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Elagolix

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Elagolix
Clinical data
Pronunciation/ˌɛləˈɡoʊlɪks/
EL-ə-GOH-liks
Trade namesOrilissa, Oriahnn
Other namesNBI-56418, ABT-620
AHFS/Drugs.comMonograph
MedlinePlusa618044
License data
Pregnancy
category
  • Contraindicated
Routes of
administration		By mouth[1]
Drug classGnRH antagonist
ATC code
Legal status
Legal status
Pharmacokineticdata
BioavailabilityLow (5.8% in rats, 11% in monkeys; no human data)[4]
Protein binding80%[1]
MetabolismLiver(CYP3A)[1]
Eliminationhalf-lifeTypical: 4–6 hours[1]
Single dose: 2.4–6.3 hrs[5][6]
Continuous: 2.2–10.8 hours[5]
ExcretionUrine:<3%[1]
Feces:90%[1]
Identifiers
  • 4-[[(1R)-2-[5-(2-Fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoic acid
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.259.758Edit this at Wikidata
Chemical and physical data
FormulaC32H30F5N3O5
Molar mass631.600g·mol−1
3D model (JSmol)
  • COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NCCCC(=O)O)c3ccccc3)c2=O)c1F
  • InChI=1S/C32H30F5N3O5/c1-19-28(21-11-6-14-26(45-2)29(21)34)30(43)40(18-25(20-9-4-3-5-10-20)38-16-8-15-27(41)42)31(44)39(19)17-22-23(32(35,36)37)12-7-13-24(22)33/h3-7,9-14,25,38H,8,15-18H2,1-2H3,(H,41,42)/t25-/m0/s1
  • Key:HEAUOKZIVMZVQL-VWLOTQADSA-N

Elagolix,sold under the brand nameOrilissa,is agonadotropin-releasing hormone antagonist(GnRH antagonist) medication which is used in the treatment ofpainassociated withendometriosisin women.[1][2][3][7][6][4][8][9]It is also under development for the treatment ofuterine fibroidsandheavy menstrual bleedingin women.[9]The medication was under investigation for the treatment ofprostate cancerandenlarged prostatein men as well, but development for these conditions was discontinued.[9]Elagolix is takenby mouthonce or twice per day.[1][9]It can be taken for up to 6 to 24 months, depending on the dosage.[1]

Side effectsof elagolix includemenopausal-like symptomssuch ashot flashes,night sweats,insomnia,amenorrhea,moodchanges,anxiety,and decreasedbone density,among others.[1]Elagolix is a GnRH antagonist, or anantagonistof thegonadotropin-releasing hormone receptor(GnRHR), thebiological targetof thehypothalamichormonegonadotropin-releasing hormone(GnRH).[1]By blocking the GnRHR, it dose-dependently suppresses thegonadalproductionand hence circulating levels ofsex hormonessuch asestradiol,progesterone,andtestosterone.[1]Elagolix is a short-acting GnRH antagonist, and can be used to achieve either partial or more substantial suppression of sex hormone levels.[8]Reducedestrogenlevels in theendometriumare responsible for theefficacyof elagolix in the treatment of endometriosis.[8]

Elagolix was first described in 2008 and was approved for medical use in July 2018.[10][9]It has been described as a "second-generation"GnRH modulatordue to itsnon-peptideandsmall-moleculenature and itsoral activity.[6][9]UnlikeGnRH agonistsand olderGnRH antagonists,which arepeptidesand first-generation GnRH modulators, elagolix is not aGnRH analogueas it is not structurally related to GnRH.[6][9]Elagolix was the first second-generation and orally active GnRH modulator to be introduced for medical use.[9]The introduction of elagolix in the United States andCanadawas followed by that ofrelugolix(brand name Relumina), the next second-generation GnRH antagonist, inJapanin January 2019.[11]The U.S.Food and Drug Administration(FDA) considers it to be afirst-in-class medication.[12]

Medical uses

[edit]

Elagolix is used in the treatment of moderate to severepainassociated withendometriosisinpremenopausalwomen.[1]Endometriosis is a condition in which theendometrium,the inner lining of theuterus,grows outside of the uterus into surroundingtissuesand causessymptomssuch aspelvic painandinfertility.[13]Around 10% of women may be affected by endometriosis.[13]Elagolix significantly decreases symptoms ofdysmenorrhea(menstrual pelvic pain), non-menstrualpelvic pain,anddyspareunia(pain duringsexual intercourse) in women with endometriosis.[1][14][15][16]The medication is used at a lower dosage of 150 mg once per day or at a higher dosage of 200 mg twice per day, depending on the severity of symptoms.[1][14]

The effectiveness of elagolix in the treatment of symptoms of endometriosis was demonstrated in the 6-month Elaris Endometriosis I and II (EM-I and EM-II)phase IIIclinical trials.[8][1]In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P < 0.001 for all comparisons).[15]In Elaris EM-I, the percentage of women who had a clinical response with respect to non-menstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P < 0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P = 0.003 and P < 0.001, respectively).[15]The reductions in symptoms of endometriosis with elagolix resulted in an improvedquality of life.[8][16]

The duration of use of elagolix in the treatment of endometriosis should be limited due to a progressive risk ofbone loss,and the lowest effective dosage should be used.[1]Elagolix can be used for up to 24 months at the 150 mg once per day dosage and for up to 6 months at the 200 mg twice per day dosage.[1]

Because of its relatively shortduration,elagolix should be taken at approximately the same time each day.[1]In the case of twice-daily administration, elagolix should be taken at approximate 12-hour intervals, for instance once in the morning and once at night.[1]It can be taken with or withoutfood.[1]

Elagolix is approved only for the treatment of endometriosis.[1]Other approved and off-label uses of GnRH antagonists in general are the same as those of GnRHRdesensitizationtherapy with GnRH agonists such asleuprorelin,and include uterine fibroids andbreast cancerin premenopausal women,prostate cancerin men,precocious pubertyin children, andhormone therapyintransgenderadolescents and adults, among others.[17][18]

Available forms

[edit]

Elagolix is available in the form of Orilissa 150 and 200 mgoraltablets.[1]The 150 mg tablets are light pink, oblong, and film-coated with "EL 150" debossed on one side, while the 200 mg tablets are light orange, oblong, and film-coated with "EL 200" debossed on one side.[1]Theinactive ingredientsin the tablets includemannitol,sodium carbonate monohydrate,pregelatinized starch,povidone,magnesium stearate,polyvinyl alcohol,titanium dioxide,polyethylene glycol,talc,and a distinctcolor additive(carmine high tintin the 150 mg tablets andiron oxide redin the 200 mg tablets).[1]

Contraindications

[edit]

Contraindicationsof elagolix includepregnancy,knownosteoporosis,severehepatic impairment,and concomitant use with strongorganic anion-transporting polypeptide(OATP)1B1inhibitorssuch asciclosporinandgemfibrozil.[1]Elagolix may increase the risk ofmiscarriagein early pregnancy.[1]Women should avoid pregnancy while taking elagolix, for instance by usingbirth control,and should discontinue the medication if they become or wish to become pregnant.[1]Elagolix should not be used in women with osteoporosis because it may increase the risk of furtherbone loss.[1]Severe hepatic impairment is associated with 7-fold increased exposure to elagolix, which may increase the risk of bone loss.[1]In women with moderate hepatic impairment, which is associated with 3-fold increased exposure to elagolix, the medication at 200 mg twice per day should not be used, while 150 mg once per day should be used for no more than 6 months.[1]OATP1B1 inhibitors are likely to greatly increase exposure to elagolix similarly to moderate to severe hepatic impairment.[1]

Combined birth controlis not contraindicated with elagolix, but because of theestrogencomponent, is expected to decrease the effectiveness of elagolix in the treatment of endometriosis, and hence is not recommended.[1]Other forms of birth control, such as non-hormonal birth control, can be used instead.[1]Elagolix is not contraindicated in women who arebreastfeeding,but it is unknown whether the medication isexcretedinbreast milkor if it has adverse effects onmilk productionor thebreastfedchild.[1]The use of elagolix in women who are breastfeeding should be considered carefully, weighing both benefits and risks.[1]

Side effects

[edit]
Side effects of elagolix in clinical trials (mostly ≥5% incidence)[1][19][20]
Side effect 150 mgq.d.
[n=475] (%) 		200 mgb.i.d.
[n=477] (%) 		Placebo
[n=734] (%)
Hot flashes/night sweats 23–24 45–46 9
Amenorrhea 4; 6–17 7; 13–57 <1
Headaches 17 20 12
Nausea 11 16 13
Mood changes/swings 6 5 3
Anxiety 3 5 3
Depressive symptoms 3 6 2
Insomnia 6 9 3
Upper respiratory tract infection 6 4 5
Nasopharyngitis 6 6 4
Sinusitis 5 6 4
Arthralgia 3 5 3
>8%BMDdecrease(6 months) <1–2 6–7 <1
>8%BMDdecrease(12 months) 2–8 21 <1
Elevated liver enzymesa 0.2 (n=1) 1.1 (n=5) 0.1 (n=1)
Suicidal ideation 0.2 (n=1) 0.2 (n=1) 0
Suicide 0.2 (n=1) 0 0
Notes:Side effects reported in ≥3% but <5% includeddiarrhea,abdominal pain,constipation,weight gain,dizziness,irritability,anddecreased libido.Footnotes:a= Asymptomatic;ALTTooltip alanine transaminase>3 times upper limit.

Theside effectsof elagolix are in general similar tomenopausal symptoms.[1]The most common side effects of elagolix (incidence ≥10%) arehot flashes,night sweats,headaches,nausea,andamenorrhea(cessation ofmenstruation).[1][2][3]The next most frequent side effects of elagolix (incidence ≥5%) areinsomnia,anxiety,arthralgia(joint pain),depression,andmoodchanges.[1][2][3][16]Less common side effects of elagolix (incidence ≥3% and <5%) includedecreased sex drive,diarrhea,abdominal pain,weight gain,dizziness,constipation,andirritability.[1]Other common side effects of elagolix include decreasedbone mineral density(BMD) and changes in theblood lipidprofile.[1][16]Rare but serious adverse effects that were observed during elagolix therapy in clinical trials includedappendicitis(0.3%), abdominal pain (0.2%), andback pain(0.2%), though it is unknown if these were due to elagolix.[1][16]Other serious adverse effects of elagolix may includebone loss,miscarriage,suicidality,andelevated liver enzymes.[1]Elagolix was discontinued due to side effects by 5 to 10% of women in clinical trials, with the most common reasons being hot flashes or night sweats, nausea, and decreased BMD.[1]

Elagolix dose- and duration-dependently decreases BMD inpremenopausalwomen with long-term therapy.[1]After 6 months of treatment with elagolix,lumbar spineBMD was decreased by 0.3 to 1.3% with 150 mg once per day and by 2.5 to 3.1% with 200 mg twice per day.[1]The decrease in BMD during elagolix therapy may not be fully reversible with discontinuation, as only partial recovery was observed 12 months after discontinuation of therapy.[1]The cause of the decrease in BMD with elagolix isestrogen deficiency,and is analogous to that associated withpostmenopause.[1]The consequences of the effects of elagolix on BMD are unknown, but may be an increase in the risk ofbone lossandfractures.[1]This is why the duration of use of elagolix should be limited.[1]In women with risk factors for bone loss and osteoporosis, such as a history of low-trauma fracture, assessment of BMD may be considered.[1]Elagolix should not be used in premenopausal women with known osteoporosis.[1]Supplementation withcalciumand/orvitamin Dduring treatment with elagolix has not been studied, but may be beneficial for helping to maintain bone health.[1]

Elagolix decreases the amount, intensity, and duration ofmenstrual bleeding.[1]Amenorrhea, the cessation of menstruation, was observed in 4 to 17% of women with 150 mg once per day and in 7 to 57% of women with 200 mg twice per day, compared to less than 1% of women given placebo.[1]The decreased menstrual bleeding caused by elagolix may impede the ability to recognizepregnancyin a timely manner.[1]Based on its mechanism of action, elagolix may increase the risk ofmiscarriagein early pregnancy, and so should be discontinued if pregnancy occurs.[1][21]If pregnancy is suspected,pregnancy testingcan be performed.[1]Elagolix decreases the rate ofovulationand thereby decreases the likelihood of pregnancy, but has not been shown to be a fully effectivecontraceptiveand should not be relied on to prevent pregnancy.[1]

The incidence of depression and mood changes in clinical trials with elagolix was increased in premenopausal women taking elagolix relative to placebo.[1]Mood- and depression-type side effects such as altered mood,mood swings,depressed mood, depression, depressive symptoms, andtearfulnessoccurred in 3 to 6% of women with 150 mg per day and in 5 to 6% of women with 200 mg twice per day, compared to 2 to 3% in women givenplacebo.[1]Suicidal ideation and behavioroccurred in a few women (0.2–0.4%), with one suicide observed.[1]People taking elagolix with new or existing depressive symptoms should be promptly evaluated to determine whether the benefits of treatment outweigh the risks.[1]In those with new or existing depressive symptoms, referral to amental health professional,as appropriate, may be warranted.[1]Immediate medical attention should be sought for those with suicidal ideation and behavior.[1]

Elagolix dose-dependently producedelevated liver enzymes,including elevations ofserumalanine aminotransferaseof at least 3-fold the upper limit, in clinical trials.[1]This was observed in one woman (0.2%) with 150 mg once per day and in five women (1.1%) with 200 mg twice per day, compared to one woman (0.1%) given placebo.[1]Medical attention should be sought if signs or symptoms ofliver injury,such asjaundice,are noticed.[1]The lowest effective dosage of elagolix may be used to minimize the risk of liver problems, and in those who develop elevated liver enzymes during elagolix therapy, prompt evaluation should be done to determine whether the benefits of treatment outweigh the risks.[1]

Overdose

[edit]

In the event of anoverdoseof elagolix, the person should be monitored for any signs or symptoms ofadverse reactionsand should be treated on a symptomatic basis as needed.[1]Elagolix has been assessed in clinical studies at a dose as high as a single administration of 1,200 mg, which resulted in concentrations of the medication that were 17 times higher than with the typical high clinical dosage of 200 mg twice per day.[1]No adverse effects were mentioned.[1]Chronic overdosage of elagolix may result in greater suppression of estradiol levels and a consequent increased risk of bone loss with long-term therapy.[1]

Interactions

[edit]

Elagolix has a number of potentialdrug interactionswith other medications.[1]Elagolix is asubstrateof thecytochrome P450(CYP450)enzymeCYP3A,andinhibitorsandinducersofCYP3A4may alter themetabolismof elagolix and increase or decrease its circulating levels.[1]The strong CYP3A4 inhibitorketoconazolehas been found to increase peak levels of and total exposure to a single 150 mg dose of elagolix by about 2-fold.[1]Paradoxically,rifampin,a strong inducer of CYP3A4 and other CYP450 enzymes, increased peak levels of and total exposure to a single 150 mg dose of elagolix as well.[1]A single dose of rifampin increased peak levels of elagolix by 4.4-fold and total exposure by 5.6-fold, whereas continuous rifampin therapy increased peak levels of elagolix by 2-fold and total exposure by 1.7-fold.[1]The use of elagolix at 200 mg twice per day concomitantly with rifampin is not recommended, whereas the concomitant use of elagolix at 150 mg once per day with rifampin should be limited to 6 months.[1]No significant changes in exposure to elagolix were observed with concomitant administration ofrosuvastatin(asubstrateofOATP1B1,OATP1B3,andBCRP),sertraline(a moderate inhibitor ofCYP2D6andCYP2B6), orfluconazole(a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4).[1][22]

Elagolix is a substrate of the hepaticOATP1B1transporter.[1]Levels of elagolix have been found to be increased by 78% in people with agenotypecharacterized by reduced OATP1B1 transporter function.[1]The concomitant use of elagolix with medications that inhibit OATP1B1 may increase elagolix levels, and the use of elagolix with strong OATP1B1 inhibitors likeciclosporinandgemfibrozil,which may markedly increase elagolix exposure, is contraindicated.[1]

Elagolix is a weak to moderateinducerof CYP3A, and may decrease levels of medications that are substrates of CYP3A4.[1]In addition, elagolix is an inhibitor ofP-glycoprotein,and may increase levels of medications that are substrates of P-glycoprotein, such asdigoxin.[1]Elagolix has been found to increase exposure to digoxin andethinylestradiol,whereas it has been found to decrease exposure torosuvastatin,midazolam,norethisterone,norelgestromin,andnorgestrel.[1]

Becausecombined birth control pillsand other forms ofcombined birth controlcontain an estrogen, and because elagolix treats endometriosis by decreasing estrogen levels in the endometrium, these form ofhormonal birth controlare likely and expected to decrease the effectiveness of elagolix in the treatment of this condition.[1]The effect ofprogestogen-only birth controlon the effectiveness of elagolix in endometriosis is unknown.[1]However, progestogens areantiestrogenicin theuterus,and high-doseprogestintherapy is known to be effective in the treatment of endometriosis similarly to GnRH antagonists.[23][24]On the basis of limited clinical research, combined birth control pills have also been found to be effective in the treatment of endometriosis, but are likely not as effective as GnRH modulator monotherapy.[23]It is advised that women use non-hormonal methods ofbirth controlduring elagolix therapy and for one week following discontinuation of elagolix.[1]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Elagolix acts as apotentandselectivecompetitive antagonistof thegonadotropin-releasing hormone receptor(GnRHR), thebiological targetof thehypothalamicpeptide hormonegonadotropin-releasing hormone(GnRH).[1]As such, it is aGnRH antagonist.[1]Theaffinity(KD) of elagolix for the GnRHR is 54 pM.[1][10][25]By blocking the GnRHR in thepituitary gland,elagolix suppresses the GnRH-inducedsecretionof thegonadotropinsluteinizing hormone(LH) andfollicle-stimulating hormone(FSH) from theanterior pituitary,and thereby decreases theproductionofsex hormonesby thegonads.[1][26]In women, elagolix dose-dependently suppresses the production ofovarianhormones includingestradiol,progesterone,andtestosterone,and thereby decreases the circulating levels of these hormones.[1][26]In men, GnRH modulators suppress thetesticularproduction of testosterone and estradiol, decreasing the circulating levels of these hormones similarly.[27]Unlike previousGnRH agonistsand antagonists, referred to collectively asGnRH analogues,elagolix is anon-peptideandsmall-moleculecompoundthat can be takenorally.[1][8]

Estrogenslike estradiol stimulate thegrowthof theendometrium,and thereby aggravatesymptomsofendometriosis.[8]By suppressing estrogen production and levels, elagolix decreases the growth of the endometrium and decreases endometriosis symptoms such as pelvic pain.[8][1]

Elagolix is a short-acting GnRH antagonist, with aterminal half-lifeof typically about 4 to 6 hours.[1][26][8]Because of the shortdurationof elagolix in the body, the activation of the GnRHR by GnRH is not fully blocked throughout the day with once-daily administration of elagolix.[6][5]As a result, gonadotropin and sex hormone levels are only partially suppressed when elagolix is taken once per day.[1][6][5]In addition, the degree of suppression can be dose-dependently adjusted as needed, for instance with higher-dose twice-daily administration to achieve greater hormonal suppression.[1][6][5]Because of its short duration in the body, the effects of elagolix are rapidly reversible upon discontinuation.[6][5]In addition, due to its partial and incomplete suppression of estradiol levels, the side effects of elagolix, such as hot flashes and decreased BMD, are lower than with first-generation GnRH modulators.[6][5][28][29]

External images
image iconLevels of LH, FSH, estradiol, and progesterone over a 21-day period with elagolix in premenopausal women[26]
image iconLevels of LH, FSH, estradiol, and progesterone after the first dose on day 1 and after the last dose on day 21 with elagolix in premenopausal women[26]

In clinical trials, elagolix produced dose-dependent decreases in gonadotropin, estradiol, and progesterone levels in women.[1][26][5]Median levels of estradiol were partially suppressed to 42 pg/mL (follicular phaselevels) with 150 mg once daily and were fully or near-fully suppressed to 12 pg/mL (postmenopausallevels) with 200 mg twice daily.[1]In a 21-day study in premenopausal women, the effects of elagolix on FSH levels were found to be maximal at a dosage of 300 mg twice per day or above, whereas its effects on LH and estradiol levels were maximal at a dosage of 200 mg twice per day or above.[26]Levels of progesterone were maintained atanovulatorylevels (<2 ng/mL) across the 21-day study period at dosages of elagolix of 100 mg twice per day and above.[26]A dosage of elagolix of 400 mg twice per day appears to produce no greater suppression in gonadotropin or estradiol levels than a dosage of 300 mg twice per day in premenopausal women.[26]Suppression of gonadotropin and sex hormone levels with elagolix occurs rapidly, within hours, and upon discontinuation of elagolix, gonadotropin and sex hormone levels remain suppressed for at least 12 hours, but show recovery within 24 to 48 hours.[26]As a consequence of its suppression of gonadotropin and sex hormone levels, elagolix inhibitsovulationin women.[1]Over the course of threemenstrual cycles,the ovulation rate with elagolix was 50% at 150 mg once daily and 32% at 200 mg twice daily.[1]Because ovulation is triggered by a surge in estradiol levels atmid-cycle,estrogen exposure during elagolix therapy might be greater around this time in some women.[30]

In addition to its activity as a GnRH antagonist, elagolix is a weak to moderateinducerofCYP3Aand aninhibitorofP-glycoprotein.[1]As a result, elagolix may affect themetabolismand/ortransportof other medications, and this may contribute todrug interactionswith elagolix.[1]

Pharmacokinetics

[edit]
Levels of elagolix following a single oral dose of different doses of elagolix in women.[5]
External image
image iconLevels of elagolix over 12- or 24-hour dosing intervals on days 1 and 21 with elagolix in premenopausal women[26]

Elagolix is taken by theoralroute of administration,in contrast to other GnRH modulators.[1][26][8][6]The oralbioavailabilityof elagolix in humans is not described in theFood and Drug Administration(FDA)labelfor the medication, but inanimal researchelagolix showed a low oral bioavailability of 5.8% in rats and 11% in monkeys.[4]Following administration, elagolix is rapidlyabsorbed,withpeak concentrationsoccurring after 0.5 to 1.5 hours.[1][26]Thedrug accumulation ratioof elagolix at 150 mg once per day is 0.98 and at 200 mg twice per day is 0.89, indicating that it is not accumulated in the body with continuous administration.[1][26][5]Atsteady state,peak levels of elagolix at 150 mg once per day are 574 ng/mL and at 200 mg twice per day are 774 ng/mL whilearea-under-the-curve levelsof elagolix at 150 mg once per day are 1,292 ng•hour/mL and at 200 mg twice per day are 1,725 ng•hour/mL.[1]Atoxicologystudy found that levels of elagolix in women after a single dose of 1,200 mg were 17 times higher than in women taking 200 mg twice daily.[1]Taking elagolix with a high-fatmealhas been found to decrease its peak levels by 36% and its area-under-the-curve levels by 24%.[1]In terms ofdistribution,theplasma protein bindingof elagolix is 80% and itsblood-to-plasma ratiois 0.6.[1]Thevolume of distributionatsteady stateis 1,674 L at 150 mg once per day and 881 L at 200 mg twice per day.[1]

Elagolix ismetabolizedin theliver,with the majorpathwaybeing byCYP3Aand minor pathways including byCYP2D6,CYP2C8,andUDP-glucuronosyltransferases.[1]Theterminal half-lifeof elagolix is typically about 4 to 6 hours.[1][26]A study found that its half-life was 2.4 to 6.3 hours with a single dose and was 2.2 to 10.8 hours with continuous administration.[5][6]The oralclearanceof elagolix is 123 L/hour at 150 mg once per day and 144 L/hour at 200 mg twice per day.[1]The major pathway ofeliminationof elagolix is hepatic metabolism.[1]Elagolix is taken up from thecirculationinto the liver by the hepaticOATP1B1carrier.[1]In people with two reduced functionallelesof thegenethatencodesOATP1B1 (SLCO1B1 521T>C; SLCO1B1 521 C/Cgenotype),plasmalevels of elagolix have been found to be increased by 78% relative to in people with normal OATP1B1 function (SLCO1B1 521T/T genotype).[1]The frequency of this reduced function OATP1B1genotypeis generally less than 5% in mostracialandethnicgroups.[1]Elagolix isexcretedless than 3% inurineand 90% infeces.[1]

Exposure to elagolix is not affected byrenal impairmentor mildhepatic impairment,but is increased by approximately 3-fold in women with moderate hepatic impairment and by approximately 7-fold in women with severe hepatic impairment.[1]There were no differences in thepharmacokineticsof elagolix between individuals of different racial and ethnic groups.[1]Similarly, the pharmacokinetics of elagolix were unaffected bybody weightandbody mass index.[1]Peak and area-under-the-curve levels of elagolix have been shown to be altered byCYP3A4inhibitorslikeketoconazoleand CYP3A4inducerslikerifampin.[1]Inhibitors of OATP1B1 may increase circulating levels of elagolix, and elagolix is considered to be contraindicated in combination with strong OATP1B1 inhibitors.[1]Elagolix is asubstrateofP-glycoprotein,but the effect of inhibitors and inducers of P-glycoprotein on the pharmacokinetics of elagolix is unknown.[1]Elagolix itself is an inhibitor of P-glycoprotein.[1]

Chemistry

[edit]
See also:Gonadotropin-releasing hormone receptor § Antagonists

Elagolix is asmall-moleculeandnon-peptidecompound.[9][31][1]This is in contrast toGnRH analoguessuch asleuprorelinandcetrorelix,which arepeptidesandanaloguesof GnRH.[6][9]Other small-molecule and non-peptide orally active GnRH antagonists besides elagolix includelinzagolix,opigolix,relugolix,andsufugolix,although none of these compounds have been introduced for medical use at this time.[32]

Elagolix is used as elagolix sodium, thesodiumsaltof elagolix.[1]It is a white to off white to light yellowpowder.[1]The compound is freelysolubleinwater.[1]Thechemical nameof elagolix sodium is sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate.[1]It has amolecular formulaof C32H29F5N3O5Na and amolecular weightof 653.58 g/mol.[1]Thefree acidform of elagolix has a molecular formula of C32H29F5N3O5and a molecular weight of 631.60 g/mol.[1]

History

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Elagolix was first described in the literature in 2005.[33][34][10]It was originally developed by thepharmaceutical companyNeurocrine Biosciences,and was later developed together by Neurocrine Biosciences andAbbVie(previouslyAbbott Laboratories).[9][10][25]In June 2010, Neurocrine Biosciences and Abbott announced a global agreement to develop and commercialize elagolix for the treatment of endometriosis.[35]The medication completedphase IIIclinical trialsfor endometriosis in November 2016.[4]Two phase III clinical trials, the Elaris Endometriosis I and II (EM-I and EM-II) studies, were conducted.[8][1]The studies included almost 1,700 women, about 950 of whom were treated with elagolix.[8][1][14]In September 2017, AbbVie filed aNew Drug Application(NDA) for elagolix for the treatment of pain associated with endometriosis in theUnited States.[4]The medication was approved by the FDA for the treatment of endometriosis-associated pain in the United States on 23 July 2018.[9][36]It was the first new medication to be approved by the FDA for the treatment of endometriosis in more than a decade.[37][38]Elagolix was the first member of a new class ofGnRH modulatorsdescribed as "second-generation" due to theirnon-peptideandsmall-moleculenature andoral activityto be marketed.[4][6]A second member of this group,relugolix(brand name Relumina), was introduced inJapanin January 2019.[11]In addition to endometriosis, elagolix is under development for the treatment of uterine fibroids and menorrhagia.[9]It is in phase III clinical trials for these indications.[9]

Society and culture

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Generic names

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Elagolixis thegeneric nameof the drug and itsINNTooltip International Nonproprietary NameandUSANTooltip United States Adopted Name.[31]It is also known by its former developmental code namesNBI-56418andABT-620.[9][31]

Brand names

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Elagolix is marketed under the brand name Orilissa.[1]

Availability

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Elagolix is available in the United States and Canada.[1][2][3]A similar medication,relugolix,is available in Japan.[11]

Economics

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Prior to its introduction, elagolix was estimated to cost aboutUS$850per month.[14]It is not available as ageneric medication.[citation needed]

Research

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As of November 2018,elagolix inphase IIIclinical trialsfor the treatment ofuterine fibroids(uterine leiomyoma) andmenorrhagia(abnormally heavy bleeding duringmenstruation) in women.[6][9]Anefficacyandsafetystudy of elagolix in combination with add-backestradiol,anestrogen,andnorethisterone acetate,aprogestin,for the treatment of menorrhagia associated with uterine fibroids in premenopausal women has been published.[4]The medication was also under investigation for the treatment ofprostate cancerandbenign prostatic hyperplasia(enlarged prostate) in men, but development for these indications was discontinued.[9]

References

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Further reading

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[edit]
  • "Elagolix".Drug Information Portal.U.S. National Library of Medicine.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Elagolix&oldid=1223318887"