Monograph of Mifepristone

Introduction

Definition and Overview

Mifepristone, also referred to as RU‑486, is a synthetic steroidal compound that functions primarily as a selective progesterone receptor antagonist and, to a lesser extent, as a glucocorticoid receptor antagonist. The drug has been employed in diverse therapeutic contexts, most notably in medical abortion and the management of Cushing’s syndrome. Its pharmacological profile is characterized by high affinity for progesterone receptors (PR) and a moderate affinity for glucocorticoid receptors (GR), enabling dual blockade of hormonal pathways that sustain early pregnancy and drive hypercortisolemia, respectively.

Historical Background

The development of mifepristone commenced in the early 1970s within the United Kingdom, driven by the need for a pharmacologic agent capable of terminating early gestation pregnancies without surgical intervention. Initial investigations focused on its antagonistic activity at the progesterone receptor, leading to the identification of its efficacy in inducing decidual breakdown and cervical ripening. Following regulatory approvals in the early 1990s, the compound received widespread clinical adoption, particularly in regions permitting medical abortion. Subsequent research expanded its therapeutic scope to include endocrine disorders such as Cushing’s syndrome, where its glucocorticoid receptor antagonism proved beneficial.

Importance in Pharmacology and Medicine

Mifepristone occupies a pivotal position in contemporary pharmacotherapy due to its unique dual receptor antagonism. From a pharmacodynamic standpoint, it provides a mechanistic basis for non-surgical gestational termination, thereby reducing surgical morbidity and expanding access to reproductive healthcare. In endocrinology, its GR antagonism offers a novel approach to attenuate cortisol excess, addressing a condition that historically required prolonged steroid therapy or surgical adrenalectomy. Consequently, the drug exemplifies the translation of receptor-level pharmacology into tangible clinical outcomes, underscoring its relevance to both pharmaceutical development and patient-centered care.

Learning Objectives

• Describe the chemical structure and receptor-binding characteristics of mifepristone.
• Explain the pharmacokinetic parameters that influence dosing regimens in diverse patient populations.
• Identify the clinical indications, contraindications, and safety considerations associated with mifepristone therapy.
• Apply case-based reasoning to optimize therapeutic outcomes in medical abortion and endocrine disorders.
• Critically evaluate potential drug–drug interactions and formulate guidance for clinical practice.

Fundamental Principles

Core Concepts and Definitions

The core concept underlying mifepristone therapy is receptor antagonism. At the progesterone receptor (PR), the drug competes with endogenous progesterone, thereby preventing luteal maintenance and placental function. At the glucocorticoid receptor (GR), mifepristone interferes with cortisol signaling, reducing the transcriptional activation of glucocorticoid-responsive genes. In addition to receptor blockade, the drug’s physicochemical properties—lipophilicity, high plasma protein binding, and limited aqueous solubility—contribute to its distribution and bioavailability.

Theoretical Foundations

Receptor theory posits that ligand efficacy is determined by affinity (K_d) and intrinsic activity. Mifepristone exhibits a low K_d for PR (~10 nM) and a moderate K_d for GR (~10 nM), with intrinsic activity approaching zero in both contexts, categorizing it as a pure antagonist. The competitive nature of antagonism is often modeled mathematically: IC₅₀ = K_d × (1 + [agonist]/K_m), where [agonist] represents endogenous progesterone or cortisol concentrations. This framework informs the dosing strategies required to achieve sufficient receptor occupancy across various physiological states.

Key Terminology

• Progesterone Receptor (PR)
• Glucocorticoid Receptor (GR)
• Competitive Antagonist
• Half-life (t_1/2)
• Area Under the Curve (AUC)
• Maximum Concentration (C_max)
• Clearance (Cl)
• Volume of Distribution (V_d)

Detailed Explanation

Pharmacodynamics

Mifepristone’s pharmacodynamic profile is characterized by rapid onset of action, attributable to its high lipophilicity and membrane permeability. Upon binding to PR, it induces a conformational change that prevents recruitment of coactivators necessary for transcriptional regulation of pregnancy-maintaining genes. The blockade of PR leads to decidual apoptosis, cervical softening, and myometrial contractions, culminating in expulsion of the gestational sac. In the context of Cushing’s syndrome, GR antagonism attenuates feedback inhibition of the hypothalamic-pituitary-adrenal axis, thereby reducing cortisol-mediated metabolic disturbances. The therapeutic window remains narrow; thus, dose titration is often guided by clinical response and biochemical markers.

Pharmacokinetics

Following oral administration, mifepristone is absorbed with peak plasma concentrations (C_max) reached within 2–4 hours. The absolute bioavailability is approximately 50–70%, influenced by food intake and first-pass metabolism. The drug undergoes extensive hepatic metabolism via cytochrome P450 3A4 (CYP3A4), yielding inactive metabolites that are excreted primarily in feces. The terminal half-life (t_1/2) is reported to be 20–30 hours, enabling once-daily dosing in most indications. Pharmacokinetic parameters can be described by the following relationships:

C(t) = C₀ × e^-k_elt

where k_el = ln(2) ÷ t_1/2

AUC = Dose ÷ Clearance

These equations underscore the importance of clearance in determining systemic exposure, particularly in patients with hepatic impairment, where reduced clearance may lead to accumulation and heightened adverse event risk.

Formulation and Delivery

The commercial preparations consist of 200 mg or 300 mg tablets, formulated with excipients that enhance dissolution in gastrointestinal fluids. In the setting of medical abortion, a single 200 mg dose is typically administered, followed by a progesterone antagonist such as misoprostol. For chronic conditions such as Cushing’s syndrome, oral daily dosing ranges from 200 to 600 mg, contingent upon therapeutic response and tolerability. Transdermal or intravenous formulations are not currently approved, and research into alternative delivery routes remains exploratory.

Drug Interactions and Metabolism

Given its reliance on CYP3A4 for metabolism, mifepristone is subject to significant drug–drug interactions. Concomitant use of potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) may increase systemic exposure by up to 3-fold, necessitating dose adjustments or alternative therapies. Conversely, strong CYP3A4 inducers (e.g., rifampicin, carbamazepine) can decrease plasma concentrations, potentially compromising efficacy. Additionally, the drug’s high protein binding (~95%) predisposes it to displacement interactions with other highly bound agents such as warfarin, which may alter anticoagulant activity. Monitoring of laboratory parameters and clinical status is recommended when initiating or discontinuing interacting medications.

Mathematical Models

Population pharmacokinetic models have been developed to predict variability in clearance and volume of distribution. A typical two-compartment model can be expressed as:

C(t) = A × e^-αt + B × e^-βt

where A and B are intercepts, and α and β are rate constants for distribution and elimination phases, respectively. Such models aid in optimizing dosing for specific patient cohorts, including pregnant women, elderly patients, and those with hepatic dysfunction. Simulation studies indicate that a 200 mg oral dose yields a C_max of approximately 1200 ng/mL, with an AUC of 20,000 ng·h/mL in healthy volunteers. Adjustments to the dose may be warranted in populations exhibiting altered pharmacokinetic profiles.

Clinical Significance

Relevance to Drug Therapy

Mifepristone’s ability to selectively block progesterone and glucocorticoid signaling positions it as a versatile therapeutic agent. In reproductive medicine, it offers a non-invasive alternative to surgical abortion, reducing provider burden and patient morbidity. In endocrinology, its GR antagonism provides a pharmacologic bridge for patients awaiting definitive surgical intervention or those unsuitable for surgery due to comorbidities. The drug’s wide therapeutic spectrum exemplifies the translation of receptor pharmacology into multimodal clinical practice.

Practical Applications

In the setting of medical abortion, mifepristone is typically administered 24–48 hours prior to a prostaglandin analogue. The timing of administration is critical to maximize PR blockade before prostaglandin-induced uterine contractions. For Cushing’s syndrome, dosing regimens are individualized, commencing at 200 mg daily and titrated up to 600 mg as tolerated. Monitoring of serum cortisol, urinary free cortisol, and clinical signs guides dose adjustments. Additionally, the drug’s interaction profile necessitates careful medication reconciliation, particularly in patients on antiretroviral therapy or antifungal agents.

Clinical Examples

Case 1: A 28-year-old woman with an early intrauterine pregnancy of 7 weeks gestation receives 200 mg mifepristone followed by 800 µg misoprostol. Within 48 hours, she experiences complete expulsion of gestational tissue without surgical intervention. Case 2: A 45-year-old patient with endogenous Cushing’s syndrome presents with hyperpigmentation and hypertension. Initiation of 200 mg mifepristone daily results in gradual normalization of cortisol levels and blood pressure over 6 weeks, obviating the need for adrenalectomy. These scenarios highlight the drug’s efficacy across distinct clinical contexts.

Clinical Applications/Examples

Case Scenario 1: Medical Abortion

Patient Profile: 32-year-old female, 6 weeks gestation, desires termination. No contraindications to mifepristone. The standard protocol involves a single 200 mg oral dose, followed by 800 µg misoprostol administered sublingually 24 hours later. The patient reports mild cramping and bleeding, which resolves within 48 hours. Follow-up imaging confirms complete abortion. This case underscores the importance of timing and patient counseling regarding potential side effects.

Case Scenario 2: Cushing’s Syndrome Management

Patient Profile: 38-year-old male with ACTH-independent Cushing’s syndrome secondary to adrenal adenoma. The patient is not a candidate for adrenalectomy due to comorbid cardiac disease. A starting dose of 200 mg mifepristone daily is initiated, with concurrent monitoring of serum cortisol and blood pressure. Over 8 weeks, the patient exhibits a 40% reduction in urinary free cortisol and improved glycemic control. Dose escalation to 400 mg is performed cautiously, with vigilance for hyperglycemia and hypertension. This illustrates the drug’s role as a medical therapy in endocrine disorders.

Case Scenario 3: Other Potential Uses

Emerging evidence suggests mifepristone may benefit patients with steroid-sensitive asthma or severe allergic rhinitis, given its GR antagonism. In a small cohort study, patients receiving 100 mg daily exhibited reduced exacerbation frequency. While not yet approved for these indications, such data warrant further investigation. The potential for repurposing mifepristone highlights the broader implications of receptor antagonism in diverse disease states.

Summary and Key Points

• Mifepristone is a selective progesterone and glucocorticoid receptor antagonist with a dual therapeutic profile.
• Pharmacokinetic parameters: oral bioavailability ~50‑70%, t_1/2 20‑30 hours, extensive CYP3A4 metabolism.
• Clinical indications include medical abortion (200 mg single dose) and Cushing’s syndrome (200‑600 mg daily, titrated).
• Drug interactions with CYP3A4 inhibitors/inducers can markedly alter exposure; dose adjustments may be necessary.
• Monitoring of clinical response and laboratory markers (cortisol, blood pressure, glucose) is essential for safe and effective use.
• Potential for repurposing exists, but further research is required to establish efficacy and safety in new indications.

References

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