Study to Evaluate the Effect of Multiple Doses of Itraconazole and Rifampin on the Single-Dose Pharmacokinetics of Mitapivat Sulfate (AG-348) in Healthy Adult Participants

NCT03991312 | Completed Phase 1 FDA Drug

• 1 other identifier: AG348-C-012
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

Part 1 of this study will determine the effect of multiple-dose itraconazole, a strong cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) inhibitor, on the single-dose pharmacokinetic(s) (PK) of mitapivat sulfate in healthy adult participants. Part 2 of this study will determine the effect of multiple-dose rifampin, a strong CYP3A4 and P-gp inducer, on the single-dose pharmacokinetic(s) (PK) of mitapivat sulfate in healthy adult participants.

Conditions

Healthy Volunteers

Outcome Measures

Primary Outcomes (6)

• Area Under the Concentration-Time Curve, from Time 0 to the Last Measurable Concentration (AUC0-t) of Mitapivat Sulfate with and without Itraconazole

  Predose and at various timepoints through 120 hours postdose

• Area Under the Concentration-Time Curve, from Time 0 to the Last Measurable Concentration (AUC0-t) of Mitapivat Sulfate with and without Rifampin

  Predose and at various timepoints through 120 hours postdose

• Area Under the Concentration-Time Curve from Time 0 Extrapolated to Infinity (AUC0-inf) of Mitapivat Sulfate with and without Itraconazole

  Predose and at various timepoints through 120 hours postdose

• Area Under the Concentration-Time Curve from Time 0 Extrapolated to Infinity (AUC0-inf) of Mitapivat Sulfate with and without Rifampin

  Predose and at various timepoints through 120 hours postdose

• Maximum Observed Plasma Concentration (Cmax) of Mitapivat Sulfate with and without Itraconazole

  Predose and at various timepoints through 120 hours postdose

• Maximum Observed Plasma Concentration (Cmax) of Mitapivat Sulfate with and without Rifampin

  Predose and at various timepoints through 120 hours postdose

Secondary Outcomes (21)

• Area Under the Concentration-Time Curve, from Time 0 to Hour 24 (AUC0-24) of Mitapivat Sulfate and AGI-8702 with and without Itraconazole

  Predose and at various timepoints through 120 hours postdose

• Area Under the Concentration-Time Curve, from Time 0 to Hour 24 (AUC0-24) of Mitapivat Sulfate and AGI-8702 with and without Rifampin

  Predose and at various timepoints through 120 hours postdose

• Percent of AUC0-inf Extrapolated (AUC%extrap) of Mitapivat Sulfate and AGI-8702 with and without Itraconazole

  Predose and at various timepoints through 120 hours postdose

• Percent of AUC0-inf Extrapolated (AUC%extrap) of Mitapivat Sulfate and AGI-8702 with and without Rifampin

  Predose and at various timepoints through 120 hours postdose

• Time of the Last Measurable Concentration (Tlast) of Mitapivat Sulfate and AGI-8702 with and without Itraconazole

  Predose and at various timepoints through 120 hours postdose

Study Arms (2)

Part 1

EXPERIMENTAL

Period 1: Day 1, participants will receive 20 milligrams (mg) of mitapivat sulfate. Period 2: Day 1 to Day 9, participants will receive 200 mg of itraconazole, once daily and 20 mg of mitapivat sulfate on Day 5.

Drug: itraconazole; Drug: mitapivat sulfate

Part 2

EXPERIMENTAL

Period 1: Day 1, participants will receive 50 milligrams (mg) of mitapivat sulfate. Period 2: Day 1 to Day 12, participants will receive 600 mg of rifampin, once daily and 50 mg of mitapivat sulfate on Day 8.

Drug: rifampin; Drug: mitapivat sulfate

Interventions

itraconazole DRUG

Participants will receive an oral solution as described in the arm description.

Part 1

rifampin DRUG

Participants will receive oral capsule(s) as described in the arm description.

Part 2

mitapivat sulfate DRUG

Participants will receive an oral tablet as described in the arm description.

Also known as: AG348

Part 1; Part 2

Eligibility Criteria

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

You may qualify if:

• Healthy, adult, male or female (non-childbearing potential), 18-55 years of age, inclusive, at the time of providing written informed consent;
• Continuous non-smoker who has not used nicotine-containing products for at least 12 months prior to screening, based on participant self-reporting, and agrees to abstain from use throughout the study;
• Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kilograms per meter squared (kg/m2) at screening;
• Medically healthy, with no clinically significant conditions or abnormalities, as determined by the principal investigator (PI) or designee, through evaluation of medical history and screening vital signs, 12-lead electrocardiogram (ECG) results, physical examination findings, and clinical laboratory test results;
• A female participant must be of non-childbearing potential and must have undergone one of the following sterilization procedures at least 6 months prior to the first dosing:
• hysteroscopic sterilization;
• bilateral tubal ligation or bilateral salpingectomy;
• hysterectomy;
• bilateral oophorectomy.
• or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and follicle-stimulating hormone (FSH) serum levels at screening consistent with postmenopausal status;
• A male participant (with or without prior vasectomy) must agree to use a condom with spermicide or abstain from sexual intercourse from the time of providing written informed consent until 90 days after the last dose of study drug;
• If male, must agree not to donate sperm from the first dosing until 90 days after the last dose of study drug;
• Understands the study procedures in the informed consent form (ICF), and is willing and able to comply with the study procedures and the protocol requirements, and has provided signed written informed consent prior to performing any study procedures, including screening procedures;

You may not qualify if:

• Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study;
• History or presence of any clinically significant medical or psychiatric condition or disease or clinically significant laboratory abnormality that, in the opinion of the PI or designee, might confound the results of the study, compromise the ability of the participant to complete study procedures, and/or pose an additional risk to the participant by their participation in the study. This includes seizure disorders, transient ischemic attacks, or easy bruising;
• History or presence of a medical condition or surgical procedure that, in the opinion of the PI or designee, may potentially interfere with absorption, distribution, metabolism, or excretion of the study drugs;
• History or presence of alcohol or drug abuse within the past 2 years prior to screening;
• History or presence of hypersensitivity, idiosyncratic reaction, or serious adverse reaction to any of the study drugs or to their formulation excipients;
• Female participants of childbearing potential;
• Female participants with a positive serum pregnancy test at screening or check-in or who are breastfeeding;
• Positive urine drug or alcohol results at screening or check-in;
• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody;
• Supine blood pressure is less than 90/40 milliliters of mercury (mmHg) or greater than 140/90 mmHg at screening. If the participant's systolic blood pressure reading exceeds 140 mmHg or the diastolic blood pressure reading exceeds 90 mmHg due to what may be, in the opinion of the PI or designee, an episode of transient anxiety, the reading may be repeated, and the resulting blood pressure measurement used to determine eligibility;
• Supine heart rate is lower than 40 beats per minute (bpm) or higher than 99 bpm at screening. If the participant's heart rate exceeds 99 bpm due to what may be, in the opinion of the PI or designee, an episode of transient anxiety, the reading may be repeated, and the resulting heart rate measurement used to determine eligibility;
• QTcF interval is \>450 milliseconds (msec) (males) or \>470 msec (females) or has ECG findings deemed abnormal with clinical significance by the PI or designee at screening;
• Estimated creatinine clearance \< 90 mL/min at screening (Cockcroft-Gault formula);
• Unable to refrain from or anticipates the use of any drug, including prescription and non-prescription medications, proton pump inhibitors, H2-antagonists, herbal remedies, and vitamin supplements, beginning 28 days prior to the first dosing and throughout the study. Additionally, any drugs (with the exception of the study drugs) known to be clinically significant inhibitors or inducers of CYP3A, CYP2C9, CYP2C8, CYP2C19, and CYP1A2 enzymes and/or P-gp, including St. John's Wort, beginning 28 days prior to the first dosing and throughout the study. Appropriate sources (e.g., Flockhart TableTM) will be consulted to confirm lack of PK/PD interaction with study drugs. After first dosing, acetaminophen (up to 2 g per 24 hours) may be administered at the discretion of the PI or designee;
• Has consumed foods or beverages containing caffeine or xanthines 24 hours prior to the first dosing and is not willing to refrain from consumption of these foods or beverages throughout the study;

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (1)

Celerion, Inc

Tempe, Arizona, 85283, United States

Location

MeSH Terms

Interventions

Itraconazole; Rifampin; mitapivat

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Medical Affairs

  Agios Pharmaceuticals, Inc.

  STUDY CHAIR

Study Design

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

Study Record Dates

• First Submitted: June 17, 2019
• First Posted: June 19, 2019
• Study Start: June 20, 2019
• Primary Completion: August 14, 2019
• Study Completion: September 10, 2019
• Last Updated: October 23, 2019

Record last verified: 2019-10

Locations

US (1)