Pharmacokinetic Evaluation of Etrasimod Arginine in Lactating Women with Ulcerative Colitis and Immune-Mediated Inflammatory Disorders

Trial ID: 2025-520930-44-00
Protocol: C5041053
Sponsor: Pfizer Inc.

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Diseases & Conditions

Colitis ulcerative

Objectives

The primary objective of this study is to evaluate the amount of **etrasimod** secreted in human breast milk following multiple oral doses of etrasimod 2 mg at steady state in lactating women. This is clinically relevant as it provides critical information on the potential exposure of breastfed infants to etrasimod, which is used in the treatment of **ulcerative colitis** and other immune-mediated inflammatory disorders. Understanding the secretion of etrasimod in breast milk is essential for assessing the safety of breastfeeding during maternal treatment with this medication.

Secondary objectives include: - Estimating the plasma pharmacokinetic (PK) parameters of etrasimod following multiple oral doses in lactating women. - Estimating the milk-to-plasma drug concentration ratio. - Characterizing the safety and tolerability of etrasimod in this population. - Estimating the infant dose resulting from etrasimod secretion in breast milk. These objectives aim to provide a comprehensive understanding of the drug's behavior in lactating women, which is crucial for informed clinical decision-making regarding the use of etrasimod during lactation.

Participants

The clinical trial involves a study population of **lactating women** aged 18 to 55 years, who are at least 12 weeks post-partum and are actively breastfeeding or expressing breast milk. Participants are required to be in good health, as determined by a comprehensive medical evaluation, including medical history, physical examination, laboratory tests, vital signs, and 12-lead ECGs. The trial exclusively includes female subjects, with a **body mass index (BMI)** ranging from 16 to 35 kg/m² and a total body weight exceeding 45 kg. Participants must be willing to temporarily discontinue breastfeeding for a total of 21 days and adhere to a schedule for expressing breast milk to maintain lactation. The sponsor has not provided information regarding the total number of participants. The study focuses on evaluating the secretion of etrasimod in human breast milk following multiple oral doses in this specific population.

Plans and Procedures

The clinical trial is designed as a **Phase 1**, open-label, pharmacokinetic study to evaluate the secretion of **etrasimod arginine** in human breast milk following multiple oral doses in healthy lactating women. The trial aims to assess the pharmacokinetic parameters of etrasimod in both breast milk and plasma, including AUCtau, Cmax, Tmax, and other relevant metrics. The study will involve healthy lactating women who are actively breastfeeding or expressing breast milk, at least 12 weeks post-partum, and aged between 18 to 55 years. Participants must have a body mass index (BMI) of 16-35 kg/m² and a total body weight greater than 45 kg. The trial will require participants to temporarily discontinue breastfeeding for a total of 21 days to ensure accurate data collection.

The trial will commence with a screening visit to confirm eligibility based on medical history, physical examination, laboratory tests, and ECGs. Following successful screening, participants will begin the dosing phase, during which they will receive multiple oral doses of etrasimod 2 mg at steady state. Study visits will be scheduled to monitor the pharmacokinetic parameters and ensure participant safety through clinical laboratory tests, vital signs, and ECGs. The trial will conclude with an end-of-study visit to assess the final pharmacokinetic data and overall participant health.

The expected duration of participant involvement is approximately 21 days, with the trial estimated to end by September 2026. Conditions that may lead to early termination from the study include adverse events, non-compliance with study procedures, or withdrawal of consent. The trial is not classified as low intervention and is conducted under the sponsorship of Pfizer Inc., with the investigational product being Etrasimod Arginine Blue in tablet form. The study is not intended for pediatric use and does not involve any orphan drug designation.

Treatment

The clinical trial involves the administration of **Etrasimod Arginine Blue**, an investigational medication developed by Pfizer Inc. The active substance in this medication is **etrasimod arginine**, a chemical compound also known by synonyms such as APD334 L-arginine and L-arginine mono((3R)-7-((4-cyclopentyl-3-(trifluoromethyl)phenyl)methoxy)-1,2,3,4-tetrahydrocyclopenta(b)indol-3-yl)acetate. The pharmaceutical form of Etrasimod Arginine Blue is a tablet, and it is administered orally. The dosage for this study is 2 mg, given at steady state to healthy lactating women to evaluate the secretion of etrasimod in human breast milk. The administration frequency is multiple doses, as specified in the study protocol.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the trial documentation. The study is designed to focus solely on the pharmacokinetics of Etrasimod Arginine Blue in the specified population. Participant compliance with the dosing schedule will be monitored according to the study's compliance monitoring procedures, ensuring adherence to the protocol. The trial does not involve a pediatric formulation, and the medication is not classified as an orphan drug. The investigational product is of chemical origin, and no additional medicinal products are used in conjunction with the experimental treatment.

Efficacy

Efficacy in this clinical trial will be assessed through the evaluation of pharmacokinetic (PK) parameters of **etrasimod** in breast milk and plasma. The primary endpoints include breast milk PK parameters such as AUCtau, Cmax, Aebm, Aebm%, Tmax, and CLbm, if data permit. Secondary endpoints will focus on plasma PK parameters, including AUCtau, Cmax, Tmax, and MPAUCtau, as data allows. Additionally, the trial will monitor treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, and electrocardiograms (ECGs) to ensure comprehensive safety and efficacy evaluation. The collection and analysis of these parameters will be conducted at specified intervals throughout the study to determine the secretion levels of etrasimod in human breast milk following multiple oral doses in lactating women.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Healthy (as determined by medical evaluation including medical history, physical examination, laboratory tests, vital signs and 12-lead ECGs) lactating women who are actively breastfeeding or expressing breast milk, who are at least 12 weeks post-partum and not currently pregnant (must have a negative pregnancy test), and must be 18 to 55 years of age, inclusive, at the time of signing the informed consent document (ICD).
Body mass index (BMI) of 16-35 kg/m2; and a total body weight >45 kg (99 lb).
Participants must be willing to temporarily discontinue breastfeeding their infants for a total of 21 days, ie, from the evening of the day before Day 1 through to 14 days after the last dose (approximately 8 AM the morning of Day 21). Participants must be willing to regularly pump breasts throughout the study and express breast milk according to a schedule designed to maintain lactation until the completion of breast milk collection.

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Exclusion Criteria

Evidence or history of clinically significant hematological, renal, endocrine, pulmonary (such as moderate or severe chronic pulmonary disorders like asthma or chronic obstructive pulmonary disease [COPD]), gastrointestinal, cardiovascular, hepatic, neurological/psychiatric, anaphylactic, ophthalmologic disorders (such as macular edema, uveitis, retinopathy), or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
A positive urine drug test. A single repeat for positive drug screen may be allowed.
A positive pregnancy test.
Screening supine blood pressure (BP) ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. If systolic BP is ≥140 mm Hg or diastolic ≥90 mm Hg, the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant’s eligibility.
Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF >470 ms, complete LBBB, signs of an acute or indeterminate age myocardial infarction, ST segment and/or T wave changes suggestive of myocardial ischemia, second- or third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 470 ms, or QRS exceeds 120 ms, the ECG should be repeated twice and the average of the 3 QTcF or QRS values used to determine the participant’s eligibility. Computer interpreted ECGs [with abnormal findings] should be overread by an investigator experienced in reading ECGs before excluding a participant.
Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
Known immunodeficiency disorder, including positive serology for human immunodeficiency virus (HIV), or a first degree relative with a hereditary immunodeficiency and history of organ transplant (except corneal transplant).
History or evidence of hepatitis B or hepatitis C viruses. Hepatitis B vaccination is allowed.
Participants with any of the acute or chronic infections or infection history.
History of any lymphoproliferative disorder such as Epstein-Barr virus (EBV) related lymphoproliferative disorder, history of lymphoma, history of leukemia, or signs or symptoms suggestive of current lymphatic or lymphoid disease. Known present or a history of malignancy other than a successfully treated or excised nonmetastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
Evidence of active Mycobacterium tuberculosis (TB) infection in the past. Adequately treated latent TB will be permitted.
Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality or other conditions that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
Participants with ANY of the abnormalities in clinical laboratory tests at screening or Day -1, as assessed by the study-specific laboratory and confirmed by a single repeat test, if deemed necessary. - White blood cell (WBC) <3500/mm3 (<3.5 × 109 cells/L) - Absolute neutrophil count (ANC) <1500/mm3 (<1.5 × 109 cells/L) - Absolute lymphocyte count (ALC) <800/mm3 (<0.8 × 109 cells/L) - Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) level >2 × upper limit of normal (ULN) - Total bilirubin level > 1.5 × ULN; 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 ≤ ULN; - Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. - In the opinion of the investigator, have any clinically significant laboratory abnormality that could affect interpretation of study data or the participant’s participation in the study.
Participants who in the last 6 months experienced myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or New York Heart Association (NYHA) Class III/IV heart failure.
Participants with history or presence of second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sinoatrial block.
Resting HR <50 bpm at Screening or pre-randomization on Day 1. Measurement can be repeated up to 3 times to confirm the finding. Mean values will be used if repeated.
Recurrent symptomatic bradycardia or recurrent cardiogenic syncope.