DRUG DISPOSITION
`
`Clin. Pharmacokinet. 1997 Jul; 33 (I): 7-17
`03 12-5963/97/ooo7.(XJJ7/S05.50/0
`
`© Ads International Limited. All rights reserved .
`
`Clinical Pharmacokinetics
`of Mifepristone
`Oskari Heikinheimo
`Departments of Biomedicine and Obstetrics and Gynecology, University of Helsinki,
`Helsinki, Finland
`
`Contents
`Summary
`1. Pharmacokinetics
`1 .1 Assay Systems
`1.2 Absorption ..
`1.3 Serum Kinetics.
`1.4 Metabolism in Humans .
`2. Mechanisms of Action at the Receptor Level
`3. Clinical Uses . . . . . . . . . . . . . . . . . . . .
`3.1 Termination of Early Pregnancy . . ... .
`3.2 Termination of Second or Third Trimester Pregnancy.
`3.3 Labour Induction . . . . .. . . .. . . .. ... .
`3.4 Contraceptive Strategies . "
`" "" ' "
`3.5 Possible Uses in Endometriosis and Leiomyoma.
`3.6 Treatment of Hormone Dependent Tumours
`3.7 Antiglucocorticoid Actions
`4. Conclusions . . . . . . . . . . . . . . . . . . . . . .
`
`7
`8
`8
`8
`9
`9
`9
`10
`10
`12
`12
`13
`14
`14
`14
`14
`
`Summary
`
`Mifepristone is a steroidal anti progestin and antiglucocorticoid acting at the
`receptor level. The aromatic dimethylaminophenyl side chain in position II of
`the steroid structure is essential for the antagonistic properties of mifepristone.
`The pharmacokinetics of mifepristone are characterised by rapid absorption,
`a long half-life of 25 to 30 hours and micromolar serum concentrations following
`ingestion of doses currently in clinical use. The serum transport protein <Xl-acid
`glycoprotein (AAG) regulates the serum kinetics of mifepristone. Binding to
`AAG limits the tissue availability of mifepristone, explaining the low metabolic
`clearance rate of 0.55 Llkg/day and the low volume of di stribution of mifepris(cid:173)
`tone. Also, similar serum concentrations of mifepristone following ingestion of
`single doses exceeding 100mg can be explained by saturation of the binding
`capacity of serum AAG. Following oral intake, mifepristone is extensively me(cid:173)
`tabolised by demethylation and hydroxylation, the initial metabolic steps are
`catalysed by the cytochrome P450 (CYP) enzyme CYP3A4.
`The 3 most proximal metabolites, namely the monodemethylated, didemethyl(cid:173)
`ated and hydroxylated metabolites of mifepristone, all retain considerable affinity
`toward the human progesterone and glucocorticoid receptors; in addition, the
`
`

`

`8
`
`Heikinheimo
`
`serum concentrations of these 3 metabolites are in a similar range as those of the
`parent drug. Thus, the combined pool of mifepristone, as well as that of the
`metabolites, seems responsible for the biological actions of mifepristone.
`Combination therapy with mifepristone and low dose prostaglandin is cur(cid:173)
`rently in clinical use for termination of early pregnancy in China, France, Sweden
`and the UK. The combined regimen is well tolerated and highly efficacious with
`a 95% rate of complete pregnancy terminations. Recent clinical studies on preg(cid:173)
`nancy termination have focused on dose optimisation of mifepristone and eval(cid:173)
`uation of the orally active prostaglandin derivative misoprostol. In addition,
`several other indications for the clinical use of mifepristone, such as induction of
`labour, contraception, as well as treatment of various hormone dependent disor(cid:173)
`ders, are emerging.
`The major obstacles currently inhibiting further evaluation and distribution of
`mifepristone are political rather than clinical. However, it is hoped that the even(cid:173)
`tual introduction of new anti progesterone molecules by several manufacturers
`will enhance the availability of this important class of new drugs.
`
`Rarely has the introduction, testing and distribu(cid:173)
`tion of a single drug provoked as much scientific
`and political controversy as that associated with
`the progesterone receptor antagonist mifepristone
`(RU486). Development of mifepristone was a cul(cid:173)
`mination of several decades of scientific pursuit
`emerging from the characterisation of the intracel(cid:173)
`lular steroid receptor proteins, the systematic evalu(cid:173)
`ation of steroid structure-receptor binding-relation(cid:173)
`ships as well as understanding the roles of gonadal
`steroids in the regulation of reproductive physiol(cid:173)
`ogy. Mifepristone is currently in clinical use for
`termination of early pregnancy in France, China, the
`UK and Sweden; application processes are currently
`underway in the US .
`This article reviews the current status of the
`clinical use of mifepristone with special emphasis
`on its pharmacokinetics in humans.
`
`1. Pharmacokinetics
`
`1 .1 Assay Systems
`
`Various assay methods have been employed in
`the measurement of serum mifepristone; these in(cid:173)
`clude radioimmunoassay (RIA),[I] radioreceptor(cid:173)
`assays (RRA)[2,3] as well as assays based on high
`performance liquid chromatography (HPLC).[4-6]
`However, because of the presence of cross-reacting
`metabolites, direct RIA and RRA fail to distinguish
`
`the parent mifepristone from the considerable pool
`of metabolites present in the circulation following
`oral intake of the compoundJ5] Serum concentra(cid:173)
`tions of mifepristone are in the micromolar range
`following ingestion of doses currently in clinical
`use, thus allowing the use of HPLC for detailed
`analysis of the pharmacokinetics and metabolism
`of mifepristone.
`
`1.2 Absorption
`
`Following oral ingestion mifepristone is rapidly
`absorbed and the time to peak serum concentrations
`(tmaX> is approximately 1 to 2 hours.[3,5,6] When an(cid:173)
`alysed by specific RIA or HPLC, the tmax has been
`similar within the dose range 2 to 600mg.[7,8] The
`peak drug plasma concentrations (Cmax) rise accord(cid:173)
`ing to the dose of mifepristone within the dose
`range of 2 to 25mg.l81 However, at doses of 100 to
`800mg, the Cmax does not differ significantly, this
`is most likely because of the saturability of the se(cid:173)
`rum binding capacity for mifepristone.[9]
`Because of presystemic metabolism, bioavaila(cid:173)
`bility of mifepristone has been estimated to be 40%
`following oral intake of 100mgJIO] Unfortunately,
`attempts to bypass first pass metabolism by vaginal
`administration resulted in very low serum concen(cid:173)
`trations of mifepristone. [II]
`
`© Adis International Limited . All rights reserved .
`
`Clin. Pha rmacokinet. 1997 Jul; 33 (1)
`
`

`

`Clinical Pharmacokinetics of Mifepristone
`
`9
`
`1.3 Serum Kinetics
`
`Following the absorption and distribution phase
`of approximately 4 to 6 hours, the serum concen(cid:173)
`tration of mifepristone remains in the micromolar
`range for the next 24 to 48 hours.[3,9] Interestingly,
`following ingestion of single doses of mifepristone
`100 to 800mg, the serum concentrations were all
`approximately 2.5 IlmollL at 24 hours.[9] However,
`within the dose range of 2 to 25mg, the serum con(cid:173)
`centrations of mifepristone, as well as the areas under
`the concentration-time curves (AVC), increase ac(cid:173)
`cording to the dose. [8] The same phenomenon of
`similar serum concentrations also occurs during
`multiple dose administration of 50mg or more of
`mifepristone.l 12] These micromolar serum concen(cid:173)
`trations of mifepristone also persist during long
`term (up to 20 months) daily treatment with
`200mg.l 13]
`At serum concentrations below 2.5 IlmollL, 94
`to 99% of mifepristone is protein bound in human
`serum.[2.9] Early studies by Moguilewsky and
`Philibert[14] indicated that human serum, unlike rat
`serum, contains a high affinity binding protein for
`mifepristone, which was soon identified as <XI-acid
`glycoprotein (AAG). The highly significant cor(cid:173)
`relations between the serum concentrations of
`mifepristone and AAG suggested that AAG has a
`great affect on the pharmacokinetics of mifepristone
`in humans.[9,15,16] Studies using centrifugal ultra(cid:173)
`filtration dialysis showed that the 2.5 IlmollL pla(cid:173)
`teau serum concentrations of mifepristone repre(cid:173)
`sent saturation of AAG binding capacity.l9] In
`addition, in vitro studies suggest that albumin has
`a high capacity role in the serum transport of
`mifepristone. [9]
`The profound effect of binding to AAG on the
`pharmacokinetics of mifepristone can be demon(cid:173)
`strated by comparing the differences in the distri(cid:173)
`bution of mifepristone between humans and rats.
`Rat serum does contain AAG; however, it does not
`bind mifepristone in the same manner as human
`AAG.l14] In humans the initial volume of distribu(cid:173)
`tion and the clearance rate of mifepristone are 10%
`of body weight and 0.55 Llkg/day, whereas in rats
`the corresponding figures are 135% and 71
`
`Llkg/day, respectively.[IO] Thus, in humans the
`serum AAG seems to limit the tissue availability
`of mifepristone. However, mifepristone exceeding
`the binding capacity of AAG may be more suscep(cid:173)
`tible for excretion or possibly for diffusion into
`peripheral tissues.[12]
`
`1 .4 Metabolism in Humans
`
`The elimination phase half-life (til) of mifepris(cid:173)
`tone has been reported to vary between 24 and 48
`hours when analysed by HPLC.l6,17] However,
`studies employing either RIA or RBA have reported
`tV2 values between 54 to 90 hoursp,18] most likely
`due to the presence of cross reacting metabolites of
`mifepristone.
`The metabolism of mifepristone is initiated by
`rapid demethylation and hydroxylation in humans,
`rats and monkeys.[IO] Recently, cytochrome P450
`(CYP) 3A4 has been shown to be the primary CYP
`enzyme responsible for the oxidative metabolism
`of mifepristone in human liver microsomes.[19]
`Following oral administration of 100mg or more,
`constant serum concentrations of mifepristone, but
`increasing concentrations of the monodemethylated,
`didemethylated and hydroxylated metabolites are
`found.l9,20] Within the dose range of 100 to 800mg,
`the serum concentrations of the monodemeth(cid:173)
`ylated metabolite exceed those of the parent
`drug;[9,20] in addition, following oral administra(cid:173)
`tion of doses beyond 400mg, the levels of
`didemethylated and hydroxylated metabolites ex(cid:173)
`ceed those of mifepristone.l9] The demethylated
`and hydroxylated metabolites are further metabo(cid:173)
`lised and excreted into bile, but in humans only a
`very small fraction of mifepristone can be detected
`in urine.[IO]
`
`2. Mechanisms of Action at the
`Receptor Level
`
`Mifepristone binds with - 2.5 times higher affin(cid:173)
`ity to the human progesterone receptor than pro(cid:173)
`gesterone itself and with around 4 times higher af(cid:173)
`finity to the human glucocorticoid receptor than
`dexamethasone.[7] The subsequent steps in the
`mechanism of action of mifepristone have been
`
`© Adis International limited. All rights reserved .
`
`Clln. Pharmacokinet. 1997 Jul; 33 (1)
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`

`

`10
`
`Heikinheimo
`
`subject to intensive study. Mifepristone bound pro(cid:173)
`gesterone receptors have been shown to undergo
`receptor dimerisation and they also bind to hor(cid:173)
`mone response elements in DNA, but apparently in
`an abortive manner unable to execute the final steps
`of progesterone receptor actions.[21]
`The monodemethylated, hydroxylated and dide(cid:173)
`methylated metabolites of mifepristone retain af(cid:173)
`finities of 21 to 9% towards the human progesterone
`receptor (hPR), when compared with mifepristone.
`The disassociation constant (KD) of mifepristone
`for the hPR is 1.3 x 10-9 moUL. Their binding af(cid:173)
`finities towards human glucocorticoid receptor
`(hGR) are 61 to 45%, whereas that of dexametha(cid:173)
`sone is 23%, of that of mifepristone (1.6 x 10-9
`moI/L).[7] These receptor-binding affinities, in
`combination with the high serum concentrations of
`the metabolites, suggest that the biological effects
`of mifepristone are mediated via both the parent
`compound as well as the pool of metabolites. How(cid:173)
`ever, the lower affinities towards hPR may imply a
`minor importance for the metabolites in the anti(cid:173)
`progesterone action of mifepristone.
`
`3. Clinical Uses
`
`3.1 Termination of Early Pregnancy
`
`3. 1.1 Mechanism of Action at the Uterine Level
`The effects of mifepristone on the secretory pri(cid:173)
`mate endometrium (extravasation of the red blood
`cells, neutrophil infiltration and local necrosis) are
`evident at 32 hours following administration of the
`drug.[22] Sloughing of the functional endometrium
`and that of the chorionic gonadotropin producing
`trophoblast tissue, results in cessation of the corpus
`luteum function. Following successful mifepristone(cid:173)
`induced termination of pregnancy, the serum con(cid:173)
`centrations of progesterone and chorionic gonado(cid:173)
`tropin fall to undetectable levels within 2 and 4
`weeks, respectively.l23]
`In addition to its role in the secretory transfor(cid:173)
`mation and decidualisation of the endometrium,
`progesterone also maintains the uterus in a quies(cid:173)
`cent state throughout the pregnancy,l24] Mifepris(cid:173)
`tone augments prostaglandin synthesis in in vitro
`
`cultures of endometrial and decidual ceIls.[25] How(cid:173)
`ever, mifepristone promotes uterine contractions
`even during inhibition of prostaglandin synthesis
`by indomethacin.[26] The increased levels of pros(cid:173)
`taglandin due to the administration of mifepristone
`are likely to be mediated via the inhibition of prosta(cid:173)
`glandin degradation.[27] Additionally, antiprogestins
`cause a softening of the uterine cervix. Thus, mife(cid:173)
`pristone has been used successfully to ease the di(cid:173)
`latation of the cervix during surgical termination of
`early pregnancy.[28] Therefore, at the uterine level,
`the anti progesterone effects, which result in the
`termination of early pregnancy, are mediated via
`several tissue compartments.
`
`3.1.2 Combination of Mifepristone
`and Prostaglandin
`The efficacy of the 'mifepristone only' therapy
`was evaluated in the first clinical studies. When
`used alone, the percentage of complete terminations
`of early pregnancy varied between 50 and 85% re(cid:173)
`gardless of the dose of mifepristone.[23.29] Of the
`various parameters studied, only low levels of se(cid:173)
`rum heG significantly predicted clinical effi(cid:173)
`cacy. [23,29] Also the serum concentrations of mifepris(cid:173)
`tone and those of its most proximal metabolites as
`well as the serum levels of AAG were similar in the
`patients with complete pregnancy termination and
`those with continuing pregnancy,l30]
`Mifepristone sensitises the myometrium to the
`contractile effects of prostaglandins.[31] Thus, low
`doses of prostaglandins, which normally fail to in(cid:173)
`duce uterine contractions, are effective following
`pretreatment with mifepristone. Addition of low
`dose prostaglandin to mifepristone treatment in(cid:173)
`creased the rate of complete termination of preg(cid:173)
`nancy from 60% up to 100%.[32]
`Table I summarises some of the latest studies
`evaluating the clinical use of mifepristone and low
`dose prostaglandins for termination of early human
`pregnancy. This combination therapy is also the
`only accepted regimen for the clinical use of
`mifepristone. The focus of the latest clinical re(cid:173)
`search has been directed towards optimising the
`dose of mifepristone as well as the evaluation of
`the orally active prostaglandin, misoprostol, in the
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Jul; 33 (1)
`
`

`

`Clinical Pharmacokinetics of Mifepristone
`
`11
`
`Reference
`
`WHO Task Force
`Multicenter[33J
`Peyron et al. [34J
`
`Duration of pregnancy
`(no. of patients)
`<56 days (1182)
`
`<60 days (890)
`
`96
`
`94
`
`Table I. Recent studies on the combination of mifepristone and low-dose prostaglandin for early pregnancy termination
`Mifepristone and
`Outcomeb Adverse effect
`prostaglandin doses'
`(%)
`Pain requiring medication 26%, vomiting
`200-600mg + 1 mg
`94
`23%, dizziness 19%
`gemeprost vaginally
`Pain requiring medication 13-16%,
`600mg + 4OO119
`vomiting 15-17%, diarrhoea 10-14%
`misoprostol po
`Pain requiring medication 46%, opiate
`200-600mg + 600119
`8%, NSAID 38%
`misoprostol po
`a Mifepristone was administered as a single oral dose in all of these studies. The time difference administration of mifepristone and pro(cid:173)
`stglandin was 48 hours.
`b Outcome: percentage of complete pregnancy terminations.
`Abbreviations: NSAID = nonsteroidal anti-inflammatory drug; po = oral.
`
`McKinley et al.135J
`
`<63 days (220)
`
`combination regimen. Given the long tl/2 and the
`equal serum concentrations of mifepristone fol(cid:173)
`lowing doses exceeding 100mg, a reduction of the
`mifepristone dose from the recommended 600mg
`seems plausible. In fact, several recent studies have
`reported that the mifepristone dose can be effec(cid:173)
`tively reduced from 600 to 200mg with equal
`clinical efficacy. [33,35] In 1996 Webster et aJ.l36] cal(cid:173)
`culated a saving of £28.90 per patient when the
`dose of mifepristone was reduced from 600mg to
`200mg for termination of second trimester preg(cid:173)
`nancy.
`The efficacy of the combination regimen of
`mifepristone and low dose prostaglandin has been
`surprisingly uniform in the various studies pub(cid:173)
`lished. In a summary of more than 16 000 patients,
`Ulmann et al.[37] reported a success rate of 9S.3%.
`In the latest clinical studies, the commonly reported
`complications have been incomplete termination
`of pregnancy, requiring further uterine curettage
`(O.S to 4% of the patients), continuation of the
`pregnancy (0.4 to 1 %), and excessive uterine bleed(cid:173)
`ing necessitating blood transfusion (0.1 to 1 %).
`
`3.1.3 Patterns of Uterine Bleeding
`The mifepristone-induced uterine bleeding
`starts at 2 to 3 days following administration of the
`drug and lasts for approximately 7 to 14 days. The
`bleeding patterns appear similar following inges(cid:173)
`tion of mifepristone alone or in combination with
`prostaglandin. [29,34,35] In a recent study by the
`World Health Organization (WHO),[35] 60 to 7S%
`of the patients estimated the quantity of the uterine
`
`bleeding to be more than their normal menstrua(cid:173)
`tion. Rodger and Baird[38] reported an average
`quantity of 74ml of menstrual bleeding following
`mifepristone treatment; however, the variation was
`large, extending up to SOOml. Following the com(cid:173)
`bination therapy, the fetus and placenta are aborted
`within the first 4 hours in 70% of the patients fol(cid:173)
`lowing administration of the prostaglandin ana(cid:173)
`logue. [33,35]
`
`3.1.4 Adverse Effects of Mifepristone-Induced
`Pregnancy Termination
`The frequency of the reported adverse effects
`has varied somewhat in various studies. The com(cid:173)
`monly encountered adverse effects such as nausea,
`vomiting, tiredness or breast tenderness are also
`seen during early pregnancy and spontaneous
`abortion. In the studies summarised in Table I, the
`maximal lower abdominal pain occurred soon fol(cid:173)
`lowing administration of the prostaglandin. In the
`WHO study,[35] 92% of the patients complained of
`abdominal pain in the 4 hours following adminis(cid:173)
`tration of the vaginal gemeprost suppository. In the
`study by McKinley et aI)35] the use of misoprostol
`was better tolerated in terms of abdominal pain
`when compared with gemeprost. The abdominal
`pain has been effectively treated with mild analge(cid:173)
`sics such as paracetamol (acetaminophen) or occa(cid:173)
`sionally with opiates.
`Blood haemoglobin levels declined mildly but
`significantly in all the studies summarised in table
`I. The lowest levels are seen at I week following
`initiation of the treatment, the reported mean de-
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Jul: 33 (1)
`
`

`

`12
`
`Heikinheimo
`
`Table II. Contraindications to mifepristone/low dose prostaglandin
`pregnancy termination
`
`Duration of pregnancy >64 days (UK), >50 days (France)
`Extrauterine pregnancy
`Hypocortisolaemia/adrenal insufficiency
`Continuous glucocorticoid treatment
`Coagulopathies
`Anticoagulant treatment
`Allergy to mifepristone/prostaglandin
`Age over 35 years, and smoker
`
`cline in haemoglobin was 2 to 3 g/L,[35] However,
`profuse uterine bleeding requiring uterine curet(cid:173)
`tage and blood transfusion has been reported in 0.2
`to 1 % of the patients.l34]
`
`3.1.5 Practice of Mifepristone-Induced
`Pregnancy Termination
`The following guidelines are in use in France
`and the UK where mifepristone is in clinical use
`for termination of early pregnancy. Contraindica(cid:173)
`tions to the use of mifepristone and low dose pros(cid:173)
`taglandin induced pregnancy termination are listed
`in table II. In addition to the contraindications due
`to duration or location of pregnancy, altered gluco(cid:173)
`corticoid or haemostatic status and allergy; smok(cid:173)
`ing and age over 35 years are included. This is be(cid:173)
`cause few cardiovascular complications (1 myocardial
`infarction and 3 cases of hypotension, all 4 with
`complete recovery) have been seen in the early
`clinical trials using a combination of mifepristone
`and sulprostone-prostaglandin. [37]
`When the patient chooses medical abortion she
`must also sign an informed consent. The mifepris(cid:173)
`tone tablets are ingested in the presence of person(cid:173)
`nel.[37] Patients return to the clinic for the prosta(cid:173)
`glandin treatment at 36 to 48 hours following
`ingestion of the mifepristone tablets. Approxi(cid:173)
`mately 4% of the patients abort before administra(cid:173)
`tion of p(ostaglandin,[34] in which case no further
`medication is needed. The patients are followed for
`a minimum of 4 hours following prostaglandin ad(cid:173)
`ministration. Anti-D immunoglobulin is adminis(cid:173)
`tered to the Rh-negative patients. The efficacy of
`the treatment is assessed at a follow-up at approx(cid:173)
`imately I week following the initial visit. In case
`
`of continuing pregnancy or residual tissue in the
`uterine cavity, a surgical evacuation of the uterus
`is performed.
`
`3. 1.6 Acceptance of Mifepristone-Induced
`Termination of Early Pregnancy
`The combination therapy of mifepristone plus
`low dose prostaglandin has been in clinical use in
`Sweden for pregnancy termination since 1992.
`Currently, approximately 30% of the early preg(cid:173)
`nancy terminations are carried out using mifeprist(cid:173)
`one in Sweden (Bygdeman M, personal communi(cid:173)
`cation). When asked for the reasons for choosing
`mifepristone, British patients indicated fear of an(cid:173)
`aesthesia and surgery (59 to 81 %), the slower time(cid:173)
`table of the mifepristone-induced abortion (7 to
`21 %) and the less invasive nature of the mifepris(cid:173)
`tone treatment (7 to 21 % ).[39,40] Of the patients
`treated with mifepristone, 74 to 95% were satisfied,
`and if necessary, would also choose mifepristone
`in the future.l39,40]
`
`3.2 Termination of Second or Third
`Trimester Pregnancy
`
`Mifepristone has also been used alone or in
`combination with prostaglandin for termination of
`second or third trimester pregnancy.[41 ,42] Pretreat(cid:173)
`ment with mifepristone 600mg at 36 hours prior to
`prostaglandin administration in second trimester
`pregnancy termination shortened the time interval
`between the initiation of prostaglandin treatment
`and the expUlsion of the fetus from 16 hours in the
`control group to 7 hours in the mifepristone pre(cid:173)
`treated group. [42] In addition, the total dose of pros(cid:173)
`taglandin and the number of adverse effects were
`lower in the group pretreated with mifepristone.l42]
`As in the termination of first trimester pregnancy,
`the combination of mifepristone followed by orally
`active prostaglandin misoprostol has proven to be
`highly effective in the termination of second tri(cid:173)
`mester pregnancy.[36,43]
`
`3.3 Labour Induction
`
`Progesterone antagonism at term induces, or
`facilitates induction of labour in pregnancies with
`minor complications[44] or following intrauterine
`
`© Adis International Limited. All rights reserved .
`
`Clin . Pharmacokinet. 1997 Jul; 33 (I)
`
`

`

`Clinical Pharmacokinetics of Mifepristone
`
`13
`
`fetal death.l45] In the study by Cabrol et al.,[45]
`mifepristone induced labour in 63% of the patients
`within 3 days of the mifepristone treatment, whereas
`only 17% of the control patients had a spontaneous
`induction. Frydman et al.[44] studied the use of
`mifepristone for labour induction in patients with
`complications necessitating induction at term. Ad(cid:173)
`ministration of mifepristone at 2 to 3 days prior to
`planned induction resulted in spontaneous delivery
`in 54% of the patients, whereas only 18% of the
`control patients had a spontaneous labour.
`In addition, the patients pretreated with mifepris(cid:173)
`tone, but requiring induction, needed less oxytocin
`than the placebo-treated group.[44] Even though
`mifepristone crosses the placenta and thus reaches
`the fetal circulation[46] the infants in the mifepristone
`group displayed no differences in birthweight,
`acid-base balance, Apgar scores, postpartum blood
`glucose levels or blood pressure when compared
`with the placebo-treated group.[44]
`
`3.4 Contraceptive Strategies
`
`Antagonism of progesterone action at different
`phases of the menstrual cycle offers several theo(cid:173)
`retical strategies for novel forms of hormonal con(cid:173)
`traception. The effects of mifepristone on the endo(cid:173)
`crinology ofthe menstrual cycle vary greatly based
`on the phase of the cycle studied. Administration
`of mifepristone from the beginning of the men(cid:173)
`strual cycle delays follicular development and in(cid:173)
`hibits ovulation in human.[47] The endocrine pat(cid:173)
`terns seen during mifepristone administration are
`characterised by estradiol secretion comparable
`with mid-follicular phase levels and absence of
`mid-cycle like LH-peaks. Interestingly, the serum
`levels of estradiol (E2) appeared similar following
`continuous daily treatment with mifepristone 2 or
`IOOmg,l48.49] suggesting that within this range of
`mifepristone doses, the inhibitory effects of mife(cid:173)
`pristone on the hypothalamo-pituitary-ovarian
`(HPO)-axis are not dose dependent.
`Croxatto et aU 50] showed that following treat(cid:173)
`ment with 5 mg/day, and a serum concentration of
`mifepristone -500 nmollL, ovulation was sup(cid:173)
`pressed in all volunteers. However, daily adminis-
`
`tration of Img, with the serum concentrations of
`-65 nmol/L, was insufficient for ovulation inhibi(cid:173)
`tion in women.l50]
`Several studies have suggested that the endome(cid:173)
`trium might be the most sensitive target organ to
`the biological effects of mifepristone.l50,5 1] A delay
`in endometrial development is evident even at low
`doses of I mg/day,[51] or weekly administration of
`2 or 5mg.[52] Thus, contraceptive strategies based
`on ovulation inhibition and/or disturbance of endo(cid:173)
`metrial maturation with mifepristone, or other anti(cid:173)
`progestins, are currently under intensive study.
`Couzinet et aU53j stduied the monthly use of
`mifepristone for induction of menstruation at the
`end of the cycle. Despite mifepristone treatment, 7
`pregnancies were seen during the 137 study cycles.
`Thus even though theoretically attractive, the use
`of mifepristone as a 'once-a-month' pill was disap(cid:173)
`pointing. Similiarly, mifepristone treatment alone
`did not resolve extrauterine pregnancy, however in
`a study by Paris et aU54] mifepristone did facilitate
`the subsequent laparoscopic procedure.
`
`3.4. 1 Immediate Post-Coital Contraception
`The immediate post-coital use of mifepristone
`has been evaluated in 2 large clinical studies com(cid:173)
`paring the efficacy of mifepristone 600mg within
`72 hours of unprotected intercourse to that of
`standard Yuzpe regimen (2 doses of ethinyl estra(cid:173)
`diol O.lmg and levonorgestrel 0.5mg 12 hours
`apart).[55,56] No pregnancies were reported among
`the 597 patients treated with mifepristone, whereas
`the Yuzpe regimen resulted in 9 pregnancies in to(cid:173)
`tal of 589 patients. Primate embryos are tolerant to
`mifepristone, thus, the mechanism of action most
`likely involves anti progestin-induced interruption
`of endometrial maturation.
`In addition, mifepristone treatment was better
`tolerated - 70% of the patients treated with the
`Yuzpe regimen reported nausea whereas the corre(cid:173)
`sponding figure for mifepristone was 37%. A typ(cid:173)
`ical adverse effect seen in the mifepristone groups
`was prolongation of the subsequent cycle, which is
`most likely mediated via inhibition of subsequent
`follicular maturation. Emergency post-coital con(cid:173)
`traception using mifepristone is, therefore, one of
`
`© Adis International limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Jul; 33 (1)
`
`

`

`14
`
`Heikinheimo
`
`the most promising new clinical indications for
`antiprogestins.
`
`1000
`
`3.5 Possible Uses in Endometriosis
`and Leiomyoma
`
`The growth of endometriosis and leiomyomas,
`which contain estrogen and progesterone recep(cid:173)
`tors, is regulated by sex steroids. Daily treatment
`with either mifepristone 25 or 50mg diminished the
`volume of the uterine leiomyomas by 50% during
`a l2-week study period. IS7] In addition, the prelim(cid:173)
`inary results on the use of mifepristone for treat(cid:173)
`ment of endometriosis are encouraging: the Amer(cid:173)
`ican Fertility Society score of the endometriotic
`implants decreased by 50% and the pelvic pain
`improved significantly.[S8] Since the serum estra(cid:173)
`diol levels are maintained at mid-follicular level,
`mifepristone treatment is not associated with an
`increased risk of osteoporosis. [58]
`
`3.6 Treatment of
`Hormone-Dependent Tumours
`
`Mifepristone inhibits the growth of progesterone
`receptor positive breast cancer cells both in vitro
`and in laboratory animals.[S9] Also, the combina(cid:173)
`tion of antiestrogen and mifepristone has been
`shown to be as effective as that of GnRH-analogue
`in the treatment of experimental animal models of
`breast cancer.[59] The use of mifepristone in the
`treatment of hormone resistant breast tumours ini(cid:173)
`tially resulted in partial response or stabilisation of
`the tumour in 50% of the patients.[S9] However, in
`a recent study by Perrault et al.,[60] only a 10.7%
`response rate was reported in a group of patients
`treated for a recurrence of a progesterone receptor
`positive breast cancer.
`Meningioma is a brain tumour rich in progester(cid:173)
`one receptors. The efficacy of mifepristone was
`evaluated in a group of patients with unresectable
`meningiomas.[61] Of the 14 patients treated, tumour
`regression was documented in 5 cases and stabil(cid:173)
`isation in another 5 patients.[6IJ Thus, possible
`treatment of hormone dependent malignancies is
`one of the main streams of current anti progesterone
`research.
`
`:g 10
`o
`1ii
`·c
`Co
`~ o
`~
`
`0 .1 --'---,---,------.------,-----,-
`
`Fig. 1. Dose-response relationships of mifepristone. A simplified
`summary of the effects of various doses of mifepristone on dif(cid:173)
`ferent organs and regulatory circuits is presented. Abbreviations:
`Endomet = delay in endometrial development; HPO-axis = dis(cid:173)
`ruption of hypothalamo-pituitary-ovarian-axis; leiomyoma = in(cid:173)
`hibition of myoma growth; uterus = termination of pregnancy;
`HPA-axis = activation of hypothalamo-pituitary-adrenal-axis.
`
`3.7 Antiglucocorticoid Action
`
`In contrast to its anti progesterone effects,
`mifepristone activates the hypothalamo-pituitary(cid:173)
`adrenal (HPA)-axis in a dose-dependent manner, as
`shown by rises in the serum concentrations of pro(cid:173)
`opiomelanocortin derived peptides, such as ACTH
`or ~-endorphin, as well as cortisoJ.l62.63J The acti(cid:173)
`vation of the HPA-axis is evident following single
`doses of 200 to 400mg and above. Similarly, the
`pituitary-adrenal axis is activated during long term
`daily administration of mifepristone 200mg.l64] In
`clinical practice, the antiglucocorticoid properties
`of mifepristone have been utilised in the symptom(cid:173)
`atic treatment of hypercortisolaemia of Cushing's
`syndrome. [65.66]
`
`4. Conclusions
`
`Different target organs have different sensitivi(cid:173)
`ties to the biological actions of mifepristone. High
`single doses of 400mg or more of mifepristone
`are needed for the antiglucocorticoid properties,
`mediated via the central nervous system. The main
`indication for the clinical use of mifepristone, ter(cid:173)
`mination of early pregnancy, results from the anti(cid:173)
`progesterone effects of mifepristone on several
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Jul; 33 (1)
`
`

`

`Clinical Pharmacokinetics of M