Role of Mirena in HRT - Nick Panay

HRTNew delivery systemsImperial CollegeBSc Module Post Repro Health8 thth Oct 2007Nick PanayConsultant Obstetrician & GynaecologistHonorary Senior Lecturer, Imperial CollegeQueen Charlotte’s & Chelsea Hospital

New delivery systems for HRT• Definition– Devices designed to• Modify the release of a drug• Control the rate of drug release over a period of time• Target specific compartments for release of the drug

New delivery systems for HRT• Pharmacokinetic aims• To achieve release rates close to zero order(steady state release)• Result in relatively constant blood levels overprolonged periods of time• Convenient dosing regimen

New delivery systems for HRT• Desired clinical outcome• Optimum symptom relief @ minimum bloodlevels• Minimal side effects / metabolic effects• Optimum patient compliance & satisfaction

New delivery systems for HRT• Desired clinical outcome• Restoration of 2:1 premenopausal oestradiol :oestrone ratio• Avoid 1 st pass metabolic effects e.g. clottingfactors

HRTRoutes of Administration• Nasal• Oral• Transdermal• Subcutaneous• Uterine• Vaginal

Routes of AdministrationAdvantagesOralTablets• Easy to take• Easily reversible• AffordableTransdermalPatches• Convenient• Easy to use• Easily reversible• Avoids first-pass metabolismGel• Easy to use• More natural delivery of hormoneDisadvantages• Unnatural delivery of hormones• Must be taken daily• High dose required• First-pass metabolism• Can irritate the skin• Can become detached• More expensive than tablets• Must be changed once or twice a week• Must cover correct amount of skin• More expensive than tabletsJones H. A Change for the Better. – How to survive-and thrive –during the menopause.

Routes of AdministrationAdvantagesVaginal Creams and Tablets• Greater effect if vaginalproblems are the onlysymptoms• Easily reversibleDisadvantages• Some is absorbed intothe bloodstream• Long-term use needs to considerprogestogen treatment• Messy (tablets less so)Subcutaneous (Implants)• 100% compliance• More natural deliveryof hormones• Prolonged effect(4-6 months)• Affordable• Needs a small surgical procedure• Can cause unnaturally high levels ofhormones• Not easily reversible• Progestogens need to be continued forseveral months after implantJones H. A Change for the Better. How to survive -- and thrive -- during the menopause.

HRTVaginal PreparationsP• Products that deliver only local estrogen– Creams– Pessaries– Tablets– Oestrogen ring Estring ®• Products that deliver local andsystemic estrogen– Oestrogen ring Menoring ®Monthly Index of Medical Specialties. September 2001.

Recently IntroducedMenopausal Treatment Strategies• Estrogen only ‘pulsed therapy’– Menoring ®– Aerodiol ® (nasal spray)• Gonadomimetic– Tibolone (Livial ® )• Nonhormonal therapies– Raloxifene (Evista ® )– Bisphosphonates (Fosamax ® )– PTH (Forsteo®)

HRT Delivery SystemsIntranasal

AerodiolDose 2x 150 μg sprays/dayOne pack = 63 doses = 30 days +3 toprime the pumpIndication: Replacement therapy foroestrogen deficiency symptoms in postmenopausalwomen

Aerodiol - intranasal HRT• 17 Beta oestradiol has been madewater soluble through theaddition of RAMEB (Randomlymethylated B- cyclodextrin), asolubising agent• RAMEB ’escorts’ oestradiol overthe nasal mucosa andthen releases it• Aerodiol contains nopreservatives. It is presented in asterile container fitted with anairless pump.ROOOROOROROOOOROROROROOORORORORAMEBORORROOROROOOROROROOOOORORR = H or CH 31,7 CH 3 / glucose

Aerodiol, , a unique pharmacokinetic profile• Aerodiol a new concept in HRT, pulsed oestrogen therapy.• This pulsed effect ensures effective oestrogenexposure in the target tissues• Aerodiol is characterised by an originalpharmacokinetic profile differing from the somewhatflatter, more sustained kinetic profiles seen withtransdermal and oral therapy.Devissaguet et al. (1999) Eur J Drug Metabol 24, 256-271

Aerodiol: “pulsed” pharmacokinetic profilePanay et al Maturitas 2001pg/mL140012001000800600AERODIOL ® 300µgOestradiolOestronePlasma oestradiol : rapidly distributed40020010%Untreated postmenopausal level00 2 4 6 8 12 24 (hours)

Tissue response to pulsed oestrogenRobinson JA Estrogens Antiestrogens 1997;5:43-62E 2A briefstimulation ofoestrogenreceptors

Tissue response to pulsed oestrogenRobinson JA Estrogens Antiestrogens 1997;5:43-62Leads to 24hoursefficacy

HRT Delivery SystemsOral – tissue specific therapy

Schematic representations of kinetic profiles1400NASAL - 300µg1400PATCH - 50µg1400TABLET- 2mg1200120012001000100010008008008006006006004004004002002002000-12 0 12 24 36 48 60(hours)00 24 48 72(hours)00 12 24 36 48 60 72(hours)Devissaguet et al. (1999) Eur J Drug Metabol 24, 256-271

HRT REGIMENSSEQUENTIAL HRTPROLIFERATIVE SECRETORY ENDOMETRIAL SHEDDINGContinuous oestrogenProgestogen 10–14 daysCONTINUOUS COMBINED THERAPYINACTIVE ENDOMETRIUM – NO ENDOMETRIAL SHEDDING – NO CYCLICAL BLEEDINGContinuous oestrogenContinuous progestogen

ANGELIQ ®Comparison of Drospirenone With OtherProgestogensProgestogensC-21C-19SpirolactonePregnanesEstranesGonanes• Medroxyprogesteroneacetate• Dydrogesterone• Megestrol acetate• Cyproterone acetate• Norethindrone• Noreth. acetate• Ethynodiol diacetate• Lynestrenol• Norethynodrel• Norgestrel• Levonorgestrel• Norgestimate• Desogestrel• GestodeneDrospirenone

ANGELIQ ® -Comparison of Drospirenone With OtherProgestogens (cont.)ProgesteroneEstrogenic-Androgenic-Anti-androgenic(+)Glucocorticoid(+)Antimineralocort-icoid+DrospirenoneNorethisterone-(+)-++---+Dydrogesterone----(+)Medroxyprogesterone-(+)-+-Key: + relevant activity; (+) activity not clinically relevant; – no activityAdapted from Climacteric 2004; 7(Supp 1): 11-35.

Red Clover

HRT: Maximising EfficacyMinimising ProblemsPhyto - oestrogens• Derived from plant sources such as soya beans, redclover, black cohosh, linseed - isoflavones / lignans• Evidence of mild oestrogenic activity approx 1:1000that of 17β oestradiol selective for ER β

HRT: Maximising EfficacyMinimising ProblemsPhyto-oestrogensoestrogens• Anti - oestrogenic activity on breast & endometrialtissue (ERα)• Randomised prospective studies currently in progress– Baber et al RCT Climacteric (1999)– Isoflavones (red clover) v placebo– Marginal benefit on vasomotor symptoms

Relative Isoflavone ContentReinli, K. and G. Block “Phytoestrogen Content of Foods--A Compendium ofLiterature Values.” Nutrition and Cancer 26(2): 123-148 (1996)IsoflavoneRed CloverExtractSoyChinesePeasGreenSplitPeasChickPeasBroadBeansGenisteinBiochaninDaidzeinFormononetinTotal IsoflavonesPer Serving40mg1 tablet20mg1 cup13mghalf cup10mghalf cup2mghalf cup2mghalf cup

Selectiveelective oEstrogenReceptoreceptor ModulatorodulatorAgonistAntagonistBoneCVSBreastUterus

Three-Dimensional Structure ofERα / E 2 and ERα / RLX ComplexesOestradiolBrzozowski A.M. et al. Nature 1997;389:753-8Raloxifene

Role of ERα and ERβ in Body Organ SystemsCentral nervous system:beta and alphaOvary: beta and alphaBlood vessels: betaBone: betaLungs: betaUrogenital tract: betaBreast: alphaLiver: alphaUterus: alphaCouse et al. 1997, Shughrue et al. 1996, Arts et al. 1997alphabeta

Raloxifene : Risk of Breast CancerPercentage of Randomized Patients1.51.00.50.00 1 2 3 4Cummings et al. JAMA. 1999; 281: 2189-2197Years Since RandomizationPlacebo4.3 per 1000 women yrsRR = 0.35 (0.21, 0.58)Raloxifene1.5 per 1000 women yrsp < 0.001

HRT: Maximising EfficacyMinimising ProblemsRaloxifene : Not an HRT alternative!• Side effectsPlacebo Active– 1.Leg cramps 1.9% 5.9%– 2.Flushes 18.3% 24.6%• Thromboembolic disease risks similar to HRT RR 2.16(95% CI 1.11-4.21)

Metabolic conversion of tiboloneOHCCHΔ 4 -tiboloneOCH 3OHCCHOHCCH3β-OHtiboloneOCH 3HOCH 3TiboloneOHCCH3α-OHtiboloneHOCH 3

Specific binding affinities:nuclear receptors in MCF-7 7 cellsEstrogen Progesterone Androgenreceptor receptor receptorTibolone + + +3α-/3β-OHtibolone + – –Δ 4 -tibolone isomer – + +Markiewicz et al., J Steroid Biochem 1990

Tibolone: : STEAR (selective tissue estrogenic activityregulator)Tibolone andactive metabolitesReceptorE2 receptoractivationPre-receptorEffect on Metabolismlocal enzymesBone, Vagina, ?BrainTissue stimulationLess activeestrogenic compoundsBreastrNo tissue stimulationΔ 4-isomerEndometriumr

HRT Delivery SystemsSkin – patches

HRT delivery systems - skin• Most active field of delivery system research• Areas of interest– Steroid types e.g. oestradiol, progestogen, testosterone– Adhesive technology / size of patch– Duration of delivery

HRT delivery systems - skinTransdermal skin patch systems• Mechanism of action– Passive diffusion– Lipid soluble substances– Lipophilic spaces between keratinsed cells of stratum corneum• Types– Reservoir : steroid in gel with alcohol as flux enhancer– Matrix : steroid dispersed evenly in adhesive matrix asmicronised suspension

Matrix HRT patch

HRT delivery systems - skin• Matrix patches– Rate of diffusion controlled by skin rather than by ratelimiting membrane– Protection of adhesive by semi-rigid translucentsilicone-coated film– Surface area proportional to amount of steroidabsorbed

Miniaturisation of transdermal systems

HRT Delivery SystemsSkin – creams/gels

New delivery vehicles for progestogensProgesterone creamo Progestogenic opposition– Wren BG et al 1999 Lancet• E100 v Placebo• No endometrial transformation• Progesterone cream alone– Leonetti et al 1999 Obstet Gynecol• RCT over 1 year of progesterone v placebo• Vasomotor benefits; no effect on bone density

HRT Delivery SystemsSubcutaneous implants

HRT Delivery SystemsSubcutaneous implants• Fused crystalline implants – minor op to insert• Oestradiol testosterone and progesterone• Sustained release over 6 months• Newer silastic implants being developed

HRT Delivery SystemsUterine systems

HRT: Maximising EfficacyMinimising ProblemsAdvances in HRT preparations• LNG IUS (Mirena) -20mcg• MLS (Menopause Levo.System)- 10mcg

Mirena - mechanism of action

IUS levels in contrast to other contraceptives6000Plasma concentration(pg/ml)50004000300020001000MIni-pillMIrenaLNG implantMIni-pillCOC01 2 3 4 5 6MIrenaDays after steady state

Mirena - endometrial effect

Mirena - reduces bleeding

Women on 17β oestradiol implants, switched to the levonorgestrelintrauterine system because of oral progestogen intoleranceBleeding / progestogenic side effects Panay Studd Acta 1997108VAS scores642BleedingProg SE's0Pre-LN IUS 6mths post IUS 12mths post IUS

HRT Delivery SystemsVaginal - rings

A Novel ERTMenoring ®• Intravaginal ring (IVR) utilisingestradiol acetate as prodrugfor estradiol• Delivers adequate estrogen totreat both local and systemicsymptoms for 3 months• Soft and flexible design for easyinsertion and removal• High level of patient acceptabilityand satisfaction

Menoring Technology• Central core containing 12.4 mgestradiol acetate• Drug-free, rate-controllingpolymer membrane ensurescontinuous, controlled,steady release of drug• Delivers oestradiol acetateat rate equivalentto 50 mcg/day oestradiolAl-Azzawi F, et al. Poster presented at British Menopause Society Congress. June 2001;Presentation at British Congress of Obstetrics & Gynaecology. July 2001

Menoring ® Pharmacokinetics• Estradiol acetate rapidly converted in vivo to estradiol,the naturally occurring hormone• Achieves average serum estradiol levels of 150 pmol/L—comparable to other transdermal controlled-releaseestradiol products• Levels maintained with little fluctuationfor 3 months• Avoids first-pass metabolism

3-MonthMean Serum Estradiol Profile for Menoring ®Passmore C, et al. Poster presented at British Menopause Society Congress,June 2001.

HRT Delivery SystemsVaginal - rings• Advantages– Flexibility of dosage (ultra low & higher dose)– Easy insertion & removal– Avoidance of skin irritation & unobtrusive– Physiological easy insertion– High acceptability

• Estring– 5-10mcg / dayHRT Delivery SystemsUltra low – dose rings– 3 months– Little or no systemic absorption– High acceptability compared to creams

HRT Delivery SystemsVaginal - gels

New delivery vehicles for progestogens• Progesterone vaginal gel (Crinone)– Progesterone in oil / water suspension– Hydrogen bonds with vaginal epithelium– Lower concentration in serum relative to endometrialtissue• 4% in HRT• 8% in assisted conception

New delivery vehicles for progestogens• Mechanism of endometrial action– Progestogenic and anti-progestogenic effects– Absence of spiral arterioles in endometrial biopsies– Weak secretory effect in endometrium– Suppression of menstruation in phase I and phase II trials• 83% amenorrhoea @ 12 weeks

AsoprisnilAdvantages over prexisiting Rxs e.g. GnRHa• Premenopausally– Normal oestrogen levels, no menopausal symptoms– No concerns re osteoporosis / CV disease• HRT– No PMS side effects!– ?Minimal Effect on Breast

HRT delivery systemsConclusions• Future developments– Greater individual flexibility in dosing– Minimising side effects whilst maximising efficacy– More long term user friendly methods needed

HRT delivery systemsConclusions• Products with minimum effective estrogen andprogestogen / new progestogens / local delivery• ?The Future – the ideal….– STEAR / SPRM / SERM

Thank you for your attention!