Pharmacology of Mifepristone

Introduction/Overview

Mifepristone, initially developed as RU-486, represents a pivotal agent in reproductive medicine and endocrinology. As a synthetic steroid derivative, it functions primarily as a competitive antagonist at progesterone and glucocorticoid receptors. Its introduction marked a significant advancement in pharmacotherapy, providing a medical alternative to surgical procedures for pregnancy termination. The clinical relevance of mifepristone extends beyond its most recognized application, encompassing several endocrine disorders where modulation of steroid hormone action is therapeutic. Understanding its pharmacology is essential for healthcare professionals involved in family planning, obstetrics and gynecology, endocrinology, and oncology.

The importance of this agent lies in its ability to modulate fundamental physiological processes governed by progesterone, including endometrial proliferation, uterine quiescence, and immune tolerance during pregnancy. Its mechanism provides a foundation for non-invasive medical management of early pregnancy termination, management of miscarriage, and treatment of conditions like Cushing’s syndrome. The drug’s pharmacokinetic and pharmacodynamic profile necessitates careful clinical administration and monitoring to ensure efficacy and patient safety.

Learning Objectives

• Describe the molecular mechanism of action of mifepristone as an antagonist at progesterone and glucocorticoid receptors and its downstream physiological effects.
• Outline the pharmacokinetic properties of mifepristone, including absorption, distribution, metabolism, excretion, and key parameters such as half-life and bioavailability.
• Identify the approved clinical indications for mifepristone, including its use in medical abortion and the management of Cushing’s syndrome, and recognize common off-label applications.
• Analyze the major adverse effect profile, contraindications, and significant drug-drug interactions associated with mifepristone therapy.
• Evaluate special considerations for mifepristone use in specific patient populations, including those with renal or hepatic impairment and during lactation.

Classification

Mifepristone is classified within multiple therapeutic and chemical categories, reflecting its diverse pharmacological actions.

Therapeutic and Pharmacological Classification

• Antiprogestin: This is the primary classification, denoting its ability to antagonize the action of progesterone at its receptor.
• Glucocorticoid Receptor Antagonist: At higher doses, mifepristone acts as a competitive antagonist at glucocorticoid receptors, which forms the basis for its use in hypercortisolism.
• Abortifacient: When used in combination with a prostaglandin analogue for the termination of early pregnancy.
• Antineoplastic Agent (investigational): Explored for use in progesterone receptor-positive cancers, such as meningiomas and certain breast cancers.

Chemical Classification

Mifepristone is a synthetic 19-norsteroid derivative. Its chemical name is 11β-[p-(Dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one. The molecular structure features modifications that confer high affinity for intracellular steroid receptors, particularly the progesterone receptor (PR) and the glucocorticoid receptor (GR). Its structure is closely related to norethindrone but includes a bulky dimethylaminophenyl substitution at the 11β position, which is critical for its antagonist properties by preventing receptor activation and recruitment of coactivators.

Mechanism of Action

The pharmacological effects of mifepristone are mediated through its action as a competitive antagonist at intracellular steroid hormone receptors. Its affinity and resultant effects vary depending on the receptor type and the dose administered.

Receptor Interactions and Binding Affinity

Mifepristone exhibits high binding affinity for two primary receptors: the human progesterone receptor (PR) and the human glucocorticoid receptor (GR). Its relative binding affinity for the PR is approximately five times greater than that of natural progesterone. For the GR, its binding affinity is approximately four times greater than that of dexamethasone and over 18 times greater than cortisol. The drug demonstrates negligible affinity for the mineralocorticoid receptor and the androgen receptor, and only very weak binding to the estrogen receptor, which is not considered clinically significant.

Molecular and Cellular Mechanisms

As a steroid analogue, mifepristone passively diffuses across the cell membrane and binds to the ligand-binding domain of cytosolic progesterone receptors. In the absence of progesterone, these receptors are complexed with heat shock proteins. Binding of an agonist like progesterone induces a conformational change, dissociation of heat shock proteins, dimerization, and translocation to the nucleus, where the receptor complex binds to progesterone response elements (PREs) on DNA to regulate gene transcription.

Mifepristone binds to the PR but induces an alternative conformational change. This mifepristone-bound receptor complex can still dimerize and bind to DNA at PREs. However, the altered conformation recruits corepressor proteins (e.g., N-CoR, SMRT) instead of coactivators, effectively blocking gene transcription that is normally stimulated by progesterone. This results in a pure antiprogestogenic effect at the molecular level. In tissues dependent on progesterone, such as the endometrium and decidua, this leads to:

• Degeneration and necrosis of the decidua, disrupting the implantation site.
• Release of endogenous prostaglandins and an increase in prostaglandin sensitivity.
• Softening and dilation of the cervix.
• Increased uterine contractility, partly due to the withdrawal of progesterone’s inhibitory effect on myometrial gap junctions and oxytocin receptors.

When used for medical abortion, these antiprogestogenic effects are synergistically augmented by the subsequent administration of a prostaglandin analogue (typically misoprostol). The prostaglandin induces strong, coordinated uterine contractions, leading to the expulsion of the products of conception.

Antiglucocorticoid Activity

At doses significantly higher than those used for abortion (300 mg vs. 200 mg), mifepristone’s binding to the glucocorticoid receptor becomes therapeutically relevant. It acts as a competitive antagonist, blocking the binding of cortisol and other endogenous glucocorticoids. This prevents glucocorticoid receptor activation and the subsequent anti-inflammatory and metabolic actions of cortisol. In patients with Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) production or adrenal tumors, this antagonism can ameliorate hyperglycemia, hypertension, and other manifestations of cortisol excess. The antiglucocorticoid effect also explains the dose-dependent risk of adrenal insufficiency when mifepristone is administered at high doses or in susceptible individuals.

Pharmacokinetics

The pharmacokinetic profile of mifepristone is characterized by high oral bioavailability, extensive metabolism, and a long terminal half-life, which has implications for its dosing and the management of drug interactions.

Absorption

Mifepristone is administered orally and is rapidly absorbed from the gastrointestinal tract. Its absolute bioavailability is estimated to be approximately 69%. Peak plasma concentrations (C_max) are typically achieved within 1 to 2 hours after a single oral dose. Absorption is not significantly affected by food, although taking the drug with a high-fat meal may delay the time to C_max without altering the overall extent of absorption (AUC).

Distribution

Mifepristone is extensively distributed throughout the body. Its volume of distribution is large, estimated at approximately 1 to 2 L/kg, indicating significant tissue penetration. The drug is highly bound to plasma proteins (>98%), primarily to alpha-1-acid glycoprotein (AAG). Binding to albumin is less significant. This high degree of protein binding, particularly to AAG—an acute-phase reactant—can be influenced by clinical conditions that alter AAG levels, potentially affecting the free, pharmacologically active fraction of the drug.

Metabolism

Mifepristone undergoes extensive hepatic metabolism, primarily via the cytochrome P450 (CYP) system. The major isoform responsible is CYP3A4. Metabolism occurs through two primary pathways: N-demethylation and hydroxylation. The initial N-demethylation produces three primary monodemethylated metabolites (RU-42,633, RU-42,848, and RU-42,698), which retain significant pharmacological activity, particularly as antiglucocorticoids. These metabolites are subsequently hydroxylated to form inactive compounds. The extensive first-pass metabolism contributes to the drug’s variable pharmacokinetics among individuals.

Excretion

Following metabolism, the drug and its metabolites are excreted primarily via the fecal route. Approximately 83% of an orally administered dose is recovered in feces, with only about 9% excreted in urine. The elimination is biphasic. The initial phase has a half-life of approximately 18 hours, corresponding to distribution and early elimination. The terminal elimination half-life is prolonged, ranging from 20 to 40 hours for mifepristone itself. However, due to the presence of active metabolites with similar or longer half-lives, the cumulative pharmacological effect persists for a considerably longer duration, which can extend to several days.

Pharmacokinetic Parameters and Dosing Considerations

Key pharmacokinetic parameters include a C_max of approximately 2 mg/L after a 600 mg dose, achieved in about 1.5 hours. The area under the curve (AUC) increases disproportionately with dose, suggesting non-linear pharmacokinetics at higher doses, likely due to saturation of metabolic pathways or protein binding sites. This non-linearity is a critical consideration when adjusting doses for different indications. The long effective half-life necessitates careful scheduling of concomitant prostaglandin administration for abortion (typically 24 to 48 hours after mifepristone) and dictates caution with drugs that may interact with CYP3A4, as effects may be prolonged.

Therapeutic Uses/Clinical Applications

The clinical applications of mifepristone are directly linked to its receptor antagonism, with distinct dosing regimens for its different indications.

Approved Indications

• Medical Termination of Intrauterine Pregnancy: This is the most common use. A single 200 mg oral dose of mifepristone is followed 24 to 48 hours later by administration of a prostaglandin analogue, most commonly 800 mcg buccal or vaginal misoprostol. This regimen is highly effective (success rates >95%) for terminating pregnancies up to 70 days (10 weeks) of gestation. The mechanism involves mifepristone-induced decidual necrosis and cervical ripening, followed by misoprostol-induced uterine contractions.
• Management of Early Pregnancy Loss (Miscarriage): Mifepristone is used in combination with misoprostol for the medical management of missed or incomplete miscarriage. A 200 mg dose followed by misoprostol can facilitate complete uterine evacuation, offering an alternative to surgical dilation and curettage.
• Hyperglycemia Secondary to Hypercortisolism in Cushing’s Syndrome: For patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery, mifepristone is approved at a starting dose of 300 mg once daily. The dose may be titrated up to 1200 mg daily based on clinical response and tolerability. It improves glycemic control by antagonizing the peripheral effects of cortisol.

Off-Label and Investigational Uses

• Labor Induction and Cervical Ripening: A single dose may be used to ripen the cervix prior to induction of labor in term pregnancies, particularly in cases with an unfavorable cervix.
• Emergency Contraception: A high dose (600 mg) has demonstrated efficacy as emergency contraception when used within 120 hours of unprotected intercourse, though it is not a first-line agent for this indication in most regions.
• Uterine Leiomyomas (Fibroids): Daily low-dose administration (5-25 mg) has been shown to reduce fibroid size and associated symptoms like menorrhagia, likely by creating a hypoestrogenic, hypoprogestogenic environment.
• Endometriosis: Investigated for pain relief by inducing amenorrhea and decidualization of ectopic endometrial tissue.
• Psychiatric Disorders: Research has explored its potential in psychotic depression, based on the hypothesis of cortisol dysregulation, and in mitigating weight gain associated with antipsychotic medications via its antiglucocorticoid effects.
• Oncology: Investigated for the treatment of progesterone receptor-positive meningiomas and breast cancers, often in combination with other agents.

Adverse Effects

The adverse effect profile of mifepristone is closely related to its pharmacological actions and varies with the dose and indication.

Common Side Effects

When used for pregnancy termination or miscarriage management, adverse effects are frequently attributable to the intended pharmacological effect and the concomitant use of misoprostol.

• Gastrointestinal: Nausea, vomiting, diarrhea, and abdominal pain or cramping are very common. Diarrhea and cramping are more strongly associated with the prostaglandin component.
• Uterine Bleeding: Vaginal bleeding and spotting are expected and necessary parts of the treatment process. Bleeding is typically heavier than a menstrual period and may last for an average of 9 to 16 days. Prolonged heavy bleeding (>2 sanitary pads per hour for 2 consecutive hours) is a recognized complication requiring medical evaluation.
• General: Fatigue, headache, dizziness, and fever/chills may occur.

For the treatment of Cushing’s syndrome (higher doses), common side effects often reflect cortisol receptor blockade and may include fatigue, nausea, anorexia, arthralgia, peripheral edema, and headache.

Serious/Rare Adverse Reactions

• Incomplete Abortion and Ongoing Pregnancy: Treatment failure occurs in a small percentage of cases, necessitating surgical intervention. The risk increases with gestational age.
• Heavy Bleeding and Hemorrhage: Although heavy bleeding is common, clinically significant hemorrhage requiring transfusion occurs in approximately 0.1-0.2% of cases.
• Infection and Sepsis: Rare cases of serious bacterial infection and septic shock, including those caused by Clostridium sordellii, have been reported, sometimes presenting without fever. This underscores the importance of patient education regarding signs of infection.
• Adrenal Insufficiency: With high-dose therapy for Cushing’s syndrome, blockade of glucocorticoid receptors can precipitate symptoms of adrenal insufficiency, including fatigue, nausea, hypotension, and hypoglycemia. This can be challenging to diagnose as serum cortisol levels will be elevated but are functionally antagonized.
• Hypokalemia: Observed in some patients receiving high-dose mifepristone for Cushing’s syndrome, potentially due to the unmasking of mineralocorticoid effects of very high cortisol levels.
• Endometrial Hypertrophy: With long-term use, unopposed estrogen action due to progesterone blockade can lead to endometrial thickening.

Warnings and Precautions

Mifepristone carries a boxed warning (black box warning) in its labeling for the termination of pregnancy. This warning highlights the risk of serious and sometimes fatal infections and bleeding following its use. It mandates that the drug be dispensed only in certain healthcare settings by certified providers who can ensure access to emergency medical care for complications such as incomplete abortion, severe hemorrhage, or sepsis. It also stresses the requirement for patients to return for a follow-up visit approximately 7 to 14 days after administration to confirm complete termination and rule out complications.

Drug Interactions

Given its metabolism via CYP3A4 and its role as both a substrate and an inhibitor of this enzyme, mifepristone has a significant potential for drug-drug interactions. Its long half-life means that interactions may be prolonged.

Major Drug-Drug Interactions

• CYP3A4 Inhibitors: Concomitant use with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) can significantly increase mifepristone plasma concentrations. This raises the risk of dose-related adverse effects, particularly QT interval prolongation and adrenal insufficiency. Co-administration should be avoided.
• CYP3A4 Inducers: Drugs that induce CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) can substantially decrease mifepristone plasma levels, potentially leading to therapeutic failure. Alternative therapies or dose adjustments may be necessary.
• Drugs Prolonging the QT Interval: Mifepristone itself can cause dose-related QT interval prolongation. Concurrent use with other QT-prolonging agents (e.g., class IA and III antiarrhythmics, certain antipsychotics, antibiotics like moxifloxacin) may have additive effects and increase the risk of torsades de pointes. Caution is advised, and ECG monitoring may be warranted.
• Corticosteroids: Mifepristone antagonizes glucocorticoid receptors. Therefore, the therapeutic effects of systemic corticosteroids (e.g., prednisone, dexamethasone) may be reduced or abolished. This interaction is critical for patients relying on corticosteroid therapy for conditions like asthma or autoimmune diseases.
• CYP3A4 Substrates: At steady-state high doses, mifepristone can act as a strong inhibitor of CYP3A4. It can markedly increase exposure to sensitive CYP3A4 substrates with narrow therapeutic indices, such as simvastatin, lovastatin, cyclosporine, sirolimus, and certain benzodiazepines (e.g., midazolam). Co-administration is generally contraindicated or requires substantial dose reduction and close monitoring of the substrate drug.

Contraindications

• Confirmed or suspected ectopic pregnancy (mifepristone is ineffective and delays necessary treatment).
• Chronic adrenal failure or current long-term systemic corticosteroid therapy.
• Known allergy or hypersensitivity to mifepristone, misoprostol, or other prostaglandins.
• Hemorrhagic disorders or concurrent anticoagulant therapy (due to risk of heavy bleeding).
• Inherited porphyrias.
• An intrauterine device (IUD) in place (must be removed prior to administration).
• For the Cushing’s syndrome indication: pregnancy is a contraindication, and primary hypoadrenalism.

Special Considerations

Use in Pregnancy and Lactation

Pregnancy: By design, mifepristone is used to terminate early pregnancy. It is contraindicated in desired pregnancies. For its use in Cushing’s syndrome, pregnancy must be excluded prior to initiation due to the drug’s abortifacient potential. Effective contraception is required for women of childbearing potential during and for one month after treatment for Cushing’s syndrome.

Lactation: Data on the excretion of mifepristone into human breast milk are limited. Given its high lipophilicity and long half-life, transfer into milk is probable. The effects on a nursing infant are unknown, but could theoretically include anti-glucocorticoid effects. A decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. For the abortion indication, breastfeeding can typically be resumed shortly after the process is complete, as the treatment course is very short.

Pediatric and Geriatric Considerations

Pediatric: Safety and efficacy for medical abortion have been established in adolescents. Clinical studies included women under 18 years of age, and no unique safety concerns were identified. However, access may be governed by local regulations regarding parental consent. For Cushing’s syndrome, use in pediatric patients has not been well-studied.

Geriatric: Clinical studies for the approved indications did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently. In general, dose selection should be cautious, considering the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this population.

Renal and Hepatic Impairment

Renal Impairment: Formal pharmacokinetic studies in renal impairment are lacking. Since renal excretion is a minor pathway for elimination (≈9%), significant impairment is not expected to drastically alter mifepristone pharmacokinetics. However, patients with severe renal disease were excluded from clinical trials, so caution is advised. Monitoring for adverse effects related to accumulation, such as QT prolongation, may be prudent.

Hepatic Impairment: Mifepristone is extensively metabolized in the liver. Its pharmacokinetics are likely to be significantly altered in patients with hepatic impairment. In patients with mild to moderate impairment, increased exposure is expected. The drug is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). For other patients, careful monitoring for signs of toxicity is necessary, though specific dose adjustments have not been established.

Summary/Key Points

• Mifepristone is a synthetic steroid that acts as a competitive antagonist at progesterone and glucocorticoid receptors, with affinity for the progesterone receptor being highest.
• Its mechanism for medical abortion involves decidual necrosis, cervical softening, and increased myometrial sensitivity to prostaglandins, which are administered 24-48 hours later to induce contractions.
• Pharmacokinetically, it is well-absorbed orally, highly protein-bound, extensively metabolized by CYP3A4, and has a long terminal half-life (20-40 hours) with active metabolites prolonging its effect.
• Approved indications include medical termination of intrauterine pregnancy (≤70 days) in combination with misoprostol, management of early pregnancy loss, and control of hyperglycemia in endogenous Cushing’s syndrome.
• The most common adverse effects are gastrointestinal distress, uterine bleeding, and cramping. Serious risks include hemorrhage, incomplete abortion, infection (including rare C. sordellii sepsis), and, with high doses, adrenal insufficiency and hypokalemia.
• It has a significant drug interaction profile, primarily mediated through CYP3A4. It is contraindicated with strong CYP3A4 inhibitors, many CYP3A4 substrates, and in patients with ectopic pregnancy, adrenal failure, or on chronic corticosteroid therapy.
• Special precautions are required for its use, including administration only by certified providers with access to emergency care, mandatory follow-up, and careful consideration in patients with hepatic impairment or during lactation.

Clinical Pearls

• The efficacy of the medical abortion regimen is highest when gestational age is less than 49 days, though it remains effective up to 70 days.
• Patient counseling must emphasize the expectation of heavy bleeding and the critical importance of returning for the follow-up visit to confirm complete expulsion.
• Signs of potential complications requiring immediate medical attention include fever >100.4°F for >4 hours, severe abdominal pain not relieved by analgesics, and heavy bleeding (soaking >2 maxi pads per hour for 2 consecutive hours).
• When used for Cushing’s syndrome, monitoring serum cortisol levels is not useful for assessing efficacy or adrenal insufficiency, as levels will be high. Clinical assessment of symptoms (e.g., glucose control, hypertension, hypokalemia) is paramount.
• Due to its long half-life and CYP3A4 inhibition profile, the effects of mifepristone and its potential to interact with other drugs can persist for weeks after the last dose.

References

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