Roy M. Pitlcin, MD, Editor
`
`
`
`
`Professor, Department of Obstetrics and Gynecology,
`
`
`
`UCLA School of Medicine, Los Angeles, California
`
`James R. Scott, MD, Editor
`
`
`
`
`Professor, Department of Obstetrics and Gynecology,
`
`
`
`University of Utah School of Medicine, Salt Lake City, Utah
`
`HIV Infection in Women
`MICHAEL K. LINDSAY, MD, MPH
`
`Guest Editor
`
`N ew Applications of
`
`
`Mifepristone (RU 486)
`STEVE LONDON, MD
`
`Guest Editor
`
`.J-1.a, I i--1 n ho,1 �;)
`Exhibit No. �
`Date:�--ó{ . ¡qT. Alfaro
`
`Corcept Therapeutics, Inc.
`Exhibit 2011
`Neptune Generics, LLC v. Corcept Therapeutics, Inc.
`Case IPR2018-01494
`
`Ex. 2011-0001
`
`

`

`
`
`June 1996
`
`/ Volume 39 / Number2
`
`Ex. 2011-0002
`
`

`

`CLINICAL OBSTETRICS AND GYNECOLOGY (ISSN 0009-9201)
`A Quarterly Publication
`Copyright © 1996 by Lippincott—Raven Publishers. At! rights reserved No part of this book may be used or
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`@ Tex-l. printed on acid-[roe paper.
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`EX. 2011—0003
`
`Ex. 2011-0003
`
`

`

`Contents
`
`J1me I996
`
`Contributors
`
`vii
`
`Forthcoming Symposia
`
`xi
`
`HIV INFECTION IN WOMEN FOREWORD
`
`275
`
`MICHAEL K. LINDSAY, MD, MPH, Guest Editor
`
`Immunopathogenesis and Detection ofHIV Infection in
`Women and Newborns
`277
`
`DAWN K. SMITH, MD, MS, MPH and MARTHA F. ROGERS, MD
`
`Epidemiology ofHIV Infection in Women and
`Newborns
`292
`
`MARTA GWINN, MD, MPH
`and PASCALE M. WORTLEY, MD, MPH
`
`Routine Voluntary Antepartmn HIV Antibody Counseling
`and Testing: A Sound Public Health Prevention
`Strategy
`305
`MICHAEL K. LINDSAY MD. MPH
`
`Substance Abuse and HIV in Pregnancy
`MARGARET E. SPRAUVE, MD, MPH
`
`316
`
`Reproductive Decision-Makin and Determinants of
`Contraceptive Use in HIV-Infected Women
`333
`
`HARRIET A. WILLIAMS, RNC, BSN,
`CATHY E. WATKINS, RNC, BSN,
`
`and JOANNE A. RISBY RN, MN
`
`Management ofH1V Infection for the Childbearing Age
`Woman
`344
`
`ARLENE D. BARDEGUEZ, MD, FACOG
`
`The Role ofAntiretroviral Therapy in the Management of
`HIV Infection in Women
`361
`LYNNE M. MOFENSON, MD
`
`386
`Determinants ofPerinatal HIV-I Transmission
`SHERRY L. ORLOFF, RJ. SIMONDS, RICHARD W. STEKETEE,
`and MICHAEL E. ST. LOUIS
`
`V
`
`EX.2011—0004
`
`Ex. 2011-0004
`
`

`

`CLINICAL OBSTETRICS AND GYNECOLOGY
`Volume 39, Number 2. pp 436—450
`© 1996, Lippineort—Raven Publishers
`
`Mifepristone: Clinical
`Pharmacology
`
`
`
`ANN ROBBINS, PhD and IRVING M. SPITZ, MD
`
`The Population Council Center for Biomedical Research
`New York, New York
`
`Many processes in female reproductive
`physiology depend on progesterone. This
`hormone facilitates the action of estradiol
`
`in inducing the luteinizing hormone (LH)
`surge in the follicular phase of the menstrual
`cycle and supports corpus luteum function
`in the luteal phase. It is also essential for
`the initiation and maintenance of preg-
`nancy. A compound that could block the
`action of progesterone would thus play an
`important role in the prevention and dis-
`ruption of pregnancy. With the identifica-
`tion of the progesterone receptor (PR) came
`the realization that a PR antagonist was a
`potential candidate for such a compound.
`The first highly effective progesterone
`receptor antagouist was synthesized in 1981
`by researchers at Roussel-Uclaf (Romain-
`ville, France). Designated RU 38486, and
`subsequently abbreviated to RU 486, this
`progesterone antagonist is identified by the
`generic name mifepristone. In addition to
`its potent antiprogestin effects, mifepristone
`also acts as an antiglucocorticoid through
`its binding to the glucocorticoid receptor.
`Biologic tests in animals showed that the
`
`Correspondence: Arm Robbins, PhD. The Population
`Council Center for Biomedical Research. 1230 York
`Avenue. New York, New York lOOZl.
`
`compound is a potent antagonist for pro-
`gestins and glucocorticoids.‘
`Several clinical applications that take
`advantage of the antiprogestin properties
`of mifepristone are being pursued.2 Most
`well-known are its abortifacient uses. When
`
`used alone in early pregnancy, mifepristone
`causes abortion in 60480% of women. Its
`
`efficacy is enhanced to approximately 95%
`by the addition of a prostaglandin 48 hours
`later. Because of its ability to dilate and
`soften the cervix, mifepristone is used in
`the preoperative preparation for
`first
`trimester surgical abortions as well as pre-
`treatment for prostaglandin—induced first
`and second trimester abortion. In these ap-
`plications, it has been shown to decrease
`pain and side effects, and when used with
`prostaglandins the interval to expulsion. It
`is effective for labor induction in late stages
`of pregnancy in cases of intrauterine fetal
`death, and its use to induce labor at term
`is under clinical study.
`Another potential use of mifepristone,
`based on its antiprogestin properties,
`is
`as a contraceptive agent. Several differ—
`ent contraceptive methods are undergoing
`clinical
`study.3 Mifepristone has been
`shown to be highly effective as a post-coital
`emergency contraception method.‘ Mife-
`
`
`
`CLINICAL OBSTETRICS AND GYNECOLOGY
`
`VOLUME 39
`
`l NUMBERZ l
`
`JUNE l996
`
`436
`
`
`Hr. mnnial l-Ilr bro-mane Ih- row-gm bun-nu tm I. r.~I-|
`
`
`EX. 2011—0005
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`Ex. 2011-0005
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`

`

`Mifepristone: Clinical Pharmacology
`
`437
`
`
`
`CH
`
`leepristone
`Progesterone
`
`
`Norathlndrone
`
`FIG. 1. Chemical structure of progesterone, mifepristone (I 1-[4-
`(dimethylamino)phenyl]-17-hydroxy-l7-[l-propynyl]-{ [1.8, l7fil]-estra-4,9-
`dien-3-one) and norethindrone (17-hydroxy-[l Tad-1 9-norpregn-4-en-20-
`yn-3~one).
`
`pristone also may have a contraceptive ef-
`fect due to its ability to impair endometrial
`maturation at low doses, which do not alter
`
`hormonal events of the menstrual cycle or
`bleeding patterns. Continuous or intermit-
`tent administration as a potential contra-
`ceptive to block ovulation also is under
`ev.’:11n£tti4£)n.3
`
`Mifepristone is being tested for several
`other antiprogestin applications} including
`treatment of endometriosis and uterine
`
`myornata, as well as PR-positive tumors
`such as those in the breast or brain (menin-
`
`gioma).
`Treatment of a variety of other clinical
`conditions is under evaluation based on the
`
`antiglucocorticoid properties of mifepri-
`stone.5 These include Cushing‘s disease due
`to ect0pic adrenocorticotrophic hormone
`(ACTH) secretion and adrenal carcinoma,
`reduction of intraocular pressure in glau-
`coma, and steroid-induced myopathy.
`This article will review the structure,
`metabolism, and pharmacology of mifepri-
`stone, as well as the major biologic efl‘ects
`that occur due to its antiprogestin and an-
`tiglucocorticoid activities. Although other
`antiprogestins subsequently have been dis-
`covered and are under evaluation, such as
`the Sehering (Kenilworth, NJ) AG com-
`pounds ZK 98734 (lilopristone) and ZK
`98299 (onapristone), or Organon (West 0r-
`ange, NJ) compounds ORG 31710 and
`
`ORG 33628, at the present time only mi-
`fepristone has been extensively studied in
`humans and, as a consequence. is the major
`focus of this review.
`
`Structure
`
`Mifepristone is similar in structure to pro-
`gesterone and glucocorticoids, but lacks the
`C19 methyl group and the 2-carbon side
`chain at C1? of these hormones and has a
`
`conjugated C9-C10 double bond (Figure 1).
`Mifepristone is a derivative of norethin-
`drone, differing from it by a 4-(dimethyl-
`amino) phenyl group at the 113 position
`and a l-propynyl chain at the 17.2: position.
`The 170: substitution probably accounts for
`the higher binding affinity of mifepristone
`for the PR compared to norethindrone. The
`substitution at the 1 118 position is likely to
`be responsible for mifepristone’s antago-
`nistic action, by inducing or stabilizing a
`biologically inert receptor conformation.
`The chemical structures of other synthetic
`antiprogestins are similar to that of mife-
`pristone. Lilopristone has a 015(2) configu—
`ration at the 17a position. Onapristone has
`a similar structure but different molecular
`
`shape, due to inversions at the C13 and C17
`positions. Some antiprogestin compounds,
`such as ORG 31710, are l7-spir0furan an-
`alogs of mifepristone and have a very high
`
`EX. 2011—0006
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`Ex. 2011-0006
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`

`

`438
`
`ROBBINS AND SPITZ
`
`binding affinity to the PR compared to mi-
`t‘epristone.6
`
`Receptor Binding
`The antiprogestin action of mifepristone is
`mediated by the PR, a ligand-activated
`transcription factor with domains for DNA
`binding, hormone binding, and transacti-
`vation. Members of this nuclear receptm-
`superfamily include androgen, estrogen,
`and mineralocorticoid receptors, as well as
`receptors for thyroid hormones, retinoids,
`and vitamin D. As mentioned previously,
`mifepristone binds to the progesterone and
`glucocorticoid receptors. The affinity of
`mifepri stone for both receptors was not un-
`expected because numerous biologic studies
`have shown that progestins have weak glu-
`cocorticoid activity and vice versa. More-
`over, the predicted amino acid sequence of
`the glucocorticoid and mineralocorticoid
`receptor steroid binding domains shows a
`greater similarity to that of the PR than to
`any of the other receptors in this family.
`Although other antiprogestins, such as ORG
`33628, ORG 317l0, onapristone, and lil-
`opristone, reportedly have less activity as
`antiglucocorticoids, none are pure antipro—
`gestins.
`In terms of relative binding affinity to
`these and other receptors, mifepristone has
`binding activity five times greater than pro-
`gesterone to the rabbit uterine progestin re-
`ceptor and three times greater than dexa-
`methasone to the rat thymus glucocorticoid
`receptor. Binding affinity for the rat prostate
`androgen receptor was 25% of that of tes-
`tosterone, and there was no binding to the
`mouse uterine estrogen or rat kidney min-
`eralocorticoid receptors.
`A iarge hydrophobic pocket in the PR of
`most species accommodates substitutions
`at position 116 like that of mifepristonefi
`The amino acid glycine at position 722
`(Glym), which is in the hormone binding
`domain of the human PR and at the com-
`
`parable position of the PR of most other
`species, appears to be critical for mifepri-
`
`stone binding and action (Figure 2). This
`has been demonstrated by experiments in
`the hamster and the chicken, which are in~
`
`sensitive to mifepristone and have a PR
`with a cysteine rather than a glycine residue
`at this position. The PR of these species
`binds progesterone but not mifepristone.
`After substitution of this cysteine with gly-
`cine in the chicken PR, binding of mifepri-
`stone and antagOnistic action of this com-
`pound are observed. Likewise, substitution
`of Gly722 with cysteine in the human PR
`generates a receptor that no longer binds
`mifepristone. It is possible that this type of
`
`
`
`FIG. 2. Schematic diagram of the primary
`structure of the human progesterone receptor
`(hPR) showing: (I) transactivation domain; (2)
`DNA binding domain; and (3) hormone
`binding domain. The amino acid glycine
`(Glym) in the hormone binding domain is
`critical for mifepristone, but not progesterone,
`binding. For comparison, amino acids
`corresponding to Gly"22 in the rabbit PR
`(erR), chicken PR (cPR), hamster PR
`
`(haPR), human glucocorticoid receptor (hGR),
`human androgen receptor (hAR), and human
`mineralocorticoid receptor (hMR) are also
`shown. Receptors with glycine at this positiOn
`bind and respond to mifepristone; those with
`other amino acids do not. G = glycine; C =
`cysteine; A : alanine. From Spitz and Bardin,5
`with permission of Buttenvorth-Heinemann.
`
`EX. 2011—0007
`
`Ex. 2011-0007
`
`

`

`spontaneous mutation in the PR of humans
`may account for the unresponsiveness to
`mifepristone observed in some women.’
`The human glucocorticoid receptor also has
`a glycine in this corresDonding position. A
`cysteine substitution at this position in the
`glucocorticoid receptor results in a loss of
`binding not only to mifepristone but also
`to dexamethasone. Taken together, these
`results suggest that Glym in the human
`PR is at a critical position in the 116—
`pocket of the receptor for mifepristone’s
`biologic action. Because glycine is the only
`amino acid without a side chain, the pres-
`ence of amino acid side chains in this po-
`sition may sterically impede mifepristone
`binding to PR.T
`
`Mechanism ofAction
`Progesterone and mifepristone produce a
`conformational change in the the form of
`the PR that permits it to bind to DNA.8
`The activation ofthe PR by progesterone
`or mifepristone is accompanied by a loss
`of associated heat-shock proteins and di-
`merization. The activated receptor dimer
`
`binds to progesterone response elements
`in the promoter region of progesterone-
`responsive genes. in the case of proges-
`terone, this binding will increase the tran-
`5cription rate of these genes, producing
`progestin effects.
`in contrast, a receptor
`dimer complex that has been activated by
`mifepristonc also binds to progesterone
`response elements, but an inhibitory
`function in the C-terminal region of the
`hormone binding domain renders these
`DNA-bound receptors transcriptionally
`inactive. This is the basis for the proges-
`terone antagonistic action of mifepri-
`stone, underlying its abortifacient and
`comraceptive actions.
`It has been suggested that not all anti-
`progestins act in the same manner as mi-
`fepristone. For example. there is evidence
`that Baa-configured progesterone antago-
`nists, such as onapristOne, do not permit
`the antiprogestin—rcceptor complex to bind
`
`Mifepristone: Clinical Pharmacology
`
`439
`
`to progesterone response elements, indicat-
`ing the existence of different classes of pro—
`gesterone antagonists (Figure 3). Other ev-
`idence argues against the existence of two
`types of antagonists, by demonstrating that
`the PR-onapristone complex does bind to
`progesterone response elements but at ten
`times lower affinity than does the mifepri-
`stone-PR complex.3
`Under certain circumstances, such as
`
`situations characterized by the absence of
`progesterone, mifepristone may display
`progesterone agonistic activity. One possi-
`ble mechanism for the agonist and antag-
`onist activities of mifepristone may be re-
`lated to the existence of two separate iso-
`forms of the PR, 3 PR-A isoform and a
`PR-B isoform.” Some in vitro transfection
`
`experiments indicate that PR-B behaves as
`a partial agonist in the presence of mife-
`pristone. However, when A and B isoforms
`are present together, the antagonistic effects
`of PR-A can override the agonistic effects
`of PR-B. Therefore, mifepristone may ex-
`hibit antagonistic or agonistic actions. de-
`pending on the relative expression of the
`PR-A and PR-B isoforms in target tissues.9
`This may have important clinical conse-
`quences (i.e., the ratio of the two isoforms
`
`changes in the endometrium during the fol-
`licular and the luteal phase of the menstrual
`cycle).3
`In some circumstances, antiprogestins
`also may act as antiestrogens. These effects
`were unexpected because mifepristone
`does not bind to the estrogen receptor.
`This phenomenon has been termed “non-
`competitive."10 The antiestrogen effects
`may reflect agonistic properties of anti-
`progestins, because long-term progester-
`one treatment is also associated with an-
`
`tiestrogenic effects. An alternative expla-
`nation is that difierential contributions of
`
`the two isoforms of the PR may account
`for some of these effects.9 The antiestro-
`
`genic effects of mifepristone are of inter-
`est. because this would form the basis of
`
`its clinical use in estrogen—dependent
`
`EX. 2011—0008
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`
`

`

`440
`
`ROBBINS AND SPITZ
`
`transactlvatlon
`
`FIG. 3. Proposed
`mechanisms of action of
`
`Antagonist (O >m s
`
`progesterone (P), and the
`anti-progestins
`mifepristone (MIF) and
`onapristone (ONA). In the
`absence of ligand, the
`progesterone receptor
`(PR) is associated with
`heat-shock proteins
`(HSP). AssociatiOn of PR
`with either P, MlF, or
`ONA induces different
`conformational changes in
`PR, resulting in
`dissociation of HSP and dimerization of PR. In the ease of? and MIF, the PR complex binds to
`specific progesterone response elements in the promoter regiOns of progesterone-responsive genes.
`When bound, the P-PR complex is transcriptionally active resulting in agonistic effects (upper
`panel). Despite binding to the promoter region of progesterone-responsive genes, the MIF—PR
`complex is not transcriptionally active. resulting in antagonistic effects (middle panel). In contrast.
`it has been suggested that the ONA-PR complex does not bind to progesterone response elements
`(lower panel).
`
`PM) 0
`
`GED
`
`i
`
`conditions, such as uterine fibroids and
`some forms of breast cancer.
`
`Pharmacokinetics and
`
`Metabolism
`
`Mifepristone is administered orally and
`readily absorbed in all species, although
`metabolism in the splanchnic circulation
`reduces its bioavailability to 40% in man
`and rats and 15% in monkeys.” Because of
`a depot effect, it is released more slowly into
`the circulation after intramuscular admin-
`
`istration to monkeys. Vaginal administra-
`tion in humans is not an effective means of
`
`delivering the doses usually necessary for
`pregnancy termination. However, because
`of the striking sensitivity of the endome-
`trium to low doses of mifepristone, va-
`ginal administration may deliver adequate
`amounts of mifepristone making the route
`suitable for contraceptive purposes.
`The metabolic clearance rates were 72,
`36. and 0.55 lfkglday in rats, monkeys, and
`humans, respectively.“ The clearance rate
`
`for an average woman would therefore be
`30 lfday, which is considerably slower than
`cortisol (200 Uday) and estrone sulfate (160
`llday), two natural steroids that are consid-
`ered to be cleared at slow rates. The differ-
`ences in the clearance rates between man
`
`and animals result in part from an or] acid
`glycoprotein, orosomucoid, in serum that
`binds mifepristone in humans (kD lpM)
`but not in other species. Mifepristone does
`not bind to cortisol binding globulin or sex-
`steroid binding globulin?
`Serum mifepristone levels reached a
`maximum in 1 hour after oral administra-
`
`tion of single doses ranging from 50—800
`mg in women. There were two distinct
`pharmacokinetic patterns observed de-
`pending on the oral dose administered. Af-
`ter single doses of 100 mg or less, the dis—
`appearance of mifepristone follows first or-
`der kinetics with a half—life of 20—25 hours.
`
`After higher doses (200—800 mg), there is
`an initial redistribution phase of 6—10 hours
`followed by a plateau in serum levels for 24
`hours or more. With these larger doses,
`
`EX. 2011—0009
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`
`

`

`there is no significant dose-dependent dif—
`ference in serum concentrations within the
`first 48 hours (Figure 4).5 During this pe-
`riod, serum mifepristone levels are in the
`micromolar range (i.e., 2.5 ,urnolz’l). One of
`the pOSSible explanations for this unusual
`pattern of metabolism is that orosomucoid
`binding sites are saturated at doses of mi-
`fepristone of more than 100 mg. Detectable
`levels of unmetabolized mifepristone have
`been found in the circulation for up to 10
`days after oral administration.
`Different pharmacokinetic profiles are
`observed with other anti progestins. For ex—
`ample, after oral administration in humans,
`the half-life of onapristone is only 2 to 3
`hours.'2 The compound ORG 31710 may
`have an even [Onger half-life than mifepri-
`stone, as predicted from its binding affinity
`to orosomucoid. Like mifepristone, none of
`these antiprogestins bind to sex hormone
`binding globulin.
`The major excretory pathway for RU 486
`is fecal, with less than 10% being recovered
`in the urine." Animal studies have shown
`
`that the first steps of mifepristone metab-
`olism involve a two—step demethylation of
`the (dimethylamino)phenyl ring at the Cl 1
`position and hydroxylation of the 17-pro-
`pynyl chain. The demethylated metabolites
`are further hydroxyiated or acetylated. In
`the human, micromolar concentrations of
`
`monodemethylated. didemethylated, and
`the non-demethylated hydroxylated (alco—
`holic) metabolite were observed within 1
`hour after oral administration of mifepri-
`stone (Figure 5)- In contrast to the parent
`compound, circulating concentrations of
`metabolites increase in a dose—dependent
`fashion, and with higher doses, the metab-
`olite concentrations (especially the mono-
`demethylated derivative) are in excess of
`the parent compound.
`A comparison of the binding affinities
`and the antiprogestin and antiglucocorti-
`coid activities of mifepristone and its me-
`tabolites is presented in Table l. The bio-
`logic effects of each of these metabolites
`have not been evaluated directly in humans;
`
`Mifepristone: Clinical Pharmacology
`
`44]
`
`(uglml)
`SaturnHlloprlstonaConcentration
`
`
`
`1
`
`2
`
`4
`
`6
`Hours
`
`1O
`
`24
`
`48
`
`FIG. 4. Half disappearance time of
`mifepristone after administration of 50—800
`mg in the mid-luteal phase. Results show mean
`1 SEM in 4-5 subjects.
`
`however, they bind to the human proges-
`terone and glucocorticoid receptors. In the
`rat, the monodemethylated and hydroxyl-
`ated derivatives are effective for pregnancy
`termination, although at one—third the po-
`tency of mifepristone. Similarly, the anti-
`glucocorticoid activity of these compounds
`is also one-third that of mifepristone. The
`didemethylated compound, however, is less
`potent than the other metabolites in the
`rat." Although the aflinity and efi‘ectiveness
`is less than that of mifepristone, these me-
`tabolites may contribute to the overall ef-
`fects of the drug in view of their high con-
`centrations in serum.
`
`The tissue distribution of mifepristone
`in humans is not well studied. although it
`is distributed into all tissues of the rat.“ In
`
`women, mifepristone and its demethylated
`metabolites were detected in the myome-
`trium and abdominal adipose tissue col-
`lected during hysterectomy 12—1 5 hours af-
`ter oral administration of 200 mg ofthe an-
`tiprogestin. Lower than expected levels of
`mifepristone in fat are believed to be due
`to its avid binding to serum protein. Mi-
`fepristone and its monodemethylated me-
`
`EX. 2011—0010
`
`Ex. 2011-0010
`
`

`

`442
`
`ROBBINS AND SPITZ
`
`
`
`
`
`FIG. 5. The mean (:SEM)
`concentration of
`
`mifepristone and three of its
`metabolites after oral
`
`administration of 100 mg
`and 600 mg in five subjects.
`The upper panels depicts
`levels of mifepristone (left)
`and the monodemethylated
`(RU 42633) metabolite
`(right). Circulating levels of
`the didemethylated (RU
`42848) and alcoholic
`nondemethylated (RU
`42698) derivatives are shown
`in the left and right lower
`panels. respectively. The
`concentrations of
`
`mifepristone were similar
`after these doses, but the concentrations of metabolites were higher after the 600 mg dose of
`mifepristone. Concentrations of the monodemethylated metabolites are higher than those of the
`parent compound at all time points.
`
`tabolite cross the placental barrier during
`the second trimester, although at least in
`monkeys, it has been suggested that the ef-
`ficacy of placental transfer may decrease
`with advancing pregnancy.5
`
`major effects of mifepristone on the brain,
`pituitary, and reproductive organs are de-
`soribed.
`
`BRAIN AND PITUITARY
`
`Clinical Pharmacology
`Because of the widespread locations of PR
`and glucocorticoid receptor, antiprogestins
`act at many sites throughout the body. The
`
`Ganadot‘ropins
`Several types of evidence indicate that mi—
`fepristone acts at the level of the hypothal-
`amus andfor pituitary to inhibit ovulation.3
`In in vitro studies using a rat pituitary cell
`
`TABLE 1. Comparative Activities ofMierpristone and Metabolites
`
`Metabolites
`
`Activity
`
`Mifepristone
`
`Alcoholic
`
`Monodemethyl
`
`Didemethyl
`
`Binding to PR
`Binding to GR
`Antiprogestin Activity‘
`Antiglucocorticoid Activity“
`
`530
`300
`3
`4
`
`4?
`1 27
`l 0
`8
`
`39?
`294
`to
`l 2
`
`40
`l l 8
`NA
`30
`
`PR = progesterone receptor; GR = glucocorticoid receptor. NA = not active.
`’ rnglKg" oral dose.
`Comparison of binding affinities and biological activities of mifepristone and the metabolites at 24 hours‘ Antiprogestin activity
`measured by ED 100 dose needed for abortion. Antiglucocorticoid activity measured by ED 50 dose needed to inhibit thymolytic
`eli’ect of dexamethasone. Modified from Deraedt et a1.“
`
`EX. 2011—0011
`
`Ex. 2011-0011
`
`

`

`culture system primed with estradiol, mi-
`fepristone inhibited Gan—l—induced secre-
`tion of LH and follicle stimulating hormone
`in a dose-dependent manner. Pregesterone
`administration stimulated GnRH-induced
`gonadotropin secretion and blocked rnife-
`pristone’s inhibition of GnRH. Because no
`effect of mifepristone on GnRH-induced
`gonadotropin secretion was observed in pi-
`tuitary cells obtained without attention to
`the stage of estrous cycle,3 the presence of
`estradiol may be important for the inhibi-
`tory effect of mifepristone on GnRH. In
`rats, progesterone can directly activate
`Gan—l neurons, which results in the release
`of LH; mifepristone treatment reduces the
`effect, indicating that the inhibition by mi-
`fepristone of GnRH-induced gonadotropin
`release could occur at the hypothalamic
`level.5 Antiprogestins bind to progesterone
`receptors in hypothalamic neurons in areas
`that control reproductive processes. Further
`evidence of direct neural involvement is the
`
`increase in GnRH mRNA levels produced
`by progesterone and blacked by antipro-
`gestins in estrogen—treated rats.”
`Non-human primate studies also provide
`evidence for the role of mifepristone in go-
`nadotropin inhibition.5 Preovulatory mi-
`fepristone administration blocked the LH
`surge in monkeys. This could not be re-
`versed by simultaneous treatment with
`dexamethasone, suggesting that the anti-
`gonadotropic effects of mifepristone are due
`to its antiprogestational rather than its an-
`tiglucocorticoid properties. Oral adminis-
`tration of 25 mg of mifepristone once
`weekly to monkeys blocked the expected
`midcycle LH and follicle stimulating hor-
`mone surge and progesterone levels re-
`mained undetectable. Inhibition of proges-
`terone secretion was not complete when half
`the dose of mifepristone was administered.3
`Effects on gonadotropins by mifepristone
`also have been observed in humans, al-
`though they appear to be dependent on
`close, duration, and time of administration
`during the cycle.3 No decrease in basal go-
`nadotropin level is observed after early fol-
`
`Mrfepristone: Clinical Pharmacology
`
`443
`
`licular or luteal administration of mifepri-
`stone. During the mid-luteal phase, mife-
`pristone also decreased mean LH secretion
`and LH pulse amplitude and blunted the
`pituitary response to Gan—l. In the late-lu-
`teal phase, LH pulse frequency and ampli—
`tude decreased. A single dose of 10 or 100
`mg of mifepristone during the mid and late
`follicular phase reduced plasma gonadotro-
`pin levels, and daily administration for 1
`week during this stage of the cycle delayed
`in the appearance of the LH surge.3 Evi—
`dence for a pituitary site of action comes
`from studies conducted in women with hy-
`pothalamic amenorrhea receiving exoge-
`nous GnRH to induce ovulation. Admin-
`
`istration of mifepristone together with ex-
`ogenous GnRH is associated with a delay
`in the appearance of the LH surge compared
`to the control study without mifepristone.”
`In contrast to the effects of short-term mi-
`
`fepn'stone administration, treatment with
`doses of 50-100 mg/day for 3 months pro-
`duced a transient increase in mean LH lev—
`
`els and LH pulse amplitude, which returned
`to baseline after 4 weeks of treatment. No
`
`change in follicle stimulating hormone was
`observed. Because mifepristone has been
`observed to produce agonistic as well as an-
`tagonistic effects and to act at several levels
`of the reproductive axis, it is not surprising
`that its effects on LH and follicle stimulating
`hormone secretion are diverse.
`
`The ability of mifepristone to suppress
`andfor delay the LH surge led to clinical
`testing of its use as a potential contraCeptive
`agent that would block ovulation. Inter-
`mittent and continuous administration
`
`regimens have been tested.3 Administered
`intermittently to women, on a dosing
`schedule of either 10 or 50 mg once weekly
`for 5 weeks or 50 mg for 3 successive days
`at 10-day intervals for 3 months, suppres-
`sion of progesterone was not consistently
`observed. This is in contrast to what was
`observed with intermittent administration
`
`in female monkeys, suggesting that inter-
`mittent administration of mifepristone to
`humans, at least at the doses and schedules
`
`EX. 2011—0012
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`Ex. 2011-0012
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`

`

`444
`
`ROBBINS AND SPITZ
`
`tested to date, does not uniformly inhibit
`ovulation. However, continuous daily doses
`of 2, 5, or 10, but not 1 mg, of mifepristme
`for 1 month suppress ovulation. Thus con-
`tinuous as opposed to intermittent ad-
`ministration of mifepristone shows more
`promise as a contraceptive agent to block
`ovulation. However, one note of caution is
`that intermittent and continuous adminis-
`
`tration regimens may result in unopposed
`estrogen stimulation of the endometriurn.
`
`Glucocarrr'caids
`
`A single dose of mit‘epristone of 100 mg or
`more induces a significant
`increase of
`ACTH and cortisol. This inhibition of the
`
`negative feedback of cortisol on ACTH se-
`cretion by mifepristone is a dose—dependent
`phenomenon (Figure 6). In humans, it has
`been estimated that the Optimal antiglu-
`cocortiooid effect occurs at a 10:1 ratio of
`
`mifepristonezcortisol in serum.
`The effect of mifepristone on the pitu-
`itary-adrenal system occurs only at a spe-
`cific time of day? The central antigluco-
`corticoid effect of mifepristone is particu—
`larly evident during the mornin