Monograph of Mifepristone

Introduction

Definition and Overview

Mifepristone, also known by its International Nonproprietary Name (INN) and as RU‑486, is a synthetic steroidal anti‑progesterone agent that functions primarily as a competitive antagonist at the progesterone receptor (PR). It exerts additional activity as a partial agonist at the glucocorticoid receptor (GR) and a weak antagonist at the mineralocorticoid receptor (MR). The drug is available in oral tablet form and, in certain indications, as a depot intramuscular injection. Its therapeutic profile encompasses termination of early pregnancy, management of abnormal uterine bleeding, treatment of Cushing’s syndrome, and adjunctive therapy in certain endocrine disorders.

Historical Background

Research into selective progesterone antagonism began in the 1960s, driven by the desire to develop agents capable of modulating uterine activity without the broad systemic effects of earlier compounds. In 1979, the first synthesis of mifepristone was reported, followed by preclinical studies demonstrating its efficacy in aborting early gestation in animal models. The drug was approved by the U.S. Food and Drug Administration (FDA) for medication abortion in 2000, and subsequently for other indications, including Cushing’s syndrome and management of uterine fibroids. In several countries, mifepristone is also used in combination with prostaglandin analogues to achieve complete uterine evacuation.

Importance in Pharmacology and Medicine

From a pharmacological standpoint, mifepristone represents a paradigm for selective receptor modulation. Its dual antagonistic action at PR and GR provides a distinctive mechanism of action that is exploited in diverse clinical settings. In clinical medicine, mifepristone has expanded therapeutic options across obstetrics, gynecology, endocrinology, and oncology, allowing for non‑surgical interventions in conditions that previously required invasive procedures. The drug’s safety profile, when used within prescribed guidelines, has contributed to improved patient autonomy and reduced morbidity associated with early pregnancy termination and endocrine disorders.

Learning Objectives

• Describe the pharmacodynamic profile of mifepristone, including receptor interactions and downstream effects.
• Explain the pharmacokinetic characteristics of the drug, including absorption, distribution, metabolism, and elimination.
• Identify the approved clinical indications and outline the therapeutic protocols for each.
• Analyze case scenarios to determine appropriate dosing regimens and monitoring parameters.

<li. Discuss potential drug interactions and contraindications in the context of patient safety.

Fundamental Principles

Core Concepts and Definitions

Receptor antagonism is central to mifepristone’s mechanism of action. At the PR, the drug binds with high affinity and prevents progesterone from stabilizing the endometrial lining, thereby inducing decidual breakdown and facilitating uterine contractions. At the GR, mifepristone competitively inhibits cortisol, leading to transient hypercortisolemia and a subsequent decrease in ACTH release via negative feedback. These interactions are mediated through ligand-binding domains that undergo conformational changes upon drug binding.

Theoretical Foundations

Binding kinetics can be characterized by the equilibrium dissociation constant (K_D). For mifepristone, K_D at the PR is approximately 0.2 nM, indicating a strong affinity. The drug’s partial agonist activity at the GR is reflected in a lower intrinsic efficacy (α ≈ 0.3), which allows for modulation of glucocorticoid signaling without complete blockade. The selectivity between PR and GR is achieved through structural modifications that enhance steric complementarity to the PR ligand-binding pocket while reducing affinity for the GR.

Key Terminology

• Progesterone Receptor (PR): Nuclear receptor that mediates progesterone effects on the uterine endometrium.
• Glucocorticoid Receptor (GR): Nuclear receptor that mediates cortisol actions; involved in the hypothalamic-pituitary-adrenal axis.
• Mineralocorticoid Receptor (MR): Nuclear receptor regulating electrolyte balance; weakly antagonized by mifepristone.
• Competitive Antagonism: Binding of a drug to a receptor that prevents endogenous ligand from activating the receptor.
• Partial Agonism: Ligand that activates a receptor but elicits a submaximal response relative to full agonists.

Detailed Explanation

Pharmacodynamics

Mifepristone exhibits a dual pharmacodynamic profile: it functions as a full antagonist at the PR and as a partial agonist at the GR. The blockade of PR leads to shedding of the decidua and activation of uterine contractile mechanisms, thereby facilitating pregnancy termination. In the context of Cushing’s syndrome, mifepristone competitively inhibits cortisol at the GR, diminishing downstream glucocorticoid signaling. The partial agonist activity at the GR is characterized by a bell-shaped dose-response curve, where low concentrations may yield modest activation, whereas higher concentrations achieve maximal antagonism. The drug’s interaction with MR is negligible at therapeutic doses but may be relevant in overdose scenarios.

Pharmacokinetics

Oral absorption occurs rapidly, with peak plasma concentrations (C_max) reached within 1–4 h post‑dose. The bioavailability is approximately 30–40 % due to first‑pass metabolism. Distribution is extensive, with a volume of distribution (V_d) estimated at 20–30 L/kg, reflecting high tissue penetration. Mifepristone is highly protein‑bound (≈ 99 %) primarily to albumin and α‑1‑acid glycoprotein. Metabolism occurs mainly via cytochrome P450 (CYP) 3A4 and 2C9 pathways, yielding several hydroxylated metabolites that retain weak activity. Elimination follows a biphasic pattern, with an elimination half‑life (t_1/2) of 18–30 h for the parent compound and a prolonged terminal phase due to extensive tissue binding. Clearance (Cl) is approximately 2–3 L/h, and the area under the concentration–time curve (AUC) is proportional to the dose: AUC = Dose ÷ Cl.

Mathematical Relationships

Binding kinetics can be approximated by the Michaelis–Menten equation adapted for receptor occupancy:
Occupancy = (Dose × K_a) ÷ (K_D + Dose × K_a), where K_a denotes absorption rate constant. The concentration–time profile follows first‑order decay: C(t) = C₀ × e^−k_el t. The elimination rate constant (k_el) can be derived from t_1/2 using the relationship k_el = ln(2) ÷ t_1/2.

Factors Affecting Pharmacokinetics and Dynamics

• Age and Physiology: Renal and hepatic function decline with age, potentially prolonging elimination.
• Drug Interactions: Concomitant use of CYP3A4 inhibitors (e.g., ketoconazole) may increase plasma concentrations, whereas inducers (e.g., rifampin) may decrease efficacy.
• Genetic Polymorphisms: Variations in CYP2C9 and CYP3A4 can alter metabolic rates.
• Food Intake: High‑fat meals may delay absorption but do not significantly alter overall bioavailability.
• Pregnancy: Physiologic changes can increase plasma volume and alter protein binding, impacting distribution.

Clinical Significance

Relevance to Drug Therapy

In obstetrics, mifepristone is administered to terminate pregnancies up to 10 weeks gestation, either alone or in combination with prostaglandin analogues. The drug’s safety profile allows for outpatient management, reducing healthcare costs and procedural risks. In endocrinology, mifepristone’s GR antagonism serves as a cornerstone therapy for Cushing’s syndrome, providing a non‑surgical alternative that improves quality of life. Additionally, its anti‑progesterone activity is leveraged in the treatment of heavy menstrual bleeding due to uterine fibroids, thereby offering a pharmacologic option when surgery is contraindicated or delayed.

Practical Applications

Standard dosing regimens vary by indication: for medication abortion, a single 200 mg oral dose is followed by a 50–100 mg dose of a prostaglandin analogue within 24 h; for Cushing’s syndrome, daily doses typically range from 100 mg to 300 mg, titrated to achieve clinical response while monitoring for hyperglycemia and hypertension. In uterine fibroid management, 200 mg daily is common, with treatment duration ranging from 3 to 6 months depending on symptom severity and patient preferences.

Clinical Examples

Case studies frequently illustrate the balancing of efficacy and safety. For instance, a 28‑year‑old woman seeking early pregnancy termination may receive 200 mg of mifepristone, followed by misoprostol 800 µg administered sublingually 24 h later. The regimen achieves complete abortion in > 95 % of patients. In contrast, a 45‑year‑old patient with endogenous Cushing’s syndrome may commence mifepristone 200 mg daily, with gradual titration to 300 mg to control hypercortisolism while monitoring for glucose intolerance and electrolyte disturbances.

Clinical Applications/Examples

Case Scenario 1: Medication Abortion

A 32‑year‑old woman presents at 8 weeks gestation, requesting termination. She has no significant comorbidities and no contraindications to mifepristone. The protocol involves oral administration of 200 mg mifepristone, followed by sublingual misoprostol 800 µg within 24 h. She is advised to monitor for bleeding and pain, with a follow‑up visit scheduled 24–48 h post‑misoprostol. If incomplete abortion occurs, additional misoprostol or surgical evacuation may be considered. This approach minimizes invasive intervention and is associated with a low complication rate.

Case Scenario 2: Cushing’s Syndrome

A 52‑year‑old man presents with hypercortisolism, characterized by central obesity, hypertension, and glucose intolerance. Endogenous ACTH levels are suppressed, confirming ACTH‑independent Cushing’s syndrome. Mifepristone is initiated at 200 mg daily, with subsequent titration to 300 mg over 4–6 weeks based on clinical response. Monitoring includes regular glucose tolerance tests, blood pressure measurements, and serum cortisol levels. Adverse effects such as hyperglycemia and hypokalemia are managed with adjunctive therapy. After 12–18 months, remission is achieved, and mifepristone may be tapered or discontinued if disease control persists.

Case Scenario 3: Uterine Fibroids

A 38‑year‑old woman experiences menorrhagia attributed to multiple intramural fibroids. Surgical options are deferred due to personal preference. Mifepristone 200 mg daily is prescribed for 3 months, with periodic ultrasound assessment to evaluate fibroid size and symptomatology. Hemoglobin levels are monitored to detect anemia. During therapy, menstrual bleeding is reduced by > 70 %, and patient reports improved quality of life. After completion, the patient is offered periodic reassessment and consideration of definitive treatment if symptoms recur.

Problem‑Solving Approaches

• When drug interactions are suspected, review the patient’s medication list for potent CYP3A4 inhibitors or inducers, and adjust the mifepristone dose accordingly.
• In patients with hepatic impairment, consider initiating therapy at the lower end of the dosing spectrum and monitor liver function tests closely.
• For patients with renal insufficiency, although mifepristone is not primarily renally cleared, monitor for accumulation of metabolites and adjust dosing if necessary.
• When managing side effects such as hyperglycemia, coordinate with endocrinology for glycemic control, and consider adjusting concurrent medications that influence glucose metabolism.

Summary / Key Points

• Mifepristone is a selective progesterone receptor antagonist with additional glucocorticoid partial agonist activity, enabling diverse therapeutic uses.
• Key pharmacokinetic parameters include a C_max reached within 1–4 h, a t_1/2 of 18–30 h, and extensive protein binding (≈ 99 %).
• Standard dosing regimens: 200 mg oral for medication abortion with misoprostol, 100–300 mg daily for Cushing’s syndrome, and 200 mg daily for fibroid management.
• Monitoring strategies encompass hormone levels, glucose tolerance, blood pressure, and imaging when indicated.
• Potential drug interactions involve CYP3A4 modulators; careful dose adjustments are recommended to avoid toxicity or diminished efficacy.

Clinical pearls: When initiating mifepristone for Cushing’s syndrome, a low starting dose followed by gradual titration mitigates the risk of hyperglycemia and facilitates patient adherence. In obstetric use, ensuring timely administration of prostaglandin analogues enhances completion rates and reduces the need for surgical intervention.

References

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