administered alone	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).	Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose
Secondary	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of ARV-471 and ARV-473 (an epimer of ARV-471) when ARV-471 is administered with itraconazole	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).	Period 2 - Day 5 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose
Secondary	Time to Reach Maximum Observed Plasma Concentration (Tmax) of ARV-471 and ARV-473 (an epimer of ARV-471) when ARV-471 is administered alone		Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose
Secondary	Time to Reach Maximum Observed Plasma Concentration (Tmax) of ARV-471 and ARV-473 (an epimer of ARV-471) when ARV-471 is administered with itraconazole		Period 2 - Day 5 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose
Secondary	Plasma Decay Half-Life (t1/2) of ARV-471 and ARV-473 (an epimer of ARV-471) when ARV-471 is administered alone	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose
Secondary	Plasma Decay Half-Life (t1/2) of ARV-471 and ARV-473 (an epimer of ARV-471) when ARV-471 is administered with itraconazole	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Period 2 - Day 5 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose
Secondary	Apparent Oral Clearance (CL/F) of ARV-471 when ARV-471 is administered alone	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.	Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose
Secondary	Apparent Oral Clearance (CL/F) of ARV-471 when ARV-471 is administered with itraconazole	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.	Period 2 - Day 5 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose
Secondary	Apparent Volume of Distribution (Vz/F) of ARV-471 when ARV-471 is administered alone	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.	Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose
Secondary	Apparent Volume of Distribution (Vz/F) of ARV-471 when ARV-471 is administered with itraconazole	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.	Period 2 - Day 5 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose
Secondary	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. SAE is defined as one of the following: is fatal or life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE is defined as an AE with onset date occurring during the on-treatment period. AEs include all SAEs and non-SAEs.	Time the participant provides informed consent through and including follow-up contact occurring 28 to 35 calendar days after the last administration of the study intervention.
Secondary	Number of Participants With Clinical Laboratory Abnormalities	Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); liver function (aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein); renal function (blood urea nitrogen, creatinine, uric acid, cystatinC); electrolytes (sodium, potassium, chloride, calcium, bicarbonate); clinical chemistry (glucose); urinalysis (dipstick [decimal logarithm of reciprocal of hydrogen ion activity {pH} of urine, glucose, protein, blood, ketones, nitrites, leukoesterase, urobilinogen, bilirubin], microscopy.	Baseline up to Period 2 Day 12
Secondary	Number of Participants With Electrocardiogram (ECG) Abnormalities	ECG abnormalities criteria include a) a postdose QTcF is increased by =60 ms from the baseline and is >450 ms; or b) an absolute QTcF value is =500 ms for any scheduled ECG.	Baseline up to Period 2 Day 12
Secondary	Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Blood pressure and pulse rate will be performed following at least a 5-minute rest in a supine position.	Baseline up to Period 2 Day 5

External Links

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