Methods for Treating Diseases with Terlipressin
Patent Information
- Application Number
- JP2024546209
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2022-02-03
- Filing Date
- 2023-02-03
- Publication Date
- 2025-02-19
Smart Images
Figure 2025505010000001_ABST
Abstract
Description
[Technical field]
[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 306,368, filed February 3, 2022, the entirety of which is incorporated herein by reference. [Background technology]
[0002] Terlipressin is considered a prodrug of its more potent metabolite, 8-lysine vasopressin (8-LVP), and is an analog of the human nonapeptide hormone arginine vasopressin (AVP). Terlipressin differs from AVP by the addition of three glycyl residues at the amino terminus and the substitution of arginine for lysine at position 8. After intravenous administration, the terminal glycine residues are sequentially removed to yield 8-LVP. Terlipressin mediates its vasoconstrictor activity by binding with high affinity to vasopressin type 1 receptors, which are found in high density in vascular smooth muscle of the systemic, splanchnic, renal, and coronary circulations, as well as in the myometrium and platelets. Both AVP and 8-LVP bind to vasopressin type 2 receptors in the kidney and cause antidiuretic effects by stimulating water reabsorption through aquaporin channels. The binding affinity of 8-LVP to the vasopressin type 2 receptor is approximately 12-fold lower than that of AVP. Desmopressin, an AVP analogue used chronically on an outpatient basis for the treatment of nocturnal enuresis, selectively binds to the V2 receptor and has antidiuretic activity but no vasoconstrictor activity. Oxytocin, a nonapeptide that differs from AVP by only two amino acids, also binds to the V2 receptor and exhibits antidiuretic activity.
[0003] Terlipressin is approved outside the United States for the treatment of two life-threatening complications of cirrhosis: hepatorenal syndrome type 1 (HRS-1, more recently called HRS-acute kidney injury (HRS-AKI)) and bleeding esophageal varices (BEV or EVB).
[0004] Vasopressin and its analogs, which activate the V2 receptor, produce antidiuretic effects and water retention, with the risk of serum sodium depletion and hyponatremia. The incidence of desmopressin-induced hyponatremia has been reported to be 7.6% in adults with nocturia (Neurourol. Urodyn. 23, 302-305. doi:10.1002 / nau.20038). It has been reported that when terlipressin is administered acutely as a single bolus, it produces antidiuretic effects (Krag, 2008), which may lead to water retention, hypervolemia, dilution of serum sodium concentration, and hyponatremia (dilutional hyponatremia). Indeed, during acute treatment with BEV (2 mg terlipressin bolus injections up to four times daily for up to 2 days), 67% of terlipressin-treated patients with portal hypertensive bleeding experienced hyponatremia, defined as a decrease in serum sodium of 5 mmol or more (Sola, 2010). However, because the incidence of severe hyponatremia (serum sodium decrease ≥ 10 mmol / L) is substantially increased in patients with cirrhotic versus non-cirrhotic portal hypertension (27% versus 4%) (Eriksen 2018), the incidence of hyponatremia in terlipressin-treated BEV patients with advanced cirrhosis is likely much lower.
[0005] The incidence of hyponatremia has been reported to be much lower in cirrhotic patients undergoing long-term treatment for type 1 hepatorenal syndrome compared with BEV (14% vs. 41%, Kang 2013). Administration of terlipressin for 14 days in combination with daily albumin in patients with HRS has also been reported to improve serum sodium loss (Ortega, 2002). The largest and most recent randomized placebo-controlled trial of intermittent bolus injections of terlipressin for the treatment of hepatorenal syndrome reported a hyponatremia incidence of less than 5% in 199 patients treated with terlipressin (Wong, 2021 supplemental data Table S9a).
[0006] The incidence of hyponatremia in patients with cirrhosis receiving terlipressin long-term as a continuous infusion is expected to be even less frequent. Administering terlipressin as a continuous infusion minimizes the antidiuretic effect of terlipressin and the potential for hyponatremia in this patient population, rather than repeated IV bolus dosing. With bolus IV administration, the V1-mediated pharmacodynamic effect of terlipressin lasts for 3-4 hours, but the V2-mediated antidiuretic effect may prevail 4-6 hours after the bolus (Escorsell 1997). Administering terlipressin as a continuous infusion rather than as a bolus minimizes the risk of V2-mediated antidiuretic effect by maintaining a stable plasma concentration where the V1 effect exceeds the V2 effect, reducing the risk of hyponatremia.
[0007] Indeed, it has been reported that longer-term treatment of cirrhotic patients with recurrent HRS or refractory ascites with continuous infusion of terlipressin in the outpatient setting without daily albumin not only improves renal function and reduces ascites, but also improves serum sodium concentrations (McGlure 2019).
[0008] There is growing interest in the chronic use of terlipressin, including in outpatient settings, to treat or prevent complications of cirrhosis, including hyponatremia, adrenal insufficiency, recurrent hepatorenal syndrome, and / or ascites. Because hyponatremia has been associated with hepatic encephalopathy and may increase the risk of seizures and even death, it is imperative to reduce the risk of hyponatremia associated with terlipressin use in outpatient settings, where monitoring is more limited. Similarly, in more acute care settings, such as the treatment of hepatorenal syndrome, bleeding varices, and hypotension, it is important to minimize the risk of severe hyponatremia (serum sodium reduction >10 mmol / L), which has been reported to occur in >12% of patients, of which at least 30% have neurological symptoms. In these situations, serum sodium reduction can occur rapidly, with most patients experiencing serum sodium reduction by the third day of treatment [Kang 2013]. Thus, there is a need for methods to predict and reduce the risk of hyponatremia in patients receiving terlipressin, vasopressin, analogs of vasopressin, or related peptides with V2 receptor activity, particularly in outpatient settings where patient monitoring is infrequent. Summary of the Invention
[0009] The present disclosure relates to a method of administering arginine vasopressin or an analog thereof to a subject, comprising the steps of assessing whether the subject is receiving one or more drugs selected from the group of gabapentin, gabapentin analogs, gabapentinoids, and other drugs known to cause hyponatremia, and administering arginine vasopressin or an analog thereof to the subject only if the subject is not receiving one or more such drugs.
[0010] The present disclosure also relates to a method of administering arginine vasopressin or an analog thereof to a subject, comprising the steps of assessing whether the subject is receiving one or more drugs selected from the group of gabapentin, gabapentin analogs, gabapentinoids, and other drugs known to cause hyponatremia, reducing the dosage of the one or more such drugs to the subject, and administering arginine vasopressin or an analog thereof to the subject only once the dosage of the one or more such drugs has been reduced to the subject.
[0011] The present disclosure also relates to a method of reducing the risk of hyponatremia in a subject receiving arginine vasopressin or an analog thereof, comprising the steps of: assessing whether the subject is receiving one or more drugs selected from the group of gabapentin, gabapentin analogs, gabapentinoids, and other drugs known to cause hyponatremia; if the subject is receiving one or more such drugs, ceasing or reducing the administration of arginine vasopressin or an analog thereof to the subject; and after the subject has weaned off or weaned to a reduced dose of the one or more such drugs, resuming administration of the original dose of arginine vasopressin or an analog thereof to the subject.
[0012] In any of the foregoing embodiments, one or more such drugs is gabapentin or pregabalin.
[0013] In any of the foregoing embodiments, administration of arginine vasopressin or an analog thereof includes continuous infusion, intravenous bolus administration, intravenous slow bolus administration, subcutaneous administration by injection or infusion, or intranasal delivery.
[0014] The present disclosure also relates to methods comprising administering a therapeutically effective amount of arginine vasopressin or an analog thereof to a subject and monitoring the subject's serum sodium level for hyponatremia.
[0015] For the purpose of illustrating the present disclosure, certain embodiments of the present disclosure are depicted in the drawings. However, the present disclosure is not limited to the precise arrangements and instrumentalities of the embodiments depicted in the drawings. [Brief description of the drawings]
[0016] [Figure 1] Patient 1's daily terlipressin dose, diuretic dose, and serum sodium levels are shown before and after initiation of treatment with continuous infusion of terlipressin. [Diagram 2] Patient 2's daily terlipressin dose, diuretic dose, and serum sodium levels are shown before and after initiation of treatment with continuous infusion of terlipressin. [Diagram 3] The daily terlipressin dose, diuretic dose, and serum sodium level for Patient 3 before and after initiation of treatment with continuous infusion of terlipressin are shown. [Figure 4] The daily terlipressin dose, diuretic dose, and serum sodium level for Patient 4 before and after initiation of treatment with continuous infusion of terlipressin are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] Detailed Description of the Invention The present invention relates to a novel method of administering arginine vasopressin or its analogues. Those skilled in the art will recognize that there are various analogues of arginine vasopressin. Non-limiting examples of arginine vasopressin analogues include terlipressin, argipressin, desmopressin, felypressin, lypressin, or ornipressin. The method reduces the risk of hyponatremia in subjects receiving arginine vasopressin or its analogues by administering arginine vasopressin or its analogues only to subjects who are not simultaneously receiving gabapentin, gabapentin analogues, gabapentinoids, or other drugs known to cause hyponatremia, or by administering arginine vasopressin or its analogues only to subjects who are receiving reduced doses of gabapentin, gabapentin analogues, gabapentinoids, or other drugs known to cause hyponatremia.
[0018] Another embodiment of the invention includes a method of reducing the risk of hyponatremia in a subject receiving arginine vasopressin or an analog thereof by assessing whether the subject is receiving one or more drugs selected from the group of gabapentin, gabapentin analogs, gabapentinoids, and other drugs known to cause hyponatremia, and if the subject is receiving one or more such drugs, reducing the dose of arginine vasopressin or an analog thereof or ceasing administration of arginine vasopressin or an analog thereof to the subject, and resuming administration of arginine vasopressin or an analog thereof to the subject at a dose equal to or less than the previous dose only if the subject has transitioned to discontinuing one or more such drugs or to a reduction in the dose of one or more such drugs.
[0019] Gabapentin, an anticonvulsant approved in the United States in the mid-1990s, is increasingly being used off-label to treat neuropathic pain. In fact, in 2019, gabapentin was reported to be the seventh most commonly prescribed drug in the United States (Mattson CL, Chowdhury F, Gilson TP. Note from the Field: Trends in Gabapentin Detection and Involvement in Drug Overdose Deaths - 23 States and the District of Columbia, 2019-2020. MMWR Morb Mortal Wkly Rep 2022;71:664-666; http: / / dx.doi.org / 10.15585 / mmwr.mm7119a3external icon). The recent increase in off-label prescriptions of gabapentin in patients with cirrhosis is due to its recognized effectiveness in managing diabetic neuropathic pain and the increasing proportion of patients with cirrhosis due to nonalcoholic steatohepatitis disease who also have diabetes and diabetic neuropathic pain. Because it is not metabolized in the liver or bound to proteins, it is recommended as a first-line antiepileptic drug in patients with cirrhosis (Pediatr Neurol. 2017 Dec; 77:23-36; doi: 10.1016 / j.pediatrneurol.2017.09.013), and gabapentin is considered a first-line non-opioid therapy, especially for patients with neuropathic pain (Rakoski et al., Pain management in patients with cirrhosis, Clinical Liver Disease, 11:6, 135-140 (June 2018);https: / / doi.org / 10.1002 / cld.711). Although not substantially addictive, complete cessation of gabapentin treatment may result in withdrawal symptoms, including confusion, disorientation, gastrointestinal upset, sweating, hypertension, insomnia, and seizures. For these reasons, it is recommended that subjects gradually taper their gabapentin dose before discontinuing use.
[0020] The present invention is based on the surprising finding that gabapentin, an anticonvulsant with no reported antidiuretic / vasopressin / V2 receptor / aquaporin association, not included in the list of drugs that can cause hyponatraemia (drug-induced-hyponatraemia.pdf (resourcepharm.com)), and with the lowest risk of hyponatraemia among antiepileptic drugs (Falhammar 2018), may increase the risk of hyponatraemia in patients with cirrhosis treated with terlipressin. Because the use of gabapentinoids in patients with cirrhosis has only recently been recommended, this association may not have been recognized in previous studies with terlipressin.
[0021] In some embodiments, the risk of developing hyponatremia is reduced by treating a subject with arginine vasopressin or an analog thereof only if the subject is not concurrently receiving gabapentin, gabapentin analogs, gabapentinoids such as pregabalin, or other drugs known to cause hyponatremia, such as albamazepine, oxcarbazepine, eslicarbazepine, sodium valproate, lamotrigine, and levetiracetam.
[0022] In some embodiments, in a subject already receiving arginine vasopressin or an analog thereof, administration of arginine vasopressin or an analog thereof is discontinued, interrupted, or reduced in dose if it is discovered that the subject is also receiving gabapentin, gabapentin analogs, gabapentinoids such as pregabalin, or other drugs known to cause hyponatremia, such as albamazepine, oxcarbazepine, eslicarbazepine, sodium valproate, lamotrigine, levetiracetam. Administration of arginine vasopressin or an analog thereof is continued only if the subject transitions to discontinuation or reduction in dose of gabapentin, gabapentin analogs, gabapentinoids such as pregabalin, or other drugs known to cause hyponatremia, such as albamazepine, oxcarbazepine, eslicarbazepine, sodium valproate, lamotrigine, levetiracetam.
[0023] In any of the foregoing embodiments, administration of arginine vasopressin or an analog thereof may include continuous or bolus administration. As a non-limiting example, to treat BEV, a subject may initially receive an intravenous bolus of 2 mg terlipressin every 4 hours. When bleeding is under control, the dose is adjusted to 1 mg terlipressin acetate intravenously every 4 hours. Treatment should not continue for more than a total of 48 hours. As another non-limiting example of terlipressin administration, to treat HRS-1, a subject may receive a bolus injection of 1-2 mg terlipressin every 6 hours for up to 14 days.
[0024] The number of doses will be readily apparent to one skilled in the art and will depend on a variety of factors, including, but not limited to, the type and severity of the disease being treated. The actual dosage of the arginine vasopressin or analogs thereof of the present disclosure can be varied to provide an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration and is not toxic to the patient. A medical practitioner (such as a physician or veterinarian) having ordinary skill in the art will be able to readily determine and prescribe the effective amount of the pharmaceutical composition required.
[0025] Administration of arginine vasopressin or an analog thereof to a subject, preferably a mammal, more preferably a human, can be carried out using known procedures at a dosage and for a duration effective to treat or prevent BEV or HRS-1 or reduce ascites in the subject. The effective amount of a therapeutic compound required to achieve a therapeutic effect can vary depending on factors such as the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the state of the disease or disorder, the age, sex, weight, physical condition, mental health and medical history of the patient being treated, and other factors well known in the medical arts. Dosing regimens can be adjusted to provide the optimal therapeutic response. For example, several divided doses can be administered daily, or the dose can be proportionally reduced depending on the exigency of the therapeutic situation.
[0026] The present disclosure provides for the administration of arginine vasopressin or an analog thereof (e.g., by continuous infusion, intravenous bolus, slow bolus, or subcutaneous injection or infusion). With bolus intravenous administration, the V1-mediated pharmacodynamic effect of terlipressin persists for 3-4 hours, with the V2-mediated antidiuretic effect predominating 4-6 hours after the bolus administration. By administering arginine vasopressin or an analog thereof as a continuous infusion rather than a bolus, the risk of V2-mediated antidiuretic effects can be minimized by maintaining stable plasma concentrations where the V1 effect exceeds the V2 effect. EXAMPLES
[0027] The present disclosure will now be described with reference to the following examples, which are provided for illustrative purposes only, and the present disclosure should in no way be construed as being limited to these examples, but rather as embracing any and all variations that become evident as a result of the disclosure provided herein.
[0028] Without further elaboration, it is believed that one skilled in the art can use the above description and the following illustrative examples to practice the methods described in the claims, which should not be construed as limiting the present disclosure in any way.
[0029] Example 1: Clinical observations of hyponatremia in patients treated with terlipressin. The following clinical findings were observed in an ongoing clinical trial evaluating the safety and efficacy of terlipressin administered by continuous infusion in patients with cirrhosis and refractory ascites:
[0030] Patient 1, a 65-year-old woman with cirrhosis due to NASH and recurrent ascites, whose treatment with the diuretic furosemide was ineffective, began an infusion of terlipressin (3 mg / day) on day 1. Patient 1's terlipressin dose (mg / day), daily furosemide dose, and serum sodium are recorded in Figure 1. After 6 days of treatment with terlipressin at a dose of 3 mg / day, the dose of terlipressin was increased to 4 mg / day as per the study protocol. A modest decrease in serum sodium from baseline (3 mmol / L) was noted before the increase. After 7 days of treatment with 4 mg / day, serum sodium decreased by an additional 8 mmol / L, for a total decrease of 11 mmol / L versus baseline over the 13 days of treatment (128 mmol / L versus 139 mmol / L). The diuretic furosemide was discontinued for 7 days, and serum sodium decreased by an additional 4 mmol / L to 124 mmol / L. The patient was asymptomatic. The terlipressin infusion was discontinued. Two days later, serum sodium increased by 7 mmol / L to 131 mmol / L and then increased gradually further to 135 mmol / L 10 days after discontinuation. The hyponatremia was thought to be related to terlipressin.
[0031] Patient 2 was a 63-year-old man with alcoholic cirrhosis and recurrent ascites, refractory to diuretic therapy, and was started on treatment with 3 mg / day terlipressin. Patient 2's daily terlipressin dose and serum sodium value are recorded in Figure 2. The following day, serum sodium had decreased from a baseline of 137 mmol / L to 131 mmol / L, and the patient was asymptomatic, so treatment was continued until day 7, when serum sodium was noted to have decreased to 123 mmol / L. The patient remained asymptomatic and treatment was continued until day 14, when serum sodium remained at 124 mmol / L. When the terlipressin infusion was discontinued, serum sodium recovered to 134 mmol / L 3 days later. The hyponatremia was thought to be related to terlipressin.
[0032] Patient 3 was a 52-year-old man with cirrhosis due to NASH and uncontrolled ascites despite continued treatment with the diuretics furosemide and spironolactone. He was started on continuous intravenous infusion of terlipressin at a dose of 3 mg / day. Patient 3's terlipressin dose (mg / day), daily furosemide dose, and serum sodium are recorded in Figure 3. After 14 days of treatment, serum sodium decreased slightly from 134 mmol / L before treatment to 132 mmol / L. The dose of terlipressin was increased to 4 mg / day, and serum sodium was 129 mmol / L 2 and 6 days later. Treatment was continued, and serum sodium was noted to have decreased to 117 mmol / L on day 28, at which point the infusion was stopped. The patient was asymptomatic but was instructed to visit the emergency department. Serum sodium gradually increased by 10 mmol / L over the next 3 days to 127 mmol / L. The hyponatremia was thought to be related to terlipressin.
[0033] Patient 4, one of six patients who received terlipressin infusion in our previous phase 2a study, was a 63-year-old man with recurrent ascites due to liver cirrhosis despite taking the antidiuretics spironolactone and furosemide. The terlipressin, furosemide, and serum sodium values for patient 3 are recorded in Figure 4. As per the study protocol, the patient began treatment with terlipressin at an initial dose of 2 mg / day, which was increased to 3 mg / day on day 5. Serum sodium gradually decreased over time, reaching a decrease of 10 mmol / L on day 5, at which point the patient stopped taking furosemide. Serum sodium continued to decrease, and spironolactone was stopped for 2 days, but this did not affect the decrease in serum sodium. The terlipressin infusion was stopped after 9 days of treatment, and serum sodium recovered 2 days after the drug was discontinued. The asymptomatic severe hyponatremia was thought to be related to terlipressin treatment.
[0034] Given the low expected incidence of hyponatremia when terlipressin is administered as a continuous infusion in patients with cirrhosis, it was surprising to find that 3 of 10 (30%) patients with cirrhosis and ascites treated chronically with terlipressin as a continuous infusion developed hyponatremia (a decrease in serum sodium of 10 mmol / L or more) that was thought to be related to terlipressin (see Examples below). Furthermore, one patient in our previous Phase 2a study (n=6) similarly developed asymptomatic hyponatremia in response to terlipressin administration.
[0035] Commonalities among the three patients in this study who developed hyponatremia in response to terlipressin treatment include that these patients were taking daily gabapentin (patients 1 and 2) or pregabalin (patient 3), whereas none of the other seven patients randomized to terlipressin treatment were taking these medications, and one of the six patients in the previous phase 2a study who developed hyponatremia in response to terlipressin was also taking gabapentin.
[0036] Example 2: Detection of hyponatremia in outpatient care. Because of the known association between arginine vasopressin or its analogs and hyponatremia, it has long been recommended that serum sodium levels be monitored in patients being treated with arginine vasopressin or its analogs. Monitoring of patients being treated with agents known to cause hyponatremia includes daily assessment for symptoms of hyponatremia such as confusion, nausea, vomiting, and altered mental status, monitoring serum sodium 1-2 days after initiation or dose increase and weekly throughout the entire treatment cycle, and discontinuation of treatment if sNA falls below a certain threshold (e.g., <125 mmol / L).
[0037] References TIFF2025505010000002.tif219160
Claims
1. 1. A method of administering arginine vasopressin or an analog thereof to a subject, comprising: assessing whether the subject is receiving one or more drugs selected from the group of gabapentin, gabapentin analogs, gabapentinoids, and other drugs known to cause hyponatremia; and administering arginine vasopressin or an analog thereof to the subject only if the subject is not receiving one or more of the above-mentioned drugs; The above method.
2. 2. The method of claim 1, wherein the one or more drugs is gabapentin.
3. 3. The method of claim 1 or 2, wherein administration of the arginine vasopressin or analog thereof comprises continuous infusion, intravenous bolus, intravenous slow bolus, subcutaneous administration by injection or infusion, or intranasal delivery.
4. 1. A method of administering arginine vasopressin or an analog thereof to a subject, comprising: assessing whether the subject is receiving one or more drugs selected from the group of gabapentin, gabapentin analogs, gabapentinoids, and other drugs known to cause hyponatremia; and reducing the dosage of said one or more drugs in said subject; administering arginine vasopressin or an analog thereof to the subject only after the subject has reduced the dosage of said one or more medications; The above method.
5. 5. The method of claim 4, wherein the one or more drugs are selected from gabapentin or pregabalin.
6. 6. The method of claim 4 or 5, wherein administration of arginine vasopressin or an analog thereof comprises continuous infusion, intravenous bolus, intravenous slow bolus, subcutaneous administration by injection or infusion, or intranasal delivery.
7. 1. A method for reducing the risk of hyponatremia in a subject receiving arginine vasopressin or an analog thereof, comprising: assessing whether the subject is receiving one or more medications selected from the group of gabapentin, gabapentin analogs, gabapentinoids, and other medications known to cause hyponatremia; if the subject is receiving one or more of the above drugs, discontinuing administration of arginine vasopressin or an analog thereof to the subject; Initiating administration of arginine vasopressin or an analog thereof to the subject after the subject has discontinued or reduced the administration of said one or more drugs, wherein the administration of arginine vasopressin or an analog thereof after the subject has discontinued or reduced the administration of said one or more drugs comprises the same or reduced dose of arginine vasopressin or an analog thereof. The above method.
8. 8. The method of claim 7, wherein the one or more drugs are selected from gabapentin or pregabalin.
9. 9. The method of any of claims 7 or 8, wherein administration of arginine vasopressin or an analog thereof comprises continuous infusion, intravenous bolus, intravenous slow bolus, subcutaneous administration by injection or infusion, or intranasal delivery.
10. A method comprising administering a therapeutically effective amount of arginine vasopressin or an analog thereof to a subject and monitoring the subject for hyponatremia.