Methods of treatment with elinzanetant

The present disclosure relates to methods of treating vasomotor symptoms in a female subject in need thereof by administering a therapeutically effective amount of elinzanetant or a pharmaceutically acceptable salt or deuterated thereof, wherein the female subject is concurrently administered with a moderate CYP3A4 inhibitor.

1. 11. A method of treating vasomotor symptoms in a female subject in need thereof, comprising administering a daily dose of about 25 mg to about 100 mg of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor.
2. 22. The method of claim 1, wherein about 30 mg of elinzanetant is administered once a day.
3. 33. The method of claim 1, wherein about 60 mg of elinzanetant is administered once a day.
4. 44. The method of claim 1, wherein about 90 mg of elinzanetant is administered once a day.
5. 55. The method of claim 1, further comprising treating sleep disturbances associated with vasomotor symptoms.
6. 66. The method of claim 1, wherein elinzanetant is administered once a day.
7. 77. The method of claim 1, wherein elinzanetant is administered at bedtime (h.s.).
8. 88. The method of claim 1, wherein the female subject has moderate to severe vasomotor symptoms prior to administering elinzanetant.
9. 99. The method of claim 1, wherein the female subject is an adult.
10. 1010. The method of claim 1, wherein the female subject is 40-65 years old.
11. 1111. The method of claim 1, wherein the female subject is menopausal.

BACKGROUND
Women experience a range of symptoms during menopause, including vasomotor symptoms (VMS), commonly known as hot flashes and night sweats and are associated with sleep disturbances, affecting up to 80% and 60% of women, respectively. These symptoms can significantly impact quality of life by disrupting daily activities and work productivity. Additionally, these menopause symptoms may contribute to long-term health risks such as cardiovascular disease, depression, cognitive decline, and other adverse neurological and psychological outcomes.
Research studies have identified that hypothalamic kisspeptin/neurokinin/dynorphin (KNDy) neurons play a role in thermoregulation. The KNDy neurons express several receptor/ligand systems, including NK-1 and NK-3 receptors and their respective ligands, substance P (SP) and neurokinin B (NKB). As estrogen levels decline during and after menopause, KNDy neurons become hypertrophic and hyperactive, leading to increased expression of NKB and SP. Such hyperactivation disrupts thermoregulation and is believed to trigger VMS.
Safe and effective treatment regimens are needed for women with VMS. This disclosure addresses this and other needs.
SUMMARY
The details and embodiments of the present invention are defined by the disclosure herein. When referring to method of treatment comprising the administration of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt thereof, the subject-matter also includes elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt thereof for use in the respective treatment in any embodiment and definition as set out herein. The present disclosure provides for methods of treating vasomotor symptoms or sleep disturbances in a female subject by administering a CYP3A4 substrate drug, wherein the subject is undergoing concomitant treatment with a CYP3A4 inhibitor. In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject in need thereof, comprising administering about 25% to about 75% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor. In particular, the present disclosure provides methods of treating vasomotor symptoms in a female subject in need thereof, comprising administering about 25 mg to about 100 mg of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject in need thereof, comprising administering about 25% to about 75% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor; and wherein the reference dose of elinzanetant is a daily dose of about 100 mg to about 160 mg. In embodiments, the reference dose of elinzanetant is a daily dose of about 120 mg. In embodiments, the method comprises administering 50% of the reference dose of elinzanetant. In embodiments, about 30 mg of elinzanetant is administered once a day. In embodiments, about 60 mg of elinzanetant is administered once a day. In embodiments, about 90 mg of elinzanetant is administered once a day.
In embodiments, the method further comprises treating sleep disturbances associated with menopause. In embodiments, elinzanetant is administered once a day. In embodiments, elinzanetant is administered at bedtime (h.s.). In embodiments, the female subject has moderate to severe vasomotor symptoms prior to administering elinzanetant. In embodiments, the female subject is an adult. In embodiments, the female subject is 40-65 years old. In embodiments, the female subject is menopausal. In embodiments, the female subject is post-menopausal. In embodiments, prior to administering elinzanetant, the female subject experienced: (i) at least 12 months of spontaneous amenorrhea; (ii) at least 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels>40 mIU/mL and a serum estradiol concentration of <30 pg/mL; (iii) hysterectomy with serum FSH levels>40 mIU/mL and a serum estradiol concentration of <30 pg/mL; or (iv) surgical bilateral oophorectomy with or without hysterectomy. In embodiments, the vasomotor symptoms are caused by adjuvant endocrine therapy. In embodiments, the vasomotor symptoms are associated with menopause. In embodiments, the moderate CYP3A4 inhibitor comprises amiodarone, aprepitant, ciprofloxacin, clarithromycin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, grapefruit juice, imatinib, isavuconazole, or verapamil. In embodiments, the moderate CYP3A4 inhibitor is selected from the group consisting of amiodarone, aprepitant, ciprofloxacin, clarithromycin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, grapefruit juice, imatinib, isavuconazole, and verapamil.
In embodiments, the method comprises reducing the frequency of the vasomotor symptoms compared to baseline. In embodiments, the method comprises reducing the severity of the vasomotor symptoms compared to baseline. In embodiments, the method comprises reducing the frequency of moderate to severe hot flash (HF) from baseline. In embodiments, the method comprises improving the symptoms determined by a decrease in patient-reported outcomes measurement information system sleep disturbance short form 8b (PROMIS SD SF 8b) total T-score from baseline. In embodiments, the method comprises improving the symptoms determined by a decrease in menopause specific quality of life scale (MENQOL) total score from baseline. In embodiments, the method comprises improving the symptoms determined by a decrease in Beck depression inventory (BDI-II) total score from baseline.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms and/or sleep disturbances in a female subject in need thereof, comprising administering about 25 mg to about 100 mg of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms and/or sleep disturbances in a female subject in need thereof, comprising administering about 25% to about 75% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor; and wherein the reference dose of elinzanetant is about 100 mg to about 160 mg.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms with elinzanetant in a female subject in need thereof, comprising recommending to avoid using a strong CYP3A4 inhibitor with elinzanetant. In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject in need thereof with elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein concomitant use of the strong CYP3A4 inhibitor with elinzanetant is not recommended. In embodiments, the concomitant use of elinzanetant and the strong CYP3A4 inhibitor is contraindicated. In further embodiments, the female subject discontinues the strong CYP3A4 inhibitor treatment, and then administers a reference dose of elinzanetant. In embodiments, the female subject discontinues elinzanetant treatment, and then administers the strong CYP3A4 inhibitor.



BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 illustrates the geometric mean ratio (90% CI) of steady state AUC and Ctrough following concomitant administration of 60 mg elinzanetant with a moderate CYP3A4 inhibitor, erythromycin, compared to 120 mg elinzanetant alone, as described in Example 2.
FIG. 2 illustrates the geometric mean ratio (90% CI) of steady state Cmax following concomitant administration of 60 mg elinzanetant with a moderate CYP3A4 inhibitor, erythromycin, compared to 120 mg elinzanetant alone, as described in Example 2.
FIG. 3 illustrates the geometric mean ratios (90% CI) of simulated steady state AUC, Cmax, and Ctrough following concomitant administration of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg of elinzanetant with a moderate CYP3A4 inhibitor, erythromycin, compared to 120 mg elinzanetant administration alone, as described in Example 2.
FIG. 4 illustrates the changes in the predicted median plasma concentration (μg/L) of elinzanetant over time (days) following 60 mg elinzanetant alone, 120 mg elinzanetant alone, and 60 mg elinzanetant in the presence of erythromycin, as described in Example 2.



DETAILED DESCRIPTION
All publications, patents and patent applications, including any drawings and appendices therein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application, drawing, or appendix was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.
Definitions
While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.
As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.
Elinzanetant is also known as 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl) hexahydropyrazino[2,1c]oxazin-8 (1H)-yl]pyridin-3-yl}-N,2-dimethylpropanamide, and has the structure below.




All references to elinzanetant described herein also encompass all of its pharmaceutically acceptable solvates, hydrates, polymorphs, stereoisomers, salts, and prodrugs (e.g., esters and phosphates).
As used herein, the term “about” refers to an acceptable amount of variability in the art. For example, “about” may encompass plus or minus five or ten percent of the object that “about” modifies. The term “about” also includes the value referenced. For example, a dose of about 1 mg includes 1 mg, as well as values somewhat below or above 1, such as 0.9 mg and 1.1 mg. As used herein, “and/or” refers to and encompasses any and all possible combinations of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).
As used herein, the terms “treating,” “treatment” and “treat” refer to safely and effectively reducing (to a clinically relevant extent) or eliminating vasomotor symptoms or sleep disturbances. In the context of the present disclosure, the disclosed dosing regimens do not present an unacceptable risk of serious side effects that would otherwise occur when a female subject receiving treatment with a moderate CYP3A4 inhibitor is also treated with the reference dose of elinzanetant.
“Concomitant treatment” as used herein refers to a situation in which a female subject is treated with a CYP3A4 inhibitor and elinzanetant within a 24 hour period. Thus, “concomitant” encompasses situations in which the CYP3A4 inhibitor and elinzanetant are administered at the same time, sequentially, or within 12 hours of each other. As used herein, “concomitant” is synonymous with “concurrent” and “coadminister”, and variants thereof, and may be used herein interchangeably.
“Vasomotor symptoms” are also known as “hot flashes” or “hot flushes”. The vasomotor symptoms are also referred to as “night sweats” when occurring at night or during sleep. The term “vasomotor symptoms” as used herein includes mild, moderate and severe vasomotor symptoms.
“Sleep disturbances” include night-time awakenings, Wake After Sleep Onset (WASO), difficulty falling asleep, and difficulty staying asleep.
In embodiments, the patient is administered elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, at a dose that would provide a favorable risk/benefit profile. The risk/benefit profile weighs the patient's risk(s) of potential adverse event(s) if treated compared to the benefit(s) of treatment. Non-limiting examples of factors used to assess the risk/benefit profile include: (i) the type of benefit(s) the patient would receive (e.g., treatment end points and the value of treatment to the patient); (ii) magnitude of the benefit(s); (iii) probability of the patient experiencing one or more benefit(s); (iv) duration of effect(s) and whether the duration is a benefit; (v) severity, types, number, and rates of harmful events (e.g., serious vs. non-serious adverse events); (vi) probability of a harmful event (e.g., the percentage of the patient population that would be expected to experience a harmful event; the incidence of each harmful event in the study population; degree of uncertainty in determination probability; patient's willingness to accept the probable risk of the harmful event, given the probable benefit); (vii) duration of harmful events (e.g., how long does the harmful event last and is it reversible; types of intervention required to address the harmful event); and/or (viii) medical necessity (e.g., does the elinzanetant provide a benefit or address a need unmet by other therapies). In the context of a potential drug-drug interaction between a CYP3A4 inhibitor and elinzanetant, appropriate dosing of elinzanetant in the presence of a CYP3A4 inhibitor requires balancing the various risk and benefit factors (e.g., as described above). In embodiments, the female subject is administered a reduced dose if the benefit(s) outweigh the risk(s).
As used herein, the terms “patient” and “subject” are synonymous and used interchangeably.
As used herein, a “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In embodiments, organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(C1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salt.
As used herein, “equivalent dose” refers to an amount of a pharmaceutically acceptable salt or deuterated form of elinzanetant that contains the same number of moles of free base elinzanetant.
As used herein, a “reference dose” refers to the dosage of elinzanetant used to treat an identical subject who is not undergoing concomitant treatment with a CYP3A4 inhibitor, such as with a strong or moderate CYP3A4 inhibitor.
As used herein, a “strong CYP3A4 inhibitor” or a “moderate CYP3A4 inhibitor” refers to a drug deemed so by the FDA. For example, a strong CYP3A4 inhibitor may include a drug that causes at least about a 5-fold increase in the AUC of a sensitive CYP3A4 substrate drug, or more than about an 80% decrease in the clearance of a sensitive CYP3A4 substrate drug. A moderate CYP3A4 inhibitor may include a drug that increase the AUC of sensitive index substrates of CYP3A4 greater than or equal to 2-fold to less than 5-fold.
Methods of the Present Disclosure
The present disclosure provides a method of treating vasomotor symptoms and/or sleep disturbances in female subjects comprising administering elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, in a female subject who is undergoing concomitant treatment with a CYP3A4 inhibitor. In embodiments, vasomotor symptoms are vasomotor symptoms associated with menopause. In embodiments, vasomotor symptoms are vasomotor symptoms caused or induced by adjuvant endocrine therapy, such as adjuvant endocrine therapy in breast cancer patients.
Elinzanetant is a nonhormonal therapy currently in clinical development and pre-registration with the FDA for the treatment of mild to severe vasomotor symptoms associated with menopause. Elinzanetant functions as a dual NK-1/NK-3 antagonist, specifically targeting both receptors. Once administered, elinzanetant is primarily metabolized by the CYP3A4 enzyme, which plays a key role in oxidizing small organic molecules, including drugs and toxins, to facilitate their degradation. Drugs that are primarily metabolized by the CYP3A4 enzyme are classified as “CYP3A4 substrate drugs”.
CYP3A4 inhibitors block the enzyme responsible for metabolizing the substrate drug (here, elinzanetant). As a result, the blood levels of elinzanetant may rise significantly, increasing the risk of serious adverse effects due to drug toxicity. Prior to the present disclosure, the co-administration of elinzanetant with CYP3A4 enzyme inhibitors has not been studied and therefore it was unknown how to safely and effectively co-administer elinzanetant with CYP3A4 inhibitors, such as strong inhibitors and moderate inhibitors. No established guidelines for patients who require both elinzanetant and CYP3A4 inhibitor treatment is available in the art. There is a need in the art to predict, manage, and to provide dosage adjustment to ensure safe use of elinzanetant in this patient population.
Applicant conducted the first drug-drug interaction studies with elinzanetant and strong and moderate CYP3A4 inhibitors. The effect of a strong or moderate CYP3A4 inhibitor on a CYP3A4 substrate, like elinzanetant, is unpredictable and must be determined empirically. As discussed herein, based on applicant's studies, it was determined that strong CYP3A4 inhibitors significantly increased blood plasma concentrations of elinzanetant (following administration of 120 mg) and presented an unacceptable risk of serious side effects to female subjects.
Applicant also discovered that moderate CYP3A4 inhibitors significantly increased blood plasma concentrations of elinzanetant (following administration of 120 mg) and presented an unacceptable risk of serious side effects to subjects. However, Applicant surprisingly discovered that elinzanetant can be safely co-administered with a moderate CYP3A4 inhibitor through a specific dose adjustment described in the present disclosure, balancing the various risk and benefit factors. Specifically, Applicant unexpectedly discovered that the treatment methods described herein achieve elinzanetant blood plasma concentration levels below toxic levels while still providing therapeutic efficacy in treating vasomotor symptoms.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject in need thereof, comprising administering elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor. In embodiments, the present disclosure provides a method of treating vasomotor symptoms and/or sleep disturbances in a female subject in need thereof, comprising administering elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor. In embodiments, the method comprises treating sleep disturbances that are associated with menopause. In embodiments, the sleep disturbances are caused by having vasomotor symptoms.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject comprising administering about 20 mg to about 100 mg of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor. In embodiments, elinzanetant is administered at a dose of about 20 mg to about 100 mg, about 25 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 50 mg to about 100 mg, about 30 mg to about 90 mg, about 40 mg to about 90 mg, about 50 mg to about 90 mg, about 50 mg to about 70 mg, about 55 mg to about 65 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, or any values or ranges therebetween. In embodiments, elinzanetant is administered to the female subject at a dose of about 60 mg.
In embodiments, about 30 mg of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof is administered. In embodiments, about 60 mg of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof is administered. In embodiments, about 90 mg of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof is administered.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject comprising administering about 20% to about 80% (e.g., about 25% to about 75%, about 30% to about 80%, about 35% to about 65%, about 40% to about 60%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or any values or ranges therebetween) of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor. In embodiments, the reference dose of elinzanetant is between 100 mg and 160 mg, between 100 mg and 140 mg, between 100 mg and 130 mg, such as about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, or 160 mg. In some embodiments the reference dose of elinzanetant is 100 mg, 110 mg, or 120 mg. In some embodiments the reference dose of elinzanetant is 120 mg.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject comprising administering about 25% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor, and wherein the reference dose of elinzanetant is about 100 mg. In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject comprising administering about 25% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor, and wherein the reference dose of elinzanetant is about 110 mg. In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject comprising administering about 25% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor, and wherein the reference dose of elinzanetant is about 120 mg.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject comprising administering about 50% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor, and wherein the reference dose of elinzanetant is about 120 mg. In embodiments, the present disclosure provides a method of treating vasomotor symptoms in a female subject comprising administering about 75% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor, and wherein the reference dose of elinzanetant is about 120 mg.
In embodiments, 50% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is concurrently administered with a moderate CYP3A4 inhibitor, and wherein the reference dose of elinzanetant is about 100 mg. In embodiments, 50% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is concurrently administered with a moderate CYP3A4 inhibitor, and wherein the reference dose of elinzanetant is about 110 mg. In embodiments, 50% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is concurrently administered with a moderate CYP3A4 inhibitor, and wherein the reference dose of elinzanetant is about 120 mg.
In embodiments, elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is administered once daily. In embodiments, elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is administered at bedtime (h.s.). In embodiments, elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is administered in the evening. In embodiments, elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is administered once daily at bedtime (h.s.) or in the evening.
In embodiments, about 25 mg to about 100 mg elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is administered once a day (i.e., a total daily dose of about 25 mg to about 100 mg). In embodiments, about 60 mg elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is orally administered once a day (i.e., a total daily dose of about 60 mg).
In embodiments, elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is administered for at least about 14 days, e.g., 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks, or 6 weeks, or 7 weeks, or 8 weeks, or 9 weeks, or 10 weeks, or 11 weeks, or 12 weeks, or 13 weeks, or 14 weeks, or 15 weeks, or 16 weeks, or 17 weeks, or 18 weeks, or 19 weeks, or 20 weeks, or 21 weeks, or 22 weeks, or 23 weeks, or 24 weeks, 48 weeks, 2 years, 4 years, or more.
In embodiments, the CYP3A4 inhibitor is a moderate CYP3A4 inhibitor. In embodiments, the moderate CYP3A4 inhibitor is amiodarone, aprepitant, avacopan, berotralstat, ciprofloxacin, cimetidine, clarithromycin, conivaptan, crizotinib, cyclosporine, diltiazem, duvelisib, dronedarone, erythromycin, fedratinib, fluconazole, fosamprenavir, fosaprepitant, fosnetupitant-palonosetron, grapefruit juice, imatinib, isavuconazole, lefamulin, letermovir, netupitant, nilotinib, ribociclib, schisandra, or verapamil.
In embodiments, the moderate CYP3A4 inhibitor is co-administered with elinzanetant at a dosage or dosing regimen specified in the FDA-approved drug label, published as of the filing date of the present disclosure, for that CYP3A4 inhibitor.
In embodiments, the moderate CYP3A4 inhibitor is amiodarone. In embodiments, amiodarone is co-administered for treating recurrent ventricular fibrillation and recurrent hemodynamically unstable ventricular tachycardia. In embodiments, amiodaron is co-administered at a loading dosage of 800-1600 mg/day until initial therapeutic response occurs (e.g., 1 to 3 weeks). In embodiments, amiodarone is co-administered, once adequate arrhythmia control is achieved or if side effects become prominent, at a reduced dosage of 600-800 mg/day for one month then to the maintenance dosage of 400 mg/day.
In embodiments, the moderate CYP3A4 inhibitor is aprepitant. In embodiments, aprepitant is co-administered for preventing chemotherapy induced nausea and vomiting. In embodiments, aprepitant is co-administered at a dosage of 125 mg orally 1 hour prior to chemotherapy treatment. In embodiments, aprepitant is co-administered at a dosage of 80 mg orally once daily. In embodiments, aprepitant is co-administered for preventing postoperative nausea and vomiting. In embodiments, aprepitant is co-administered at 40 mg within 3 hours prior to induction of anesthesia.
In embodiments, the moderate CYP3A4 inhibitor is ciprofloxacin. In embodiments, ciprofloxacin is co-administered for treating infections. In embodiments, ciprofloxacin is co-administered at a dosage shown in the Table below.










DOSAGE AND ADMINISTRATION


Adult Dosage Guidelines










Infection
Dose
Frequency
Duration





Skin and Skin Structure 
500-750 mg
every 12 hours
7 to 14 days


Bone and Joint
500-750 mg
every 12 hours
4 to 8 weeks


Complicated Intra-
500 mg
every 12 hours
7 to 14 days


Abdominal





Infectious Diarrhea
500 mg
every 12 hours
5 to 7 days


Typhoid Fever
500 mg
every 12 hours
10 days


Uncomplicated Gonorrhea
250 mg
single dose
single dose


Inhalational anthrax 
500 mg
every 12 hours
60 days


(post-exposure)





Plague
500-750 mg
every 12 hours
14 days


Chronic Bacterial Prostatitis
500 mg
every 12 hours
28 days


Lower Respiratory Tract
500-750 mg
every 12 hours
7 to 14 days


Urinary Tract
250-500 mg
every 12 hours
7 to 14 days


Acute Uncomplicated
250 mg
every 12 hours
 3 days


Cystitis





Acute Sinusitis
500 mg
every 12 hours
10 days









In embodiments, the moderate CYP3A4 inhibitor is clarithromycin. In embodiments, clarithromycinis co-administered for treating mild to moderate infections caused by designated, susceptible bacteria. In embodiments, clarithromycin is co-administered at a dosage of 250 mg or 500 mg every 12 hours or 1 g every 24 hours.
In embodiments, the moderate CYP3A4 inhibitor is conivaptan. In embodiments, conivaptan is co-administered for raising serum sodium in hospitalized female subjects with euvolemic and hypervolemic hyponatremia. In embodiments, conivaptan is co-administered at a dosage of 20 mg once a day.
In embodiments, the moderate CYP3A4 inhibitor is cyclosporine. In embodiments, cyclosporine is co-administered for increasing tear production in female subjects with keratoconjunctivitis sicca (dry eye). In embodiments, cyclosporine is co-administered one drop (0.9 mg/mL solution) twice daily.
In embodiments, the moderate CYP3A4 inhibitor is diltiazem. In embodiments, diltiazem is co-administered for managing chronic stable angina and angina due to coronary artery spasm. In embodiments, diltiazem is co-administered 30 mg four times a day at bedtime (h.s.), or 180 mg to 360 mg per day.
In embodiments, the moderate CYP3A4 inhibitor is dronedarone. In embodiments, dronedarone is co-administered for reducing the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF. In embodiments, dronedarone is co-administered at a dosage of 400 mg twice a day.
In embodiments, the moderate CYP3A4 inhibitor is erythromycin. In embodiments, erythromycin is co-administered for treating bacterial infection. In embodiments, erythromycin is co-administered at a dosage of 400 mg every 6 hours or 4 g per day.
In embodiments, the moderate CYP3A4 inhibitor is fluconazole. In embodiments, fluconazole is co-administered for treating vaginal candidiasis, oropharyngeal and esophageal candidiasis, and cryptococcal meningitis. In embodiments, fluconazole is co-administered at a dosage of 150 mg or 200 mg as a single oral dose, or 50-400 mg once daily.
In embodiments, the moderate CYP3A4 inhibitor is imatinib. In embodiments, imatinib is co-administered for treating chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. In embodiments, imatinib is co-administered at dosage of 600 mg/day, 600-800 mg per day, or 400 mg twice a day.
In embodiments, the moderate CYP3A4 inhibitor is isavuconazole. In embodiments, isavuconazole is co-administered for treating invasive aspergillosis and invasive mucormycosis. In embodiments, isavuconazole is co-administered at a dosage of 372 mg every 8 hours for 6 doses or 372 mg once daily.
In embodiments, the moderate CYP3A4 inhibitor is verapamil. In embodiments, verapamil is co-administered for treating supraventricular tachyarrhythmias. In embodiments, verapamil is co-administered intravenously at a dosage of 5-10 mg. In embodiments, verapamil is orally co-administered at a dose of 120 mg a day. In embodiments, verapamil is orally co-administered at a dose of 120 mg, 180 mg, 240 mg, 360 mg, or 480 mg once daily.
In embodiments, the moderate CYP3A4 inhibitor is grapefruit juice.
In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In embodiments, the strong CYP3A4 inhibitor is adagrasib, atazanavir, ceritinib, clarithromycin, cobicistat, darunavir, elvitegravir and ritonavir, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, levoketoconazole, lopinavir, lopinavir and ritonavir, mifepristone, nefazodone, nelfinavir, nirmatrelvir-ritonavir, ombitasvir-paritaprevir-ritonavir, ombitasvir-paritaprevir-ritonavir plus dasabuvir, paritaprevir and ritonavir, posaconazole, ritonavir, ritonavir and ritonavir-containing coformulations, saquinavir, saquinavir and ritonavir, tucatinib, telithromycin, tipranavir and ritonavir, or voriconazole.
In embodiments, the present disclosure provides a method of treating vasomotor symptoms and/or sleep disturbances in a female subject in need thereof with elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof wherein the concomitant use of a strong CYP3A4 inhibitor with elinzanetant is not recommended. In embodiments, co-administration of the strong CYP3A4 inhibitor with elinzanetant is contraindicated. In embodiments, the female subject is currently treated with a strong CYP3A4 inhibitor and in need of treatment with elinzanetant, and the method comprises discontinuing the strong CYP3A4 inhibitor treatment, and then administering a reference dose of elinzanetant. In embodiments, the female subject is currently treated with elinzanetant and in need of treatment with a strong CYP3A4 inhibitor, the method comprising, discontinuing elinzanetant treatment, and then administering the strong CYP3A4 inhibitor treatment.
Patient Population
In embodiments, the present disclosure provides a method of treating vasomotor symptoms (VMS) in a female subject comprising administering elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor. In embodiments, the present disclosure provides a method of treating VMS in a female subject comprising administering elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is not undergoing concomitant treatment with a strong CYP3A4 inhibitor. In embodiments, the female subject has moderate to severe VMS. In embodiments, the female subject has moderate to severe VMS associated with menopause. In embodiments, the female subject has moderate to severe VMS caused/induced by adjuvant endocrine therapy. In embodiments, the severity of VMS is assessed according to the VMS assessment scale shown in Table 1. In embodiments, the female subject had a VMS score of 3 prior to administration. In embodiments, the female subject had a VMS score of 2 prior to administration.







TABLE 1





Criteria for assessing VMS score

















0
None
No symptoms


1
Mild
Sensation of heat without sweating


2
Moderate
Sensation of heat with sweating but able to continue 




activity


3
Severe
Sensation of heat with sweating, causing cessation of 




activity









In embodiments, the female subject had at least 50 moderate to severe hot flashes (HFs, also known as “hot flushes”), including night-time HFs, per week, prior to treatment according to the present disclosure.
In embodiments, the female subject is an adult. In embodiments, the female subject is 40-65 years old, for example, 40-62 years old, 40-60 years old, 40-58 years old, 40-56 years old, 40-54 years old, 40-52 years old, 40-50 years old, or any values or ranges therebetween. In embodiments, the female subject is menopausal. In embodiments, the female subject is post-menopausal.
In embodiments, prior to administering elinzanetant, the female subject experienced one or more of:

    
    
        (i) at least 12 months (for example, at least 14 months, 18 months, 20 months, 22 months, 24 months, or any values or ranges therebetween) of spontaneous amenorrhea;
        (ii) at least 6 months (for example, at least 8 months, 10 months, 12 months, 14 months, 18 months, 20 months, 22 months, 24 months, or any values or ranges therebetween) of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels>40 mIU/mL and a serum estradiol concentration of <30 pg/mL;
        (iii) hysterectomy with serum FSH levels>40 mIU/mL and a serum estradiol concentration of <30 pg/mL, or
        (iv) surgical bilateral oophorectomy with or without hysterectomy.
    
    


In embodiments, prior to administering elinzanetant, the female subject experienced one or more of: (i) at least 12 months of spontaneous amenorrhea; (ii) at least 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels>40 mIU/mL and a serum estradiol concentration of <30 pg/mL; (iii) hysterectomy with serum FSH levels>40 mIU/mL and a serum estradiol concentration of <30 pg/mL, or (iv) surgical bilateral oophorectomy with or without hysterectomy.
In embodiments, the VMS is associated with menopause. In embodiments, the female subject has a moderate to severe hot flash (HF) associated with the menopause prior to the treatment. In embodiments, the female subject received an adjuvant endocrine therapy prior to the treatment. In embodiments, the VMS is induced by a prior adjuvant endocrine therapy. In embodiments, the female subject has sleep disturbance associated with menopause prior to the treatment. In embodiments, the female subject has hormone-receptor (HR) positive breast cancer. In embodiments, the female subject is treated with an adjuvant endocrine therapy. In embodiments, the female subject is treated with tamoxifen. In embodiments, the VMS is associated, induced or caused by anti-cancer therapy.
In embodiments, the present disclosure provides a method of treating sleep disturbances in female subjects comprising administering elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor. In embodiments, sleep disturbances are associated with menopause. In embodiments, sleep disturbances are caused or induced by adjuvant endocrine therapy, such as adjuvant endocrine therapy in breast cancer patients. In embodiments, the breast cancer is HR-positive breast cancer. In embodiments, the female subject experienced 30 minutes or more wakefulness time after initially falling asleep prior to treatment. In embodiments, the present disclosure provides a method of decreasing wakefulness after sleep or increasing sleep efficiency in female subjects comprising administering elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor.
Pharmaceutical Compositions and Formulations
In embodiments, elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is present in a pharmaceutical composition. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, and a pharmaceutically acceptable carrier or excipient. In embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration.
In embodiments, elinzanetant or the pharmaceutical compositions of the present disclosure are administered by oral administration in the form of tablets, capsules, syrups, powders or granules. In embodiments, elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, is orally administered in a pharmaceutical formulation. In embodiments, the pharmaceutical composition may be a solid, powder, liquid, or gel. In embodiments, the pharmaceutical is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates). In certain of such embodiments, the solid pharmaceutical composition comprises one or more excipients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents. In embodiments, the pharmaceutical formulation is a tablet or a capsule. In embodiments, the pharmaceutical formulation is a capsule. In embodiments, the capsule comprises edible ink, ferric oxide red, ferric oxide yellow, gelatin, sorbitol special-glycerin, and/or titanium dioxide.
For oral administration, elinzanetant, or pharmaceutically acceptable salt, deuterated form or stereoisomer thereof, may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatin or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
In embodiments, the pharmaceutical formulation comprises about 1 mg to about 100 mg of elinzanetant, or an equivalent dose of a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical formulation is a capsule comprising 30 mg or 60 mg of elinzanetant, or an equivalent dose of a pharmaceutically acceptable salt thereof.
In embodiments, the pharmaceutical formulation comprises 60 mg of elinzanetant free base, all-rac-α-Tocopherol, caprylocaproyl macrogolglycerides, glycerol monocaprylocaprate, glycerol mono-oleate, and/or polysorbate 80.
Clinical Outcomes
In embodiments, the methods of the present disclosure reduce the frequency or severity of vasomotor symptoms compared to baseline. In embodiments, the vasomotor symptoms comprise hot flashes. In embodiments, the vasomotor symptoms comprise sleep disturbances.
In embodiments, the methods of the present disclosure comprising reducing the frequency of the vasomotor symptoms compared to baseline (i.e., prior to administration). In embodiments, the treatment comprises reducing the mean frequency of the vasomotor symptoms compared to baseline. In embodiments, the treatment comprises reducing the mean frequency of the vasomotor symptoms from baseline to Week 1, Week 4, Week 12, Week 24, or Week 26 of treatment. In embodiments, the treatment comprises reducing the frequency of the vasomotor symptoms by about 10% to about 100%, about 10% to about 95%, about 15% to about 95%, about 20% to about 95%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 95%, about 40% to about 95%, or about 50% to about 95% %, including any values or ranges therebetween, compared to the frequency prior to administration. In embodiments, the treatment comprises reducing the frequency of the vasomotor symptoms by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100%, including any values or ranges therebetween, compared to the frequency prior to administration. In embodiments, the treatment comprises reducing the mean frequency of the vasomotor symptoms by about at least 30%, about 30-40%, or about 33-38% over 24 hours, following one week of treatment compared to baseline. In embodiments, the treatment comprises reducing the mean frequency of the vasomotor symptoms by about at least 50%, about 50-70%, about 50-60%, about 55-65%, or about 59% over 24 hours, following 4 weeks of treatment compared to baseline. In embodiments, the treatment comprises reducing the mean frequency of the vasomotor symptoms by about at least 60%, about 60-70%, or about 66% over 24 hours, following 12 weeks of treatment compared to baseline.
In embodiments, the methods of the present disclosure comprising reducing the severity of the vasomotor symptoms compared to baseline (i.e., prior to administration). In embodiments, the treatment comprises reducing the mean severity of the vasomotor symptoms compared to baseline. In embodiments, the treatment comprises reducing the mean severity of the vasomotor symptoms from baseline to Week 1, Week 4, Week 12, Week 24, or Week 26 of treatment. In embodiments, the treatment comprises reducing the severity of the vasomotor symptoms by about 10% to about 100%, about 10% to about 95%, about 15% to about 95%, about 20% to about 95%, about 30% to about 95%, about 40% to about 95%, about 50% to about 95%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 80%, about 30% to about 70%, or about 30% to about 60%, including any values or ranges therebetween, compared to the severity prior to administration. In embodiments, the treatment comprises reducing the severity of the vasomotor symptoms by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100%, including any values or ranges therebetween, compared to the severity prior to administration. In embodiments, the method comprises reducing the mean severity of moderate to severe vasomotor symptoms by about at least 20%, about 20% to 40%, about 20% to 30%, about 25% to 35%, or about 29% over 24 hours, following one week treatment compared to baseline. In embodiments, the treatment comprises reducing the mean severity of moderate to severe vasomotor symptoms by about at least 30%, about 30-40%, or about 36% over 24 hours, following 12 weeks of treatment compared to baseline.
In embodiments, the methods of the present disclosure comprise reducing the frequency of moderate to severe vasomotor symptoms compared to baseline (i.e., prior to administration). In embodiments, the methods of the present disclosure reduce the mean frequency of moderate to severe vasomotor symptoms compared to baseline. In embodiments, the treatment comprises reducing the mean frequency of moderate to severe vasomotor symptoms from baseline to Week 1, Week 4, Week 12, Week 24, or Week 26 of treatment. In embodiments, at Week 12, the treatment comprises reducing about 2-12 moderate to severe vasomotor symptoms per day compared to baseline, for example, about 2-11 HF per day, about 2-10 HF per day, about 2-9 HF per day, 2-8 HF per day, 2-7 HF per day, 2-6 HF per day, 2-5 HF per day, 2-4 HF per day, 2-3 HF per day, about 3-12 HF per day, 3-11 HF per day, about 3-10 HF per day, about 3-9 HF per day, 3-8 HF per day, 3-7 HF per day, 3-6 HF per day, 3-5 HF per day, 3-4 HF per day, about 4-12 HF per day, 4-11 HF per day, about 4-10 HF per day, about 4-9 HF per day, 4-8 HF per day, 4-7 HF per day, 4-6 HF per day, 4-5 HF per day, about 5-12 HF per day, 5-11 HF per day, about 5-10 HF per day, about 5-9 HF per day, 5-8 HF per day, 5-7 HF per day, 5-6 HF per day, about 6-12 HF per day, 6-11 HF per day, about 6-10 HF per day, about 6-9 HF per day, 6-8 HF per day, 6-7 HF per day, about 7-12 HF per day, 7-11 HF per day, about 7-10 HF per day, about 7-9 HF per day, 7-8 HF per day, about 8-12 HF per day, or 9-11 HF per day, including any values or ranges therebetween. In embodiments, the treatment comprises reducing about 6-12 moderate to severe vasomotor symptoms per day compared to baseline. In embodiments, the treatment comprises reducing about 7-12 moderate to severe vasomotor symptoms per day compared to baseline. In embodiments, the treatment comprises reducing the frequency of moderate to severe vasomotor symptoms by about 10% to about 100%, about 10% to about 95%, about 15% to about 95%, about 20% to about 95%, about 30% to about 95%, about 40% to about 95%, about 50% to about 95%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 80%, about 30% to about 70%, or about 30% to about 60%, including any values or ranges therebetween, compared to the frequency prior to administration. In embodiments, the treatment comprises reducing the frequency of moderate to severe vasomotor symptoms by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100%, including any values or ranges therebetween, compared to the frequency prior to administration. In embodiments, the treatment comprises reducing the mean frequency of moderate to severe vasomotor symptoms by about at least 30%, about 30-50%, about 30-40%, about 35-45%, or about 38% over 24 hours, following one week of treatment compared to baseline. In embodiments, the treatment comprises reducing the mean frequency of moderate to severe vasomotor symptoms by about at least 50%, about 50-70%, about 50-60%, about 55-65%, or about 57% over 24 hours, following 4 weeks of treatment compared to baseline. In embodiments, the treatment comprises reducing the mean frequency of moderate to severe vasomotor symptoms by about at least 60%, about 60-70%, or about 64% over 24 hours, following 12 weeks of compared to baseline.
In embodiments, the methods of the present disclosure comprise decreasing the patient-reported outcomes measurement information system sleep disturbance short form 8b (PROMIS SD SF 8b) total T-score (total 40 scores, with higher scores indicating greater severity of sleep disturbance) from baseline (i.e., prior to administration). In embodiments, the present disclosure provides a method of improving sleep quality, sleep depth and restoration associated with sleep, perceived difficulties with getting to sleep or staying asleep, perceptions of the adequacy of, and satisfaction with sleep. In embodiments, the treatment comprises decreasing the mean PROMIS SD SF 8b total T-score from baseline to Week 1, Week 4, Week 12, Week 24, or Week 26 of treatment. In embodiments, the method comprises decreasing the PROMIS SD SF 8b total T-score by about 10% to about 100%, about 10% to about 95%, about 15% to about 95%, about 20% to about 95%, about 30% to about 95%, about 40% to about 95%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 50% to about 95%, including any values or ranges therebetween, compared to prior to administration. In embodiments, the method comprises decreasing the PROMIS SD SF 8b total T-score by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100%, including any values or ranges therebetween, compared to prior to administration. In embodiments, the treatment comprises decreasing the PROMIS SD SF 8b total T-score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 points, including all ranges therein. In embodiments, the treatment comprises decreasing the PROMIS SD SF 8b total T-score by about 1 to 40 points, about 1 to 35 points, about 1 to 30 points, about 1 to 25 points, about 1 to 20 points, about 1 to 15 points, about 1 to 10 points, about 1 to 8 points, about 1 to 6 points, about 2 to 8 points, about 2 to 6 points, about 3 to 8 points, including any values or ranges therebetween. In embodiments, the treatment comprises decreasing the PROMIS SD SF 8b total T-score by about 3 to about 7 points, following 12 weeks of treatment compared to baseline.
In embodiments, the methods of the present disclosure comprise decreasing a menopause specific quality of life scale (MENQOL) total score (total score ranging 1-8) from baseline (i.e., prior to administration). In embodiments, the treatment comprises decreasing the mean MENQOL score from baseline to Week 1, Week 4, Week 12, Week 24, or Week 26 of treatment. In embodiments, the treatment comprises decreasing the MENQOL total score by about 10% to about 95%, about 15% to about 95%, about 20% to about 95%, about 30% to about 95%, about 40% to about 95%, about 50% to about 95%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 80%, about 30% to about 70%, or about 30% to about 60%, including any values or ranges therebetween, compared to prior to administration. In embodiments, the treatment comprises decreasing the MENQOL total score by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100%, including any values or ranges therebetween, compared to prior to administration. In embodiments, the method comprises decreasing the MENQOL total score by about 0.5, 1, 2, 3, 4, 5, 6, 7, or 8 points, including any values or ranges therebetween. In embodiments, the method comprises decreasing the MENQOL total score by about 0.2 to about 0.6 points, following 12 weeks of treatment compared to baseline.
In embodiments, the methods of the present disclosure comprise decreasing the Beck depression inventory (BDI-II, total score ranging from 0 to 63) total score from baseline (i.e., prior to administration). In embodiments, the treatment comprises decreasing the mean BDI-II score from baseline to Week 1, Week 4, Week 12, Week 24, or Week 26 of treatment. In embodiments, the treatment comprises decreasing the BDI-II total score by about 10% to about 95%, about 15% to about 95%, about 20% to about 95%, about 30% to about 95%, about 40% to about 95%, about 50% to about 95%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, including any values or ranges therebetween, compared to prior to administration. In embodiments, the treatment comprises decreasing the BDI-II total score by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100%, including any values or ranges therebetween, compared to prior to administration. In embodiments, the method comprises decreasing the BDI-II total score by about 1 to 63 points, about 1 to 60 points, about 1 to 55 points, about 1 to 50 points, about 1 to 45 points, about 1 to 40 points, about 1 to 35 points, about 1 to 30 points, about 1 to 25 points, about 1 to 20 points, about 1 to 15 points, about 1 to 10 points, about 2 to 10 points, about 3 to 10 points, about 4 to 10 points, about 5 to 10 points, about 2 to 20 points, about 3 to 20 points, about 4 to 20 points, about 5 to 20 points. In embodiments, the method comprises decreasing the BDI-II total score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63 points, including any ranges therebetween.
In embodiments, the methods of the present disclosure comprise decreasing the total number of minutes that a female subject is awake after having initially fallen asleep (Wakefulness After Sleep Onset, WASO), determined by polysomnography (PSG) by about 10% to about 95%, about 15% to about 90%, about 20% to about 85%, about 30% to about 80%, about 40% to about 75%, about 50% to about 70%, about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 30% to about 75%, or about 40% to about 70%, including any values or ranges therebetween, compared to prior to administration, following 4 weeks or 12 weeks of treatment. In embodiments, the methods of the present disclosure comprise decreasing the total number of minutes that a female subject is awake after having initially fallen asleep WASO, determined by PSG by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100%, including any values or ranges therebetween, compared to prior to administration, following 4 weeks or 12 weeks of treatment.
In embodiments, the methods of the present disclosure comprise increasing sleep efficiency determined by ratio between the total time a female subject is asleep (TST) to the total time spent in bed by about 10% to about 95%, about 15% to about 90%, about 20% to about 85%, about 30% to about 80%, about 40% to about 75%, about 50% to about 70%, about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 30% to about 75%, or about 40% to about 70%, including any values or ranges therebetween, compared to prior to administration, following 4 weeks or 12 weeks of treatment. In embodiments, the methods of the present disclosure comprise increasing sleep efficiency determined by ratio between the total time a female subject is asleep (TST) to the total time spent in bed by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100%, including any values or ranges therebetween, compared to prior to administration, following 4 weeks or 12 weeks of treatment.
In embodiments, the methods of the present disclosure comprise decreasing Insomnia Severity Index (ISI) by about 10% to about 95%, about 15% to about 90%, about 20% to about 85%, about 30% to about 80%, about 40% to about 75%, about 50% to about 70%, about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 30% to about 75%, or about 40% to about 70%, including any values or ranges therebetween, compared to prior to administration, following 4 weeks or 12 weeks of treatment. In embodiments, the methods of the present disclosure comprise decreasing Insomnia Severity Index (ISI) by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100%, including any values or ranges therebetween, compared to prior to administration, following 4 weeks or 12 weeks of treatment. In embodiments, the method comprises decreasing the ISI score by about 1 to 28 points, about 1 to 20 points, about 1 to 18 points, about 1 to 16 points, about 1 to 14 points, about 1 to 12 points, about 1 to 10 points, about 1 to 8 points, about 1 to 6 points, about 1 to 20 points, about 2 to 10 points, about 2 to 5 points, about 3 to 10 points, about 4 to 10 points, about 5 to 10 points, about 6 to 10 points, about 3 to 20 points, about 3 to 10 points, about 3 to 8 points, or about 4 to 10 points, including any values or ranges therebetween. In embodiments, the method comprises decreasing the ISI score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, or 28 points, including any values or ranges therebetween.
Numbered Embodiments
1. A method of treating vasomotor symptoms in a female subject in need thereof, comprising administering a daily dose of about 25 mg to about 100 mg of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor.
2. A method of treating vasomotor symptoms in a female subject in need thereof, comprising administering about 25% to about 75% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor; and wherein the reference dose of elinzanetant is a daily dose of about 100 mg to about 160 mg.
3. The method of embodiment 2, wherein the reference dose of elinzanetant is a daily dose of about 120 mg.
4. The method of embodiment 2 or 3, comprising administering 50% of the reference dose of elinzanetant.
5. The method of any one of embodiments 1-4, wherein about 30 mg of elinzanetant is administered once a day.
6. The method of any one of embodiments 1-4, wherein about 60 mg of elinzanetant is administered once a day.
7 The method of any one of embodiments 1-4, wherein about 90 mg of elinzanetant is administered once a day.
8 The method of any one of embodiments 1-7, further comprising treating sleep disturbances associated with vasomotor symptoms.
9. The method of any one of embodiments 1-8, wherein elinzanetant is administered once a day.
10. The method of any one of embodiments 1-9, wherein elinzanetant is administered at bedtime (h.s.).
11. The method of any one of embodiments 1-10, wherein the female subject has moderate to severe vasomotor symptoms prior to administering elinzanetant.
12. The method of any one of embodiments 1-11, wherein the female subject is an adult.
13. The method of any one of embodiments 1-12, wherein the female subject is 40-65 years old.
14. The method of any one of embodiments 1-13, wherein the female subject is menopausal.
15. The method of embodiment 14, wherein prior to administering elinzanetant, the female subject experienced:

    
    
        (i) at least 12 months of spontaneous amenorrhea;
        (ii) at least 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels>40 mIU/mL and a serum estradiol concentration of <30 pg/mL;
        (iii) hysterectomy with serum FSH levels>40 mIU/mL and a serum estradiol concentration of <30 pg/mL; or
        (iv) surgical bilateral oophorectomy with or without hysterectomy.
    
    


16. The method of any one of embodiments 1-15, wherein the vasomotor symptoms are caused by adjuvant endocrine therapy.
17. The method of any one of embodiments 1-15, wherein the vasomotor symptoms are associated with menopause.
18. The method of any one of embodiments 1-16, wherein the moderate CYP3A4 inhibitor is amiodarone, aprepitant, ciprofloxacin, clarithromycin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, grapefruit juice, imatinib, isavuconazole, or verapamil.
19. The method of any one of embodiments 1-18, comprising reducing the frequency of the vasomotor symptoms compared to baseline.
20. The method of any one of embodiments 1-19, comprising reducing the severity of the vasomotor symptoms compared to baseline.
21. The method of any one of embodiments 1-20, comprising reducing the frequency of moderate to severe hot flash (HF) from baseline.
22. The method of any one of embodiments 1-21, comprising decreasing a Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS SD SF 8b) total T-score compared to baseline.
23. The method of any one of embodiments 1-22, comprising decreasing a menopause specific quality of life scale (MENQOL) total score compared to baseline.
24. The method of any one of embodiments 1-23, comprising decreasing a Beck depression inventory (BDI-II) total score compared to baseline.
25. A method of treating vasomotor symptoms and/or sleep disturbances in a female subject in need thereof, comprising administering about 25 mg to about 100 mg of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor.
26. A method of treating vasomotor symptoms and/or sleep disturbances in a female subject in need thereof, comprising administering about 25% to about 75% of a reference dose of elinzanetant or stereoisomer thereof, or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein the female subject is undergoing concomitant treatment with a moderate CYP3A4 inhibitor; and wherein the reference dose of elinzanetant is about 100 mg to about 160 mg.
27. A method of treating vasomotor symptoms in a female subject in need thereof with elinzanetant or stereoisomer thereof or an equivalent dose of a pharmaceutically acceptable salt or deuterated form thereof, wherein concomitant use of the strong CYP3A4 inhibitor with elinzanetant is not recommended.
28. The method according to embodiment 27, wherein concomitant use is contraindicated.
29. The method of embodiment 27 or 28, wherein the female subject is currently treated with a strong CYP3A4 inhibitor and in need of treatment with elinzanetant, the method comprising, discontinuing the strong CYP3A4 inhibitor treatment; and then administering a reference dose of elinzanetant.
30. The method of embodiment 27 or 28, wherein the female subject is currently treated with elinzanetant and in need of treatment with a strong CYP3A4 inhibitor, the method comprising, discontinuing elinzanetant treatment; and then administering the strong CYP3A4 inhibitor treatment.
EXAMPLES
Example 1. Pharmacokinetic Analysis of Concomitant Use of Elinzanetant with a Strong CYP3A4 Inhibitor
A clinical pharmacokinetic assessment of the effect of concomitant administration of elinzanetant with a strong CYP3A4 inhibitor, itraconazole, was conducted. The female subjects were administered 120 mg of elinzanetant alone and subsequently concomitantly administered with 120 mg of elinzanetant in the presence of itraconazole, at the dosage specified in the FDA-approved drug label. The results obtained from clinical studies of elinzanetant alone or after concomitant administration with itraconazole were analyzed and further used to develop the physiologically based pharmacokinetic (PBPK) model used to evaluate the drug-drug interaction profile for elinzanetant. Treatment-emergent adverse events (TEAEs) observed in the elinzanetant development studies include fatigue, somnolence, dizziness, abnormal elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) liver enzyme levels.
Using the PBPK model, the area under the concentration curve (AUC) and the maximum plasma concentration (Cmax) geometric mean ratios (90% confidence internal) of 120 mg elinzanetant following coadministration with itraconazole were predicted as 6.10 (Cl: 5.41-6.98) and 3.26 (Cl: 2.86-3.71), respectively, compared to those observed when 120 mg of elinzanetant was administered alone. As elinzanetant has complicated pharmacokinetics, including high sensitivity to plasma protein binding and circadian rhythm fluctuation, the PBPK model was adjusted to include a modified fraction unbound (fu) with a scaling factor of 1.25 in the presence of itraconazole. After incorporating the modified fu with the scaling factor, the predicted geometric AUC and Cmax mean ratios of elinzanetant were about 4.91 (Cl: 4.36-5.57) and about 2.76-fold (Cl: 2.43-3.13), respectively, relative to 120 mg of elinzanetant alone. The observed AUC and Cmax geometric mean ratios of elinzanetant in the clinical study with itraconazole were 4.84 (CI: 4.02-5.83) for AUC and 3.31 (Cl: 2.74-4.00) for Cmax, respectively, and were consistent with the predicted AUC and Cmax ratios from PBPK modeling.
In summary, due to the significant increase in elinzanetant AUC and Cmax following co-administration with itraconazole, concomitant administration of elinzanetant at a dose of 120 mg with a strong CYP3A4 inhibitor, such as itraconazole, was not recommended.
A low dose elinzanetant (10 mg, 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg) was evaluated for safety and efficacy of elinzanetant in vasomotor symptoms treatment following coadministration with a moderate CYP3A4 inhibitor (e.g., erythromycin) to evaluate the significance of this interaction, as described in Example 2.
Example 2. Pharmacokinetic Analysis of Concomitant Use of Elinzanetant with a Moderate CYP3A4 Inhibitor
An assessment to evaluate concomitant administration of 60 mg or 120 mg of elinzanetant with a moderate CYP3A inhibitor, erythromycin, was conducted utilizing PBPK modeling as described in Example 1 along with a drug-drug interaction model for erythromycin. For erythromycin, the dosage specified in the FDA-approved drug label was used in the study.
The AUC and Cmax geometric mean ratios of elinzanetant following co-administration with itraconazole or erythromycin, compared to those observed when 120 mg of elinzanetant was administered alone, are summarized in Table A.







TABLE A







Geometric mean ratios










AUC Ratio 
Cmax Ratio 



vs EZN 120
vs EZN 120



(90% CI)
(90% CI)












Strong inhibitor (itraconazole) + 
6.10 (5.41-6.98)
3.26 (2.86-3.71)


EZN 120 mg




Moderate inhibitor (erythromycin) +
3.01 (2.71-3.33)
2.00 (1.83-2.19)


EZN 120 mg




Moderate inhibitor (erythromycin) +
1.39 (1.25-1.56)
0.96 (0.87-1.06)


EZN 60 mg









The physiologically based pharmacokinetic (PBPK) modeling predictions after co-administration of 120 mg elinzanetant with a moderate CYP3A4 inhibitor erythromycin showed a 3.0-fold increase of AUC and 2.0-fold increase for Cmax of elinzanetant. The PK profile for the administration of 120 mg elinzanetant with a moderate CYP3A4 presents an unacceptable increase in exposure to elinzanetant and risk of adverse events. However, the PBPK modeling predictions after co-administration of 60 mg elinzanetant with a moderate CYP3A4 inhibitor showed a 1.39-fold increase of AUC and 0.96-fold increase for Cmax of elinzanetant. The PK profile predicted for the co-administration of 60 mg elinzanetant with a moderate CYP3A4 inhibitor is within the therapeutically effective window.
For all simulation conditions, the highest recommended dose of CYP3A4 inhibitor (erythromycin) was selected. Duration of treatment was selected using preliminary PBPK simulations to ensure steady state. The effective time of the first administration was set to t=0. The feeding conditions were set to fasted. The simulation designs are summarized in Table B.







TABLE B







Simulation design of simulated DDI study of elinzanetant 


with a moderate CYP3A4 inhibitor













CYP3A4






YP3A4
inhibitor


Elin-
Schedule 


moderate
dose 


zanetant
for


inhibitor
per day
Schedule
Offseta
dose
elinzanetant





Erythromycin
1500 
500 mg TID 
0 h
60/120 mg
OD for 



mg/day
for 21 days


21 days





aTime interval between a moderate CYP3A4 inhibitor administration and elinzanetant dose.






To assess the drug-drug interaction (DDI) potential of low dose elinzanetant when co-administered with erythromycin, PBPK simulations were conducted evaluating the geometric mean ratios (DDI ratios) of AUC, Ctrough, and Cmax following co-administration of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg elinzanetant with erythromycin, compared to administration of 120 mg elinzanetant alone. As illustrated in FIGS. 1-3, concomitant use of 60 mg elinzanetant with erythromycin resulted in a 1.39-fold increase in AUC (0-24)ss (90% CI: 1.25-1.56) and a 1.91-fold increase in Ctrough,ss (90% CI: 1.69-2.17), while Cmax remained unchanged (0.96-fold; 90% CI: 0.87-1.06), which is in the acceptable range for safety and efficacy. Concomitant use of 10 or 20 mg elinzanetant with erythromycin resulted in subtherapeutic AUC (0-24)ss, Ctrough,ss, and Cmax. Concomitant use of 30 mg elinzanetant with erythromycin resulted in subtherapeutic AUC (0-24)ss and Cmax, while Ctrough,ss was similar to 120 mg elinzanetant alone. Concomitant use of 40 or 50 mg with elinzanetant resulted in similar AUC (0-24)ss and Ctrough,ss but lower Cmax compared to 120 mg elinzanetant alone. Furthermore, the pharmacokinetic concentration vs time curves as shown in FIG. 4 demonstrate that the plasma concentrations of 60 mg elinzanetant with erythromycin are similar to the plasma concentrations of 120 mg elinzanetant alone, while the plasma concentrations achieved by 60 mg elinzanetant alone are lower than 120 mg alone. It is known that 120 mg elinzanetant alone is safe and effective for treatment of vasomotor symptoms and/or sleep disturbances associated with menopause, while doses of less than 120 mg elinzanetant do not show significant efficacy. Thus, achieving a similar pharmacokinetic profile through administration of 60 mg of elinzanetant plus a moderate CYP3A4 inhibitor is to be expected to yield similar safety and efficacy.
In summary, PBPK modeling indicates that co-administration of 60 mg elinzanetant with a moderate CYP3A4 inhibitor erythromycin yields a comparable pharmacokinetic profile, specifically providing sufficient systemic exposure to achieve similar safety and efficacy in treating vasomotor symptoms and/or sleep disturbances, such as sleep disturbances associated with menopause, as 120 mg elinzanetant administered alone. Based on these findings, a reduced elinzanetant dose of 60 mg is recommended for patients concurrently taking moderate CYP3A4 inhibitors.