Preclinical pharmacokinetics and tolerability of a novel meglumine‐based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus.
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| Title: | Preclinical pharmacokinetics and tolerability of a novel meglumine‐based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus. |
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| Authors: | Rundfeldt, Chris (AUTHOR), Klein, Pavel (AUTHOR), Boison, Detlev (AUTHOR), Rotenberg, Alexander (AUTHOR), D'Ambrosio, Raimondo (AUTHOR), Eastman, Cliff (AUTHOR), Purnell, Benton (AUTHOR), Murugan, Madhuvika (AUTHOR), Goodkin, Howard P. (AUTHOR), Löscher, Wolfgang (AUTHOR) |
| Source: | Epilepsia (Series 4). Apr2023, Vol. 64 Issue 4, p888-899. 12p. |
| Subjects: | United States. Food & Drug Administration, Parenteral solutions, Status epilepticus, Topiramate, Pharmacokinetics, Nasoenteral tubes |
| Abstract: | Objective: For an antiseizure medication (ASM) to be effective in status epilepticus (SE), the drug should be administered intravenously (i.v.) to provide quick access to the brain. However, poor aqueous solubility is a major problem in the development of parenteral drug solutions. Given its multiple mechanisms of action, topiramate (TPM) is a promising candidate for the treatment of established or refractory SE, as supported by clinical studies using nasogastric tube TPM administration. However, TPM is not clinically available as a solution for i.v. administration, which hampers its use in the treatment of SE. Here, we describe a novel easy‐to‐use and easy‐to‐prepare i.v. TPM formulation using the U.S. Food and Drug Administration (FDA)–approved excipient meglumine. Methods: During formulation development, we compared the solubility of TPM in bi‐distilled water with vs without a range of meglumine concentrations. Furthermore, the solubility of combinations of TPM and levetiracetam and TPM, levetiracetam, and atorvastatin in aqueous meglumine concentrations was determined. Subsequently, the pharmacokinetics and tolerability of meglumine‐based solutions of TPM and TPM combinations were evaluated in rats, including animals following fluid percussion injury or pilocarpine‐induced SE. Results: The amino sugar meglumine markedly enhances the aqueous solubility of TPM. A comparison with data on dissolving TPM using sulfobutylether‐β‐cyclodextrin (Captisol) demonstrates that meglumine is much more effective for dissolving TPM. Furthermore, meglumine can be used to prepare drug cocktails where TPM is co‐administered with another ASM for SE treatment. The tolerability studies of the meglumine‐based TPM solution and meglumine‐based TPM combinations in normal rats and the rat fluid percussion injury and pilocarpine‐induced SE models demonstrate excellent tolerability of the novel drug solutions. Preclinical studies on antiseizure efficacy in the SE model are underway. Significance: In conclusion, the novel meglumine‐based solution of TPM presented here may be well suited for clinical development. [ABSTRACT FROM AUTHOR] |
| Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 163091943 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Preclinical pharmacokinetics and tolerability of a novel meglumine‐based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Rundfeldt%2C+Chris%22">Rundfeldt, Chris</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Klein%2C+Pavel%22">Klein, Pavel</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Boison%2C+Detlev%22">Boison, Detlev</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Rotenberg%2C+Alexander%22">Rotenberg, Alexander</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22D'Ambrosio%2C+Raimondo%22">D'Ambrosio, Raimondo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Eastman%2C+Cliff%22">Eastman, Cliff</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Purnell%2C+Benton%22">Purnell, Benton</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Murugan%2C+Madhuvika%22">Murugan, Madhuvika</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Goodkin%2C+Howard+P%2E%22">Goodkin, Howard P.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Löscher%2C+Wolfgang%22">Löscher, Wolfgang</searchLink> (AUTHOR) – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Epilepsia+%28Series+4%29%22">Epilepsia (Series 4)</searchLink>. Apr2023, Vol. 64 Issue 4, p888-899. 12p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22United+States%2E+Food+%26+Drug+Administration%22">United States. Food & Drug Administration</searchLink><br /><searchLink fieldCode="DE" term="%22Parenteral+solutions%22">Parenteral solutions</searchLink><br /><searchLink fieldCode="DE" term="%22Status+epilepticus%22">Status epilepticus</searchLink><br /><searchLink fieldCode="DE" term="%22Topiramate%22">Topiramate</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmacokinetics%22">Pharmacokinetics</searchLink><br /><searchLink fieldCode="DE" term="%22Nasoenteral+tubes%22">Nasoenteral tubes</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Objective: For an antiseizure medication (ASM) to be effective in status epilepticus (SE), the drug should be administered intravenously (i.v.) to provide quick access to the brain. However, poor aqueous solubility is a major problem in the development of parenteral drug solutions. Given its multiple mechanisms of action, topiramate (TPM) is a promising candidate for the treatment of established or refractory SE, as supported by clinical studies using nasogastric tube TPM administration. However, TPM is not clinically available as a solution for i.v. administration, which hampers its use in the treatment of SE. Here, we describe a novel easy‐to‐use and easy‐to‐prepare i.v. TPM formulation using the U.S. Food and Drug Administration (FDA)–approved excipient meglumine. Methods: During formulation development, we compared the solubility of TPM in bi‐distilled water with vs without a range of meglumine concentrations. Furthermore, the solubility of combinations of TPM and levetiracetam and TPM, levetiracetam, and atorvastatin in aqueous meglumine concentrations was determined. Subsequently, the pharmacokinetics and tolerability of meglumine‐based solutions of TPM and TPM combinations were evaluated in rats, including animals following fluid percussion injury or pilocarpine‐induced SE. Results: The amino sugar meglumine markedly enhances the aqueous solubility of TPM. A comparison with data on dissolving TPM using sulfobutylether‐β‐cyclodextrin (Captisol) demonstrates that meglumine is much more effective for dissolving TPM. Furthermore, meglumine can be used to prepare drug cocktails where TPM is co‐administered with another ASM for SE treatment. The tolerability studies of the meglumine‐based TPM solution and meglumine‐based TPM combinations in normal rats and the rat fluid percussion injury and pilocarpine‐induced SE models demonstrate excellent tolerability of the novel drug solutions. Preclinical studies on antiseizure efficacy in the SE model are underway. Significance: In conclusion, the novel meglumine‐based solution of TPM presented here may be well suited for clinical development. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=163091943 |
| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1111/epi.17520 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 12 StartPage: 888 Subjects: – SubjectFull: United States. Food & Drug Administration Type: general – SubjectFull: Parenteral solutions Type: general – SubjectFull: Status epilepticus Type: general – SubjectFull: Topiramate Type: general – SubjectFull: Pharmacokinetics Type: general – SubjectFull: Nasoenteral tubes Type: general Titles: – TitleFull: Preclinical pharmacokinetics and tolerability of a novel meglumine‐based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Rundfeldt, Chris – PersonEntity: Name: NameFull: Klein, Pavel – PersonEntity: Name: NameFull: Boison, Detlev – PersonEntity: Name: NameFull: Rotenberg, Alexander – PersonEntity: Name: NameFull: D'Ambrosio, Raimondo – PersonEntity: Name: NameFull: Eastman, Cliff – PersonEntity: Name: NameFull: Purnell, Benton – PersonEntity: Name: NameFull: Murugan, Madhuvika – PersonEntity: Name: NameFull: Goodkin, Howard P. – PersonEntity: Name: NameFull: Löscher, Wolfgang IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 04 Text: Apr2023 Type: published Y: 2023 Identifiers: – Type: issn-print Value: 00139580 Numbering: – Type: volume Value: 64 – Type: issue Value: 4 Titles: – TitleFull: Epilepsia (Series 4) Type: main |
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