DRUG EVALUATION
`
`Drugs 45 (3): 384-409. 1993
`0012-6667/93/0003-0384/S 13.00/0
`C Adis International Limited. All rights reserved.
`0RE1167
`
`Mifepristone
`A Review of its Pharmacodynamic and Pharmacokinetic Properties, and
`Therapeutic Potential
`
`Rex N. Brogden, Karen L. Goa and Diana Faulds
`Adis International Limited, Auckland. New Zealand
`
`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, Departe(cid:173)
`ment de Chimie Biologique. Universite Paris-Sud, Lab Hormones, Le Kremlin-Bicetre, France; K. Elkilfd-HirsciJ,
`Division of Endocrinology, Baylor College of Medicine, The Methodist Hospital, Houston. Texas, USA; /.S.
`FrtUer, Department of Obstetrics and Gynaecology, University of Sydney, Sydney, New South Wales, Australia;
`J.W. Gold:;iehtr, Department of Obstetrics and Gynecology, Baylor College of Medicine, San Antonio, Texas,
`USA; S . Gr1111btrg, Department of Medical Oncology, University of Southern California, Los Angeles, California,
`USA; 0. Heiki11heimo, 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, Obstetrique-Gy(cid:173)
`necologie, Hopi tal Maisonneuvre-Rosemont, Montreal, Quebec, Canada; B. Maria, Department of Obstetrics and
`Gynecology, Centre Hospitalier Intercommunal de Villeneuve, Villeneuve Saint-Georges, France; J. Normtlll, De(cid:173)
`partment of Obstetrics and Gynaecology, Centre for Reproductive Biology, The University of Edinburgh, Edin(cid:173)
`burgh, Scotland; A. Temp/etolf, Department of Obstetrics and Gynaecology, Foresterhill, Aberdeen, Scotland; M.
`Webster, Eastpoint Tower, Edgecliff, New South Wales, Australia.
`
`Contents
`385
`387
`387
`389
`389
`390
`390
`391
`39/
`391
`391
`391
`393
`393
`394
`394
`394
`394
`394
`397
`399
`
`Summary
`l. Pharmacodynamic Properties
`1.1 Binding to Progesterone Receptors
`1.2 Antiprogesterone Activity
`1.2.1 Effect in Normally Menstruating Women
`1.2.2 Effect in Postmenopausal Women
`1.2.3 Effect in Early Pregnancy
`1.3 Effect on Cervical Dilatation
`1.4 Antiglucocorticoid Activity
`1.5 Other Effects
`2. Pharmacokinetic Properties
`2.1 Absorption and Plasma Concentrations
`2.2 Distribution
`2.3 Metabolism and Excretion
`2.4 Plasma Concentration and Clinical Efficacy
`3. Therapeutic Efficacy
`3.1 Termination of Early Pregnancy
`3. 1.1 Mifepristone Alone
`3.1 .2 Mifepristone Combined with a Prostaglandin Analogue
`3.2 Cervical Priming
`3.3 Facilitation of Second Trimester Pregnancy Termination
`
`1
`
`TEVA1013
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`

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`Mifepristone: A Re view
`
`385
`
`399
`400
`401
`401
`401
`401
`401
`401
`401
`401
`403
`403
`403
`403
`404
`404
`404
`404
`404
`405
`
`3.4 Intrauterine Fetal Death
`3.5 Nonviable Early Pregnancy
`3.6 Induction of Labour at Term
`3.7 Fertility Control
`3.7.1 Postcoital Contraception
`3. 7.2 Postcoital Contragestion
`3.8 Treatment of Benign Gynaecological Diseases
`3.8.1 Endometriosis and Fibroids
`3.8.2 Premenstrual Synd rome
`3.9 Use in Oncology
`3.10 Cushing's Syndrome
`4. Tolerability
`4. 1 Uterine Bleeding
`4.2 Pain
`4.3 Gastrointestinal Effects
`4.4 Effects During Long Term Administration
`4.5 Effect During Ongoing Pregnancy
`4.6 Other Effects
`5. Dosage and Administration
`6. Place of Mifepristone in Therapy
`
`Summary
`Synopsis
`
`Mifepristone is a potent oral anti progestogen which acts at the level of 1he receplor, having a
`high a.f]inily for !he progeslerone receptor. Mos1 of the c/inicallrials have studied its efficacy in
`the termination of early pregnancy when used in conjunction with a low dosage of a prostaglandin
`analogue. In these sllldies, mifepris/One 100 to 600mg adminis1ered as a single dose or over 3 or
`4 days, 36 to 48 hours before a pros1aglandin analogue given vaginally. inlramuscularly or orally.
`induced complete abortion in abow 95% of women. Used alone. mifepristone is an effeclive cefl•ical
`priming agenl prior to terminal ion of firs/ trimester pregnancy by l'acuum aspiralion. and facil·
`itates termination of second trimester pregnancy by prostaglandin by reducing 1he interval be/ll'een
`!he s1art of prostaglandin /real men! and lermination. !he cumulative prostaglandin dosage. and
`the adverse effecls associa1M wi1h 1hese drugs. M({eprislone can also be used 10 induce labour in
`cases of imrauterine feial death.
`M({epris/One has been shown to be an effective postcoital contraceptive with a likely emergency
`role. since its repeated use modifies the menstrual cycle. Pilo1 studies have been performed in
`rmresectable meningioma and melaslalic breast cancer. and in Cushing's syndrome.
`M1jepris10ne is generally well tolerated. and thus is an effeclive. appropriate. medical alternalive
`to surgical termination of early pregnancy. It has as yet unexplored po1en1ial as a postcoital con·
`1raceptive 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 anti mineralocorticoid 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
`
`2
`
`

`

`386
`
`Drugs 45 (3) /993
`
`in the presence of elevated progesterone and estrogen concentrations. Administration during the
`late luteal phase resulted in bleeding within I 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
`lutein ising 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 PGF2 .. 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, adrenocor(cid:173)
`ticotrophin (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 func(cid:173)
`tion the increase in ACTH produced by mifepristone compensates for its antiglucocorticoid ac(cid:173)
`tivity 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 aq-acid
`glycoprotein (AAG) concentration and are time- and dose-dependent.
`Mifepristone is about 98% bound to plasma proteins binding with high affinity to AAG. Mi(cid:173)
`fepristone crosses the placenta; the maternal/fetal ratio in plasma for mifepristone and its mono(cid:173)
`demethylated 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 al(cid:173)
`ternative 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 com(cid:173)
`bined with the PGE1 analogues misoprostol or gemeprost, the PGE2 analogues sulprostone, me(cid:173)
`teneprost (9-methylene PGE2), or the PGF2a 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 I mg 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 termi(cid:173)
`nating 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 preg(cid:173)
`nancy by reducing the interval between PG administration a.nd expulsion of the products of
`conception, abdominal pain, and cumulative dosage of PGE.
`
`3
`
`

`

`Mifepristone: A Review
`
`387
`
`Administration of mifepristone 400 to 600 mg/day for 2 days induced labour and fetal ex(cid:173)
`pulsion following intrauterine death in the second or third trimester ~f 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 IOmm
`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 mifepristonc 600mg within 72 hours of unprotected sexual intercourse was
`as effective as ethinylestradioljnorgestrel and more effective than danazol in preventing preg(cid:173)
`nancy. 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.
`Prelimi.nary studies suggest that prolonged administration of mifepristone may be useful in
`resolving biochemical and clinical abnormalities associated with Cushing's syndrome due to ec(cid:173)
`topic 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 men(cid:173)
`struation 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 coni sol 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-0 im(cid:173)
`munoglobulin at the time of PG administration. as in surgical pregnancy termination.
`
`I. Pharmacodynamic Properties
`
`Mifepristone (fig. I) is a potent anti progestogen
`which, by its ability to block the action of proges(cid:173)
`terone on the pregnant uterus, provides a medical
`approach to termination of early pregnancy. It is a
`synthetic norsteroid which acts reversibly at recep(cid:173)
`tor level, having a high affinity for the human pro(cid:173)
`gesterone receptor. At higher dosages the drug also
`
`has potent antiglucocorticoid activity and weak
`antiandrogenic activity.
`
`1.1 Binding to Progesterone Receptors
`
`Mifepristone has a high affinity for the human
`uterine progesterone receptor; relative to proges(cid:173)
`terone mifepristone has 2 to I 0 times the affinity
`depending on experimental conditions and the tis(cid:173)
`sue tested. The metabolites of mifepristone also
`
`4
`
`

`

`388
`
`0
`
`Drugs 45 (3) 1993
`
`Conisol
`
`Progesterone
`
`Fig. 1. Structural formulae of mifepristone. cortisol and progesterone.
`
`(RU 486)
`Mifepriatone
`
`bind to the progesterone receptor, the relative
`binding of the monodemethylated, hydroxylated
`and didemethylated derivatives being 50, 36 and
`21 relative to progesterone (I 00), respectively (Na(cid:173)
`goshi et al. 1991 ).
`Mifepristone and progesterone interact differ(cid:173)
`ently with the receptor (fig. 2) and may produce
`different conformational changes in the receptor
`(Skafar 1991 ). Mifepristone induces hyperphos(cid:173)
`phorylation of the human progesterone receptor and
`although the dimerisation as well as the DNA
`binding of the receptor occurs as with agonists, it
`is generally not followed by the activation or tran(cid:173)
`scription of progestin dependent genes.
`
`1.2 Antiprogesterone Activity
`
`1.2.1 Effect in Normally Menstruating Women
`
`Follicular Phase
`Oral administration ofmifepristone 3 mgjkg for
`the first 3 days of the menstrual cycle had no effect
`on cycle length, luteinising hormone (LH) surge,
`or LH frequency or amplitude (Stuenkel et al. 1990),
`while mifepristone on days I 0 to 17 delayed LH
`surge by 15 days resulting in an increase of inter(cid:173)
`menstrual duration from 28 to 40 days (Shoupe et
`al. 1987b). As might be expected, the decrease in
`plasma levels of LH and follicle stimulating hor(cid:173)
`mone (FSH) was less pronounced when mifepri(cid:173)
`stone was administered on day 6 than on day I 0
`(Permezel et al. 1989).
`The effects of mifepristone in early pregnancy
`are shown in figure 3. In early pregnancy, mife-
`
`pristone interrupts pregnancy by opposing the ac(cid:173)
`tion of progesterone at several sites in the uterus.
`In a normal pregnancy the trophoblast (the future
`placenta) secretes human chorionic gonadotrophin
`(hCG) which maintains the corpus luteum. Pro(cid:173)
`gesterone secreted by the corpus luteum supports
`pregnancy by maintaining a secretory endome(cid:173)
`trium, inhibiting contractility of uterine muscle and
`firming the cervix and inhibiting dilatation. When
`progesterone is inhibited by mifepristone the en(cid:173)
`dometrium erodes, and the embryo is detached and
`expelled along with the endometrial tissue. Evac(cid:173)
`uation of the uterus is also favoured by the effect
`of mifepristone in softening and dilating the cervix
`(Baulieu et al.l986; Ulmann et al. 1990).
`
`Early Luteal Phase
`When administered as a single dose of 5 to
`200mg in the first half of the luteal phase, mife(cid:173)
`pristone induced uterine bleeding 40 to 57 hours
`after ingestion. Menstrual induction occurred in(cid:173)
`dependently of luteolysis possibly due to a direct
`effect of mifepristone on the endometrium (Li et
`al. 1988) and was significantly related to dosage
`and day of mifepristone administration (Li et al.
`1988; Swahn et a1.1990).
`
`Mid-Luteal Phase
`Following oral administration of mifepristone
`25, 50 or I OOmg daily for 4 days, 3 mgjkg for 3
`days or 50 to 800mg daily for 3 days, uterine bleed(cid:173)
`ing occurred within 3 days in nearly all healthy
`
`5
`
`

`

`Mifepristone: A Review
`
`389
`
`women studied. Further bleeding at the time of ex(cid:173)
`pected menses occurred in about two-thirds (Garzo
`et al. 1988; Schaison et al. 1985; Shoupe et al.
`1987a). This second bleeding episode was con(cid:173)
`temporary of spontaneous luteolysis and suggest(cid:173)
`ive of incomplete endometrial shedding at the time
`of the first bleed (Croxatto et al. 1989).
`A rapid decrease of plasma progesterone and es(cid:173)
`tradiol levels indicative of complete luteolysis oc(cid:173)
`cured in the first 48 hours after mifepristone
`administration in those who had a single bleeding
`episode. In the women with 2 bleeding episodes,
`the first episode of bleeding occurred in the pres(cid:173)
`ence of elevated progesterone levels (Garzo et al.
`1988) indicating that mifepristone blocks the ac(cid:173)
`tion of progesterone at the level of the endome(cid:173)
`trium.
`
`Late Luteal Phase
`In healthy women, administration of mifepri(cid:173)
`stone I OOmg daily for 4 days at the end of the lu(cid:173)
`teal phase resulted in bleeding within l to 3 days
`of initiating treatment. The extent of bleeding was
`similar to that in control cycles. The luteal phase
`of the treatment cycle was shortened and the fol-
`
`. ,-----------------~
`
`• • Progesterone
`
`licular phase of the subsequent cycle lengthened
`(Croxatto et al. 1987a). When mifepristone was ad(cid:173)
`ministered over 3 successive cycles, the mainten(cid:173)
`ance of normal cycle rhythm was achieved by ad(cid:173)
`ministering the drug at the time of natural
`progesterone withdrawal (Croxatto et al. 1987b).
`Mifepristone administration also induced uter(cid:173)
`ine bleeding within 48 hours in women receiving
`hCG. This effect of the drug on the endometrium
`occurred despite high plasma progesterone and es(cid:173)
`tradiol levels indicating a direct effect of mifepri(cid:173)
`stone on endometrium.
`
`1.2.2 Effect in Postmenopausal Women
`In postmenopausal women treated with intra(cid:173)
`muscular injections of estradiol benzoate 0.625mg
`daily for 15 days, separate administration of mi(cid:173)
`fepristone I 00 or 200mg orally or of progesterone
`25mg daily intramuscularly during the last 6 days
`of estradiol benzoate, induced secretory changes in
`the endometrium. Under these circumstances mi(cid:173)
`fepristone exhibited some agonist activity, whereas
`during concomitant administration of mifepri(cid:173)
`stone and progesterone, mifepristone acted as an
`antagonist (Gravanis et al. 1985).
`
`a Mifepristone
`··~--------------
`
`•11
`
`No tranactiption
`
`Endometrial cell
`
`Fig. 2. Schematic representation of the action of progesterone and mifepristone within the endometrial cell (from Ulmann
`et al. 1990). Progesterone acts within the cell (left). By occupying the progesterone receptor in the nucleus, the hormone
`modifies the receptor's shape. enabling it to bind to chromatin (DNA and associated proteins). Such binding leads to gene
`transcription and protein synthesis. Mifepristone antagonises these effects by occupying the receptor without stimulating gene
`transcription. It may block transcription by failing to induce the change in receptor shape required for chromatin binding
`(centre), or it may induce a change in shape that permits such binding but then prevents binding by critical transcription
`factors (right); mRNA = messenger ribonucleic acid.
`
`6
`
`

`

`390
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`Drugs 45 (3) /993
`
`Impaired folliculogernesis
`Luteolysis (?) t
`...
`:
`:
`
`:
`:
`
`1
`
`- -··• Myometrial contractions
`• ·• ·· · · • Decidual shedding
`··-· •• • Trophoblast I
`luteolysis
`-hCGI -
`
`··· · · • CeMcal softening
`
`Fig. 3. Schematic presentation of the principal mechanisms of action of mifepristone at the level of the uterus and ovaries
`(after Baulieu 1985).
`
`1.2.3 Effect in Early Pregnancy
`Following administration of mifepristone 50,
`100 or 600mg to women in the first trimester of
`pregnancy, uterine activity determined by intra(cid:173)
`uterine pressure recordings, was evident in 30 to
`60% of women 24 hours after ingestion and in vir(cid:173)
`tually all women 36 and 48 hours after adminis(cid:173)
`tration (Norman et al. 1991 b; Swahn & Bygdeman
`1988; Urquhart & Templeton 1990b) [fig. 4]. In
`vit;o, production of prostaglandin (PG) F2,. in cul(cid:173)
`tures from decidua increased following mifepri(cid:173)
`stone addition. PG production by decidua ob(cid:173)
`tained surgically from pregnant women of less than
`56 days' amenorrhoea was unchanged by indo(cid:173)
`methacin IOOmg 12-hourly given rectally alone, but
`the increase in PG production induced by mife(cid:173)
`pristone was attenuated by concomitant indometh(cid:173)
`acin (Norman et al. 1991b). Since the stimulatory
`effect of mifepristone on PG production was at(cid:173)
`tenuated by indomethacin while the increase in
`uterine activity was not, mechanisms other than an
`increase in decidual PG production contribute to
`the abortifacient effect of mifepristone, and an in(cid:173)
`crease in the number of gap junctions may be a
`major mechanism of action of mifepristone on
`uterine activity (Norman et at. 199lb).
`Increasing intramuscular doses of a PGE2
`analogue in early pregnancy increased uterine tonus
`on which irregular contractions of low amplitude
`were superimposed. Prior administration of mife-
`
`pristone 50 mg/day for 36 to 72 hours increased
`the sensitivity of the myometrium to PGE2 as evi(cid:173)
`denced by an increase in uterine tonus and in the
`frequency and amplitude of uterine contractions
`relative to those in a control group administered
`the prostaglandin without mifepristone pretreat(cid:173)
`ment (Swahn & Bygdeman 1988).
`
`1.3 Effect on Cervical Dilatation
`
`In pregnant women, mifepristone 50 to 600mg
`increased cervical dilatation compared with pla(cid:173)
`cebo at 24 and 48 hours after ingestion (Gupta &
`Johnson 1990; Lefebvre et al. 1990; Urquhart &
`Templeton 1990a; WHO 1990). Cervical dilatation
`tended to increase with time after administration
`irrespective of dosage (Lefebvre et al. 1990; Ra(cid:173)
`destad et at. 1990), but was not clearly dose-related
`after doses of I 00 to 600mg at 24 hours. However,
`doses of 400 to 600mg had a greater effect than
`lower doses 48 hours after ingestion (Lefebvre et
`al. 1990). Cervical dilatation was more marked
`when the gestation time exceeded 10 weeks, but
`was not influenced by parity (Lefebvre et al. 1990).
`In nonpregnant premenopausal women, mife(cid:173)
`pristone 600mg increased cervical dilatation rela(cid:173)
`tive to placebo 48 hours after ingestion (Gupta &
`Johnson 1990).
`basis of bioconversion of
`On
`the
`[14C]arachidonic acid in cervical tissue ~omoge-
`
`7
`
`

`

`Mifepristone: A Review
`
`391
`
`nates, enhancement of cervical dilatation by mi(cid:173)
`fepristone appears not to be due to altered synthe(cid:173)
`sis of hydroxy acids or prostaglandins (Radestad et
`al. 1990) and may occur in part, independently of
`progesterone blockade (Gupta & Johnson 1990).
`
`1.4 Antiglucocorticoid Activity
`
`Glucocorticoid antagonists prevent the biologi(cid:173)
`cal effects of glucocorticoids by competing with
`these hormones for binding to the intracellular glu(cid:173)
`cocorticoid receptor. Mifepristone is the first po(cid:173)
`tent glucocorticoid antagonist active
`in vivo
`(Chrousos et al. 1988). Depending on the response
`examined, mifepristone can act both as an optimal
`antagonist (devoid of any agonist activity) or a
`suboptimal antagonist (partial agonist-antagonist).
`Mifepristone binds to rat glucocorticoid receptor
`and to gfucocorticoid receptor in human mono(cid:173)
`nuclear leucocytes with an affinity about 3-fold
`higher than that of dexamethasone (Philibert et al.
`1981; Kawai et al. 1987), but the mifepristone-re(cid:173)
`ceptor complex appears to be bound to nuclear ma(cid:173)
`terial less tightly than are agonist-receptor com(cid:173)
`(Chrousos et al. 1988). Dosages of
`plexes
`mifepristone required to exert antiglucocorticoid
`effects are higher than those needed for antipro(cid:173)
`gesterone activity.
`In healthy m.ale volunteers, single-dose admin(cid:173)
`istration of mifepristone caused a dose-related in(cid:173)
`crease in plasma cortisol, lipotrophin and ACTH
`levels evident at dosages of 4.5 and 6.0 mgfkg but
`not at 2.2 mgjkg (Bertagna et al. 1984; Gaillard et
`al. 1984). The suppressive effect of I mg of dexa(cid:173)
`methasone on the hypothalamo-pituitary-adrenal
`(HP A) axis was attenuated by mifepristone I OOmg
`and completely abolished by a 400mg dose (Ber(cid:173)
`tagna et al. 1984) and 6 mgjkg (Gaillard et al. 1984)
`indicating that mifepristone antagonised the ne(cid:173)
`gative feedback action at the pituitary level of both
`the morning endogenous cortisol rise and of ex(cid:173)
`ogenously administered dexamethasone. These data
`indicate that the disinhibition of the pituitary-adre(cid:173)
`nal axis occurs only during the morning hours of
`the circadian rhythm.
`The antiglucocorticoid effect of mifepristone
`
`administered for 3 days (Bertagna et al. 1986) or 9
`weeks (Nieman et at. 1985) was studied in patients
`with Cushing's syndrome, and longer term effects
`were evaluated in patients with meningioma (Lam(cid:173)
`berts et al. 1991 ). A single 400mg dose of mifepri(cid:173)
`stone did not affect plasma cortisol in 5 patients
`with Cushing's disease whereas administration of
`the same dose for 3 days significantly increased
`plasma cortisol, plasma lipotrophin and urinary
`cortisol levels, the latter showing the greatest in(cid:173)
`crease (Bertagna et al. 1986). There was no sig(cid:173)
`nificant effect of mifepristone on steroid secretion
`in 2 patients with non-pituitary-dependent Cush(cid:173)
`ing's syndrome.
`The increase in urinary and plasma cortisol dur(cid:173)
`ing long term administration of mifepristone 200mg
`daily to 10 patients with unresectable meningioma,
`
`100
`
`c ·e
`
`0
`~
`0;
`:I:
`
`E s
`< Cl.
`....
`
`~
`'§ 1000
`~ 800
`I 600
`I
`·~
`""
`
`~
`
`0
`
`30
`
`60
`
`120
`
`150
`
`180
`
`90
`Min
`t
`0.05 0.10 0.15 0.20 0.25
`16-Phenoxy-PGE2 (mg)
`
`Fig. 4. Effect of increasing intramuscular doses of 16-phen(cid:173)
`oxy-prostaglandin E2 on uterine contractility measured as total
`pressure area (TPA) and in Montevideo units mifepristone
`in early pregnancy in untreated women (A), and 24 (e ), 36
`(6 ), and 48 (0) hours after the stan of treatment with 2Smg
`twice daily. The difference between untreated and treated
`women was significant (p ~ 0.05) at all times and with all
`dosages of prostaglandin (after Swahn & Bygdeman 1988).
`
`8
`
`

`

`392
`
`Drugs 45 (3) 1993
`
`was maximal at 3 weeks and remained unchanged
`thereafter (Lamberts et al. I 99 I). Diurnal cortisol
`rhythm was maintained although the negative feed(cid:173)
`back sensitivity of the HPA axis to dexamethasone
`was reduced.
`Symptoms suggestive of adrenal insufficiency
`(nausea, vomiting, asthenia) which occurred in 3
`patients were controlled by oral administration of
`prednisone 7 .5mg daily (Lamberts et at. 1991 ).
`Circulating levels of androgens and estradiol
`measured in 3 postmenopausal women and l man
`were increased due to activation of adrenal andro(cid:173)
`gen by the compensatory increase in ACTH. This
`led to an increase in estradiol levels (probably by
`peripheral aromatisation of androgens ) to values
`observed in the early follicular phase of a normal
`menstrual cycle (Lamberts et at. 1991 ).
`
`1.5 Other Effects
`
`Long term administration ofmifepristone 200mg
`daily to patients with unresectable meningioma re(cid:173)
`sulted in a subclinical yet significant increase in
`thyroid stimulating hormone and a decrease in
`thyroxine. These changes were evident within I
`month and persisted throughout the 5-month treat(cid:173)
`ment period. Triiodothyronine levels did not
`change significantly, but were positively correlated
`with those of thyroxine (Grunberg et al. 1990). The
`reasons for these changes were not clear.
`Animal studies show that mifepristone binds
`with a low affinity to androgen receptors (about 4
`times less than that of testosterone) and exerts weak
`antiandrogenic activity, but no androgenic activity
`in the castrated rat. Mifepristone does not bind to
`either estrogen or mineralocorticoid receptors and
`is devoid of estrogenic or antiestrogen activity in
`spayed rats or immature female mice, rats or rab(cid:173)
`bits. Mifepristone has no mineralocorticoid or
`antimineralocorticoid activity (Baulieu & Segal
`1985).
`
`1. Pharmacokinetic Properties
`
`The pharmacokinetic properties of mifepristone
`have been studied mostly following oral adminis(cid:173)
`tration to healthy women, although studies were
`
`also conducted in pregnant women and a few male
`volunteers. Plasma concentrations of mifepristone
`and its metabolites were measured by radioim(cid:173)
`muno- (Li et al. 1988) and radioreceptor assays
`(Kawai et al. 1987), or high performance liquid
`chromatography (HPLC) [Nagoshi et at. 199 I), and
`pharmacokinetic parameters calculated employing
`one- and two-compartment models as well as non(cid:173)
`compartmental analysis.
`
`2. I Absorption and Plasma Concentrations
`
`The pharmacokinetics of mifepristone and its
`metabolites are not linear. Following oral admin(cid:173)
`istration of single doses of mifepristone 100, 400,
`600 and 800mg to healthy female volunteers max(cid:173)
`imum plasma concentrations were about 2.5 mgf
`L and differed between the I 00 and 800mg doses
`only 2 hours after ingestion (Heikinheimo et at.
`1986; Lahteenmaki et al. 1987), although Nagoshi
`et al. (1991) reported maximum plasma concen(cid:173)
`trations of 1.5 and 3.3 mgJL after single doses of
`200 and 400mg, respectively. After a single 600mg
`dose maximum plasma concentration was about 2
`mgjL at 1.35 hours. High doses of lO and 25 mgf
`kg in healthy female and male volunteers proouced
`maximum plasma concentrations of progesterone
`receptor-reactive material of 5.17 to 7.5 mgJL (Ka(cid:173)
`wai et al. 1987). Maximum plasma concentrations
`were attained 0. 7 to 1. 5 hours after oral adminis(cid:173)
`tration. The parent drug and its metabolites (using
`HPLC) were still detectable 6 to 7 days after a single
`dose (Nagoshi et al. 1991) and for 10 days using
`radioimmunoassay (Lahteenmaki et al. 1987).
`Administration of 12.5, 25, 50 or IOOmg twice
`daily for 4 days to healthy female volunteers re(cid:173)
`sulted in similar plasma concentrations of 1.4 to
`l. 7 mgfL at dosages ~ 50mg twice daily (Heikin(cid:173)
`heimo 1989), and it was suggested that the lack of
`increase in plasma drug concentration when dos(cid:173)
`age increased above 50mg twice daily is partly ex(cid:173)
`plained by saturation of a-1-acid glycoprotein
`(AAG), the serum binding protein for mifepristone
`in man (Heikinheimo et al. l987a), which has a
`binding capacity lower than the therapeutic dose
`(data on file, Roussel Uclaf).
`
`9
`
`

`

`Mifepristone: A Review
`
`393
`
`During chronic administration of mifepristone
`10 to 20 mg/kg to patients with Cushing's syn(cid:173)
`drome, plasma concentrations were relatively con(cid:173)
`stant at 5.06 to I 1.8 mg/L when measured by
`radiorecept