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

Action

antagonists

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

Fuji Yakuhin Co., Ltd.

Otsuka Pharmaceutical Co., Ltd.

Inactive Organization

Otsuka Beijing Research Institute

License Organization-

Drug Highest PhaseApproved

First Approval Date

Japan (28 Mar 2022),

Body fluid retention

Regulation-

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Structure/Sequence

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 Apr 2023·Journal of Cardiology Cases

Initial clinical experience of intravenous tolvaptan sodium phosphate in patients with congestive heart failure

Author: Nakamura, Makiko ; Ushijima, Ryuichi ; Wakakuri, Eri ; Onoda, Hiroshi ; Imamura, Teruhiko ; Kinugawa, Koichiro

Tolvaptan sodium phosphate (Samtas®; Otsuka Pharmaceutical, Tokyo, Japan) is a newly available intravenous aquaretic diuretic (commercially available from May 2022), which acts as an arginine vasopressin V2 receptor antagonist. Thus far, optimal patient selection as well as safety and efficacy in real-world practice remain unknown. We experienced two patients with congestive heart failure treated with tolvaptan sodium phosphate. In one patient with right-sided heart failure, oral tolvaptan was converted to intravenous tolvaptan sodium phosphate, and another one with right and left-sided heart failure and impaired swallowing function received intravenous tolvaptan sodium phosphate on a de novo basis. Following the initiation of tolvaptan sodium phosphate, their congestive symptoms ameliorated immediately without any complications. Tolvaptan sodium phosphate may be safe and effective in real-world practice, although further studies are warranted to establish optimal patient selection and clinical management.Learning objectiveWe report here an initial experience of newly-introduced intravenous tolvaptan sodium phosphate in real-world practice. The novel medication might be particularly suitable for those with severe thirst, congestive gut edema, or requiring rapid amelioration of systemic/pulmonary congestion, although further accumulating experiences are warranted to establish optimal therapeutic strategy.

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: Yamada, Yoshihisa ; Yamashita, Tatsuya ; Menjo, Yasuhiro ; Matsunaga, Masayuki ; Mizuguchi, Hiroshi ; 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.

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	Japan	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	China	Fuji Yakuhin Co., Ltd.	15 Dec 2023
Edema, Cardiac	NDA/BLA	China	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	pwgrvlsoyf(siwmpgxnpf) = gxbctwyefr zvnigqarqv (moeawvsgoe, wxjnbfjjrm - piqifctkwv) View more	-	06 Oct 2021
NCT03962101 (CTgov)	Phase 3	Heart Failure	45	OPC-61815 injection	eaitqvyvyb(rtgiddflmc) = xnxffjbspx vqswolftsf (otkotgxkxh, jobxisjfnu - svmkzktryy) View more	-	05 Sep 2021
NCT03772041 (CTgov)	Phase 3	Heart Failure	294	OPC-61815 (OPC-61815 Injection 16 mg)	qqlxyaosjp(ntmpzaospq) = evtblnubqh ehxdcufejc (hxfnunlzzs, edixxogpkm - ukvffsxbfc) View more	-	05 Aug 2021
NCT03772041 (CTgov)	Phase 3	Heart Failure	294	Tolvaptan Tab 15 MG (Tolvaptan Tablet 15mg)	qqlxyaosjp(ntmpzaospq) = grdqxroubh ehxdcufejc (hxfnunlzzs, rbmvjyphqq - phjmxldlmp) View more	-	05 Aug 2021
NCT03254108 (CTgov)	Not Applicable	Heart Failure	61	OPC-61815 injection 2mg (OPC-61815 Injection 2mg)	efimikcxvc(swkkktrzos) = ovuryoyvrc jkqohcugxg (xeippocnfs, fpcdjlgtiw - duezurhchq) View more	-	28 Jul 2021
NCT03254108 (CTgov)	Not Applicable	Heart Failure	61	OPC-61815 injection 4mg (OPC-61815 Injection 4mg)	efimikcxvc(swkkktrzos) = akafxjbtvs jkqohcugxg (xeippocnfs, vtohekvuuf - fnitujzdcz) View more	-	28 Jul 2021