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Examensarbete Gnrh-Antagonisten Elagolix Effekter Och Biverkningar

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Examensarbete Gnrh-Antagonisten Elagolix Effekter Och Biverkningar Fakulteten för hälso- och livsvetenskap Examensarbete GnRH-antagonisten Elagolix effekter och biverkningar vid behandling av endometriosutlöst smärta Namn: Johanna Johansson Handledare: Anna Asplund Persson Termin: VT20 Ämne: Farmaci Nivå: Grundnivå Kurskod: 2FA01E GnRH-antagonisten Elagolix effekter och biverkningar vid behandling av endometriosutlöst smärta Johanna Johansson Examensarbete i Farmaci 15hp Filosofie Kandidatexamen Farmaceutprogrammet 180hp Linnéuniversitetet, Kalmar Handledare Anna Asplund Persson Inst. för Kemi och Biomedicin Universitetslektor Linnéuniversitetet SE-391 82 Kalmar Examinator Inst. för Kemi och Biomedicin Marlene Norrby Linnéuniversitetet Universitetslektor SE-391 82 Kalmar Sammanfattning Bakgrund: Endometrios är en kronisk benign östrogenberoende sjukdom som karaktäriseras av tillväxt av endometrioslesioner utanför livmodern. Sjukdomen kännetecknas av smärta. Det finns inget botemedel till sjukdomen, utan syftet med behandlingen är att minska symptom och lindra smärtan. Idag erbjuds drabbade kvinnor bl.a. kombinerade hormonella preventivmedel, gestagen eller gonadotropinfrisättande hormon (GnRH)-agonister, i kombination med icke-steroida antiinflammatoriska läkemedel (NSAID) och paracetamol. En annan tänkbar behandling mot endometrios är GnRH-antagonisten Elagolix. Läkemedlet blockerar GnRH-receptorn vilket leder till hämmad frisättning av luteinisierande hormon (LH) och follikelstimulerande hormon (FSH), och därmed minskas frisättning av könshormonet östrogen. Syfte: Syftet med arbetet var att utvärdera GnRH-antagonisten Elagolix effekter och biverkningar vid behandling mot endometriosutlöst smärta. Metod: Denna litteraturstudie är baserad på fem randomiserade kontrollerade vetenskapliga artiklar (RCT) som hämtats från den medicinska databasen PubMed. De sökord som använts är ”elagolix” och ”endometriosis”. Resultat: Elagolix blockerar omedelbart GnRH-receptorn oberoende av dos. Som svar på detta minskas nivåerna av LH och FSH, och därmed minskas frisättningen av östrogen. FSH-nivåerna minskar långsammare än LH. Högre dosering sänker LH-nivåerna under en längre period. Tiden för maximal plasmakoncentration (Tmax) uppnås inom 0,5-1 timme. Den optimala dosen Elagolix för behandling mot endometriosutlöst smärta är 150 mg en gång dagligen i maximalt tjugofyra månader, eller 200 mg två gånger dagligen i maximalt sex månader. Behandling med Elagolix leder till förlust av benmineraldensiteten (BMD). Ökad dos och behandlingslängd leder till ökad BMD reducering. Biverkningsfrekvensen vid behandling med Elagolix är hög. De låga östrogen-nivåerna resulterar i menopaus-liknande symptom. Slutsats: Denna litteraturstudie tyder på att Elagolix minskar östrogenfrisättningen och där med minskar endometriosutlöst smärta. Behandling med Elagolix bör ske under maximalt tjugofyra månader p.g.a. BMD-förlust. Studierna kring Elagolix är få, och samtliga studier är finansierade av läkemedelsföretag som deltagit i utvecklingen av läkemedlet. Ytterligare studier behövs med objektiv synvinkel. Nyckelord Endometrios; Elagolix SUMMARY Background Endometriosis is a chronic benign estrogen-dependent disease characterized by the growth of endometrial tissue outside the uterus. The disease is associated with severe pain. The purpose of all available treatment is to reduce the symptoms and relieve the pain. Today, affected women are offered combined hormonal contraceptives, progestogens or gonadotropin-releasing hormone (GnRH) agonists, in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol. Another possible treatment for endometriosis is the GnRH-antagonist Elagolix. The drug blocks the GnRH-receptor, which leads to inhibited release of luteinizing hormone (LH) and folliclestimulating hormone (FSH). Thereby reducing the release of the sex hormone estrogen. Purpose The aim of this study was to evaluate the effects and side effects of GnRH antagonist Elagolix for treatment of endometriosis-triggered pain. Method This work is a literature review based on randomized controlled scientific articles (RCTs), which were retrieved from the medical database PubMed.Gov. The article search was performed by using two keywords, namely “endometriosis” and “elagolix”, and resulted in a total of five articles to investigate. Results The results showed that Elagolix immediately blocks the GnRH receptors regardless of dosage. In response, the levels of LH and FSH are reduced, and thereby reducing estrogen release. FSH levels decrease more slowly than LH. Higher dosage lowers LH levels over a longer period of time. The time to maximum concentration (Tmax) is reached within 0,5-1 hour. The optimal dose of Elagolix for treatment of endometriosis- associated pain is 150 mg once daily for a maximum of twentyfour months, or 200 mg twice a day for a maximum of six months. Treatment with Elagolix leads to bone mineral density (BMD) loss. Increased dosage and duration of treatment lead to increased BMD reduction. Elagolix has a high frequency of adverse events. The adverse events is a result of the low estrogen levels. Conclusion The conclusion of this study imply that Elagolix reduces estrogen release and thereby reduces endometriosis-associated pain. Elagolix should only be used as treatment for a maxiumum of twenty-four months due to BMD loss. The studies around Elagolix are few, and all studies are funded by pharmaceutical companies that participated in the development of the drug. Further studies are needed with an objective point of view. FÖRORD Detta examensarbete inom området farmaci omfattar 15 högskolepoäng, och ingår i Farmaceutprogrammet 180 hp vid Linnéuniversitet i Kalmar. Arbetet motsvarar 10 veckors studier och skrevs under våren 2020. Jag vill rikta ett stort tack till min handledare Anna Asplund Persson som med sin kunskap och goda råd väglett mig under arbetets gång. Kalmar, 2020-03-19 Johanna Johansson FÖRKORTNINGAR AUC Area Under Curve (arean under plasmakoncentrationskurvan) BMD Bone mineral density B&B score - Biberoglu and Behrman score Cmax Den maximala plasmakoncentrationen CPSSS Composite Pelvic Signs and Symptoms Score DMPA-SC Depot Medroxyprogesteronacetat Subcutant EM Elaris Endometriosis FSH Follikelstimulerande hormon GnRH Gonadotropinfrisättande hormon IL Interleukin KD Dissociationskonstanten LH Luteinisierande hormon MIF Makrofagmigrations hämmande faktor MMP-3 Matrixmetalloproteinas 3 MRT Magnetresonanstomografi NRS Numeric Rating Scale NSAID Icke-steroida antiinflammatoriska läkemedel PAD Patologisk-anatomisk diagnos PGIC Patient Global Impression of Change SEM Standard Error of Mean TNF Tumörnekrosfaktor Tmax Tiden det tar för maximal plasmakoncentration VAS Visuell analog skala ORDFÖRKLARINGAR ablation - avlägsning av vävnad adenomyos - form av endometrios i myometriet amenorré - frånvaro av menstruation under sex månaders tid eller längre anovulation - utebliven ägglossning diatermi - bränna vävnad dyschezi - smärta och besvär vid tarmtömning dysmenorré - smärtsam menstruation dysparuni - smärta vid samlag dysuri - störd urinavsöndring med smärta och sveda endometrium - livmoderslemhinna excision - avlägsning av vävnad hysterektomi - avlägsning av livmoder laparoskopi - titthålsoperation laparotomi - öppen buk operation menarche - menstruationens debut myometriet - livmodermuskulaturen ooforektomi - avlägsning av en eller båda äggstockarna ovarialendometriom - blodfyllda cystor innehållande endometrievävnad i eller på äggstockarna , även kallade chokladcystor palpation - upptäcka förändringar med hjälp av händer och fingrar spekulum-inspektion - undersökning av livmoderhals och vaginala väggar salpingo-ooforektomi - avlägsning av äggledare och äggstockar INNEHÅLLSFÖRTECKNING INTRODUKTION ___________________________________________ 1 Endometrios _______________________________________________________ 1 Generell information _______________________________________________ 1 Diagnostisering ___________________________________________________ 2 Patogenes och Patofysiologi _________________________________________ 3 Behandling _______________________________________________________ 5 Elagolix __________________________________________________________ 6 Bedömningsskalor och mätverktyg som används i studierna _________________ 7 SYFTE ____________________________________________________ 8 MATERIAL OCH METOD ___________________________________ 8 RESULTAT ________________________________________________ 8 Sammanfattning av resultat __________________________________________ 8 Studie 1: Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist (34) ______________________________________________ 10 Syfte ___________________________________________________________ 10 Metod __________________________________________________________ 10 Resultat _________________________________________________________ 10 Studie 2: Long-Term Outcomes of Elagolix in Women With Endometriosis (35) _________________________________________________________________ 12 Syfte ___________________________________________________________ 12 Metod __________________________________________________________ 12 Resultat _________________________________________________________ 12 Studie 3: Elagolix, an Oral GnRH Antagonist, Versus Subcutaneous Depot Medroxyprogesterone Acetate for the Treatment of Endometriosis: Effects on Bone Mineral Density (36) ___________________________________________ 13 Syfte ___________________________________________________________ 13 Metod __________________________________________________________
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