Delving into the Latest Updates on Tolvaptan Sodium Phosphate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Samtasu, サムタス

Target

AVPR2

Mechanism

AVPR2 antagonists(Vasopressin V2 receptor antagonists)

Therapeutic Areas

Other DiseasesCardiovascular Diseases

Active Indication

Body fluid retentionHeart FailureEdema, Cardiac

Inactive Indication-

Originator Organization

Otsuka Pharmaceutical Co., Ltd.

Active Organization

Otsuka Pharmaceutical Co., Ltd.

Fuji Yakuhin Co., Ltd.

Inactive Organization

Otsuka Beijing Research Institute

Drug Highest PhaseApproved

First Approval Date

JP (28 Mar 2022),

Body fluid retention

Regulation-

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Structure

Molecular FormulaC26H26ClN2NaO6P

InChIKeyPWJANPIMBWGICU-UHFFFAOYSA-N

CAS Registry942619-79-6

OPC-61815 is an intravenous formulation vasopressin antagonist designed to treat heart failure patients, especially who have difficulty in oral intake. Tolvaptan together with DM-4103 and DM-4107 are considered as the major metabolites of OPC-61815 biotransformed in the liver via cytochrome P450 (CYP) 3A. An efficient and robust ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of OPC-61815 and its three metabolites in human plasma was developed and fully validated. To our best knowledge, it was the first published method that simultaneously quantified all of these four analytes in only one run. Simple and rapid sample preparation procedure and very short UPLC-MS/MS run time (3.5 min) offered OPC-61815 and its metabolites relatively high throughput detection, which was greatly beneficial to further clinical bio-sample analysis. The method showed good linearity and sufficient sensitivity in the range of 2.00-1000 ng/mL with a low limit of quantitation (2.00 ng/mL) for each analyte. For samples with concentrations above 1000 ng/mL, 100-fold dilution with blank plasma before sample preparation was accepted. High precision and accuracy, high selectivity and satisfactory recovery of this method were demonstrated. For all of the four analytes, no significant matrix effect or carry-over was observed. The stability of analytes and internal standards under different conditions were evaluated to ensure they were stable during the whole period of storage, preparation and detection. Also, re-injection reproducibility was investigated. In addition, the conversion test showed that almost no OPC-61815 converted into DM-4103 and DM-4107 during sample processing, while attention should be paid to the concentration difference between OPC-61815 and tolvaptan in bioanalysis. The developed UPLC-MS/MS method was successfully applied to an open, single and multiple dose administration phase I trial for monitoring the pharmacokinetics of OPC-61815. This work provided a promising way for further pharmacokinetic study of OPC-61815.

01 Nov 2022·Journal of Pharmacological Sciences

In vitro and in vivo pharmacological profile of OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan

Article

Author: Yamashita, Tatsuya ; Yamada, Yoshihisa ; Menjo, Yasuhiro ; Mizuguchi, Hiroshi ; Matsunaga, Masayuki ; Furukawa, Masayuki ; Fujiki, Hiroyuki ; Matsuda, Takakuni ; Nakamura, Shigeki ; Miyazaki, Toshiki

Tolvaptan is an orally active vasopressin V₂ receptor antagonist and used for the treatment of volume overload in some disease as an aquaretic. Tolvaptan sodium phosphate (OPC-61815) is a pro-drug of tolvaptan that was designed to improve water solubility and enable intravenous use. The conversion of OPC-61815 to tolvaptan was evaluated for in vitro and in vivo pharmacokinetic studies. The pharmacodynamics of OPC-61815 were evaluated for in vitro receptor binding affinity, in vivo aquaretic and anti-edematous action. The solubility of OPC-61815 in water at 25 °C was 72.4 mg/mL and more than 100,000 times the solubility of tolvaptan. OPC-61815 was hydrolyzed to tolvaptan by human tissue S9 fractions and main enzyme of hydrolysis was alkaline phosphatase. After intravenous administration of OPC-61815 to rats and dogs, tolvaptan was detected in plasma within 5 min and the bioavailability of tolvaptan was 57.7% and 50.9%, respectively. Binding affinity of OPC-61815 for the human V₂ receptor was 1/14 weaker than that of tolvaptan. OPC-61815 exerted dose-dependent aquaretic action in rats and dogs and a corresponding anti-edematous action in rat edema models. These results suggest that OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan, is an effective aquaretic by converting to tolvaptan after intravenous administration.

01 Oct 2022·ESC Heart Failure

Efficacy and safety of intravenous OPC‐61815 compared with oral tolvaptan in patients with congestive heart failure

Article

Author: Kurita, Yuka ; Uno, Shingo ; Kim, Seongryul ; Sato, Naoki

AbstractAimsThis multicentre, randomized, controlled, double‐blind, parallel‐group Phase III study was conducted to confirm the non‐inferiority of OPC‐61815 (tolvaptan sodium phosphate) intravenous injections to oral tolvaptan tablets in patients with congestive heart failure and volume overload despite receiving diuretics other than vasopressin antagonists.Methods and resultsCongestive heart failure patients with volume overload despite receiving diuretics other than vasopressin antagonists were randomly assigned (1:1) to receive OPC‐61815 (16‐mg injection; n = 149) or oral tolvaptan (15‐mg tablet; n = 145) once daily for 5 days. Most patients were male; the mean age and weight were 74.7 years and 62.1 kg, respectively; other demographic and clinical characteristics were similar between groups. In this study, the primary endpoint was the change in body weight from baseline to the day after the last dose. Secondary endpoints included improvement from baseline in congestive findings and New York Heart Association classification. The change in body weight was −1.67 kg [95% confidence interval (CI): −1.93, −1.41] and −1.36 kg (95% CI: −1.62, −1.10) in the OPC‐61815 group and tolvaptan group, respectively; the difference in the least squares mean between the groups was −0.31 kg (95% CI: −0.68, 0.06). Given the upper CI did not exceed the pre‐specified limit of 0.48, this confirmed the non‐inferiority of injectable OPC‐61815 to oral tolvaptan. Daily urine volume and daily fluid intake increased, and daily fluid balance was negative throughout the treatment period; changes were similar for both groups. All evaluated congestive symptoms and New York Heart Association classifications showed improvement and safety findings were similar between the groups. The incidence of hyperkalaemia was higher in the OPC‐61815 group, and the incidence of thirst and dry mouth was higher in the tolvaptan group. Most treatment‐emergent adverse events were mild to moderate; one serious treatment‐emergent adverse event of hyperkalaemia in the OPC‐61815 group was considered treatment related.ConclusionsOPC‐61815 (16‐mg injection) was confirmed as non‐inferior to oral tolvaptan (15‐mg tablet) in patients with congestive heart failure and inadequate response to diuretics; no new safety concerns were observed.

100 Deals associated with Tolvaptan Sodium Phosphate

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R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Body fluid retention	JP	Otsuka Pharmaceutical Co., Ltd.	28 Mar 2022

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	NDA/BLA	CN	Fuji Yakuhin Co., Ltd.	15 Dec 2023
Edema, Cardiac	NDA/BLA	CN	Otsuka Pharmaceutical Co., Ltd.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04182958 (CTgov)	Phase 1	-	8	OPC-61815	qfreskhezv(swnhrwkedj) = cbokomtxes kwmvilwupr (jdaufmjzrr, znxrwfirup - xrtrjjxuvn) View more	-	06 Oct 2021
NCT03962101 (CTgov)	Phase 3	Heart Failure	45	OPC-61815 injection	mldjsmshim(yylkobhwea) = sjsfdegdfb esjulqnihq (ygbpgvnyna, gwrteyjrtl - bzuhroemql) View more	-	05 Sep 2021
NCT03772041 (CTgov)	Phase 3	Heart Failure	294	OPC-61815 (OPC-61815 Injection 16 mg)	ykxortnbwf(tqkztjxfud) = lcktexerax ommiqccgbw (bgvqllcaxo, mjtyuhahyu - azdmyuezza) View more	-	05 Aug 2021
NCT03772041 (CTgov)	Phase 3	Heart Failure	294	Tolvaptan Tab 15 MG (Tolvaptan Tablet 15mg)	ykxortnbwf(tqkztjxfud) = kmbttpcdph ommiqccgbw (bgvqllcaxo, yadybbjqgx - lwycswicrp) View more	-	05 Aug 2021
NCT03254108 (CTgov)	Not Applicable	Heart Failure	61	OPC-61815 injection 2mg (OPC-61815 Injection 2mg)	uzlusaaxjl(dytuxoblwn) = lbsrilftrm wrsklrypdh (kxexjvkmkd, nxbbgllckb - vcxmulhiau) View more	-	28 Jul 2021
NCT03254108 (CTgov)	Not Applicable	Heart Failure	61	OPC-61815 injection 4mg (OPC-61815 Injection 4mg)	uzlusaaxjl(dytuxoblwn) = mbunztaumz wrsklrypdh (kxexjvkmkd, hidsucghrf - woqirtuymg) View more	-	28 Jul 2021