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Mifepristone

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential

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An Erratum to this article was published on 01 August 1993

Abstract

Synopsis

Mifepristone is a potent oral antiprogestogen which acts at the level of the receptor, having a high affinity for the progesterone receptor. Most of the clinical trials have studied its efficacy in the termination of early pregnancy when used in conjunction with a low dosage of a prostaglandin analogue. In these studies, mifepristone 100 to 600mg administered as a single dose or over 3 or 4 days, 36 to 48 hours before a prostaglandin analogue given vaginally, intramuscularly or orally, induced complete abortion in about 95% of women. Used alone, mifepristone is an effective cervical priming agent prior to termination of first trimester pregnancy by vacuum aspiration, and facilitates termination of second trimester pregnancy by prostaglandin by reducing the interval between the start of prostaglandin treatment and termination, the cumulative prostaglandin dosage, and the adverse effects associated with these drugs. Mifepristone can also be used to induce labour in cases of intrauterine fetal death.

Mifepristone has been shown to be an effective postcoital contraceptive with a likely emergency role, since its repeated use modifies the menstrual cycle. Pilot studies have been performed in unresectable meningioma and metastatic breast cancer, and in Cushing’s syndrome.

Mifepristone is generally well tolerated, and thus is an effective, appropriate, medical alternative to surgical termination of early pregnancy. It has as yet unexplored potential as a postcoital contraceptive and in oncology.

Pharmacodynamic Properties

Mifepristone is an orally active antiprogestogen which acts by competing with progesterone for receptor binding. It also possesses antiglucocorticoid and weak antiandrogenic activity. It is devoid of estrogenic, antiestrogenic, mineralocorticoid and antimineralocorticoid properties. Its ability to block the action of progesterone on the pregnant uterus provides a medical approach to termination of early pregnancy. In normally menstruating women, the effect of mifepristone depends on the timing of administration. When administered in the first half of the luteal phase menstrual induction occurs independently of luteolysis; mifepristone administration during the mid luteal phase produced bleeding within a few days in most women but there was a second bleed at the time of expected menses in about two-thirds. The first episode of bleeding occurred in the presence of elevated progesterone and estrogen concentrations. Administration during the late luteal phase resulted in bleeding within 1 to 3 days, shortening of the luteal phase of the treatment cycle and lengthening of the subsequent follicular phase. Administration on the first 3 days of the menstrual cycle had no effect on cycle length but when given in the late follicular phase mifepristone prolonged the follicular phase by preventing the development of a normal luteinising hormone (LH) surge and delaying a new surge for about 15 days.

In the first trimester of pregnancy, mifepristone induced uterine activity in virtually all women 36 and 48 hours after administration, and increased the sensitivity of myometrium to exogenous prostaglandin (PG). The accompanying increase in decidual PGF2α production is attenuated by indomethacin, but the increase in uterine activity is not, thus, mechanisms other than an increase in decidual PG production contribute to the abortifacient effect of mifepristone. Mifepristone administration also resulted in cervical ripening in pregnant women.

Single doses of mifepristone 4.5 and 6 mg/kg increase plasma levels of cortisol, adrenocorticotrophin (ACTH) and lipotrophin, and in patients with unresectable meningioma treated with 200mg daily for prolonged periods, increases in plasma cortisol, ACTH and urinary cortisol are maximal at 3 weeks, and remain unchanged thereafter. Dosages of mifepristone required to exert antiglucocorticoid effects, which are achieved by disruption of the negative pituitary feedback, are higher than those needed for antiprogestogen activity. In subjects with normal adrenal function the increase in ACTH produced by mifepristone compensates for its antiglucocorticoid activity and there have been no reports of acute adrenal insufficiency at dosages used to terminate early pregnancy.

Pharmacokinetic Properties

Following single dose administration of mifepristone 600mg to healthy female volunteers, mean maximum plasma concentrations were about 2.0 mg/L at 1.35 hours. After a 20mg dose the absolute bioavailability of mifepristone was 69%. The pharmacokinetics of mifepristone are non-linear and its volume of distribution and clearance are inversely correlated with α1 -acid glycoprotein (AAG) concentration and are time- and dose-dependent.

Mifepristone is about 98% bound to plasma proteins binding with high affinity to AAG. Mifepristone crosses the placenta; the maternal/fetal ratio in plasma for mifepristone and its monodemethylated metabolite were 9.1 and 17.1, respectively.

Metabolism occurs by successive demethylations and by hydroxylation. After administration of 600mg of tritiated mifepristone, 10% of the radioactivity was eliminated in the urine and 90% in the faeces.

Therapeutic Efficacy

Early trials of mifepristone alone at dosages of 50 to 200mg daily for 4 to 7 days reported successful termination of pregnancy in 50 to 86% of women with amenorrhoea of up to 49 days duration, with efficacy apparently related to gestational age. The maximal success rate was achieved with a single oral dose of mifepristone 600mg in pregnancies of up to 41 days of amenorrhoea. These results were not considered sufficient for large scale use of mifepristone alone as an alternative to surgical termination of pregnancy and in subsequent trials the drug was combined with a low dose of a PG analogue administered vaginally, intramuscularly or orally. When combined with the PGE1 analogues misoprostol or gemeprost, the PGE2 analogues sulprostone, meteneprost (9-methylene PGE2), or the PGF2α analogue PG05, complete abortion usually occurred in about 95% of women pregnant for up to 49 days. In a large study conducted in the United Kingdom, efficacy was similar when mifepristone 600mg was combined with gemeprost 1mg in pregnancies up to 63 days of amenorrhoea. Mifepristone 600mg as a single dose or over 4 days combined with gemeprost was as effective as vacuum aspiration or gemeprost alone in terminating pregnancies of up 56 days, but caused less severe pain then the PG analogue alone.

Mifepristone alone was shown to facilitate PG-induced termination of second trimester pregnancy by reducing the interval between PG administration and expulsion of the products of conception, abdominal pain, and cumulative dosage of PGE.

Administration of mifepristone 400 to 600 mg/day for 2 days induced labour and fetal expulsion following intrauterine death in the second or third trimester of pregnancy.

Cervical dilatation induced by mifepristone 200 to 600mg administered as a single dose or over 2 days, has been used prior to surgical termination of first trimester pregnancy. Cervical diameter was significantly increased and the force necessary to dilate the cervix to 8 to 10mm was significantly reduced by pretreatment with mifepristone compared with placebo and was comparable with that required after pretreatment with gemeprost or a laminaria tent. Encouraging preliminary results were obtained in the induction of labour at term.

Administration of mifepristone 600mg within 72 hours of unprotected sexual intercourse was as effective as ethinylestradiol/norgestrel and more effective than danazol in preventing pregnancy. Once-monthly administration of mifepristone 200mg 2 days after the LH surge was also apparently effective in preventing pregnancy, but administration in this manner delays onset of the next menstrual period in about 40% of patients.

When mifepristone was administered immediately before expected menses, as a postcoital contragestive agent, the success rate when related to confirmed pregnancies was about 80%.

Initial studies suggest that mifepristone may have a role in the management of endometriosis, but it appeared ineffective in alleviating symptoms of premenstrual syndrome.

Oncological studies with mifepristone 200mg daily for prolonged periods indicate a possible role for the drug in unresectable meningioma and metastatic breast cancer in postmenopausal women, but further studies are needed to determine the potential of mifepristone in these diseases.

Preliminary studies suggest that prolonged administration of mifepristone may be useful in resolving biochemical and clinical abnormalities associated with Cushing’s syndrome due to ectopic ACTH secretion or adrenal tumour.

Tolerability

Mifepristone is generally well tolerated, with uterine bleeding generally lasting about 12 days after termination of early pregnancy. Such bleeding is frequently comparable with normal menstruation and is seldom sufficient to require haemostatic curettage or blood transfusion. During the 4-hour period following PG administration, pain occurs in about 80% of women; it requires non-narcotic analgesia in about 30% with up to a further 30% needing oral or parenteral narcotic analgesia.

Long term administration leads to increased plasma levels of cortisol and ACTH.

Dosage and Administration

The dosage of mifepristone most commonly used in the termination of early pregnancy is 600mg administered as a single dose 36 or 48 hours before a low dose of a PG analogue. Qualified medical personnel and resuscitation equipment should be immediately available during the 4-hour period following PG administration. All rhesus negative women should receive anti-D immunoglobulin at the time of PG administration, as in surgical pregnancy termination.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Rex N. Brogden, Karen L. Goa & Diana Faulds

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Various sections of the manuscript reviewed by: R.L. Barbieri, Department of Obstetrics and Gynecology, School of Medicine, State University of New York at Stony Brook, New York, New York, USA; E-E. Baulieu, Departement de Chimie Biologique, Universite Paris-Sud, Lab Hormones, Le Kremlin-Bicêtre, France; K. Elkind-Hirsch, Division of Endocrinology, Baylor College of Medicine, The Methodist Hospital, Houston, Texas, USA; I.S. Fraser, Department of Obstetrics and Gynaecology, University of Sydney, Sydney, New South Wales, Australia; J.W. Goldzieher, Department of Obstetrics and Gynecology, Baylor College of Medicine, San Antonio, Texas, USA; S. Grunberg, Department of Medical Oncology, University of Southern California, Los Angeles, California, USA; O. Heikinheimo, Steroid Research Laboratory, Department of Medicinal Chemistry, University of Helsinki, Helsinki, Finland; N.C. W. Hill, The Royal Free Hospital, Hampstead, London, England; G.T. Kovacs, Department of Obstetrics and Gynaecology, Monash University, Box Hill, Victoria, Australia; Y. Lefebvre, Obstétrique-Gynécologie, Hôpital Maisonneuvre-Rosemont, Montreal, Quebec, Canada; B. Maria, Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Villeneuve, Villeneuve Saint-Georges, France; J. Norman, Department of Obstetrics and Gynaecology, Centre for Reproductive Biology, The University of Edinburgh, Edinburgh, Scotland; A. Templeion, Department of Obstetrics and Gynaecology, Foresterhill, Aberdeen, Scotland; M. Webster, Eastpoint Tower, Edgecliff, New South Wales, Australia.

An erratum to this article is available at http://dx.doi.org/10.1007/BF03259108.

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Brogden, R.N., Goa, K.L. & Faulds, D. Mifepristone. Drugs 45, 384–409 (1993). https://doi.org/10.2165/00003495-199345030-00007

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