Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents
Abstract Background TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-1...
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| Veröffentlicht in: | The international journal of neuropsychopharmacology 2022-02, Vol.25 (2), p.106-117 |
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| container_title | The international journal of neuropsychopharmacology |
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| creator | Watanabe, Mai Marcy, Brian Hiroki, Ayano Watase, Hirotaka Kinoshita, Kohnosuke Iijima, Michihiko Marumo, Toshiyuki Zarate, Carlos A Chaki, Shigeyuki |
| description | Abstract
Background
TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects.
Methods
This was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15–400 mg TS-161) and 10-day multiple-ascending dose (50–150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161.
Results
Following single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 |
| doi_str_mv | 10.1093/ijnp/pyab062 |
| format | Article |
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Background
TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects.
Methods
This was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15–400 mg TS-161) and 10-day multiple-ascending dose (50–150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161.
Results
Following single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a Cmax of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC50 values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness.
Conclusions
The mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects, and is a promising candidate for further clinical development in treatment of patients with depression.</description><identifier>ISSN: 1461-1457</identifier><identifier>EISSN: 1469-5111</identifier><identifier>DOI: 10.1093/ijnp/pyab062</identifier><identifier>PMID: 34534292</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Administration, Oral ; Adolescent ; Adult ; AMPA receptors ; Animals ; Antidepressants ; Antidepressive Agents - therapeutic use ; Area Under Curve ; Depression - drug therapy ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Health aspects ; Humans ; Male ; Middle Aged ; Physiological aspects ; Prodrugs ; Receptors, Metabotropic Glutamate - administration & dosage ; Regular s ; Rodentia ; Testing ; Young Adult</subject><ispartof>The international journal of neuropsychopharmacology, 2022-02, Vol.25 (2), p.106-117</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of CINP. 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of CINP.</rights><rights>COPYRIGHT 2022 Oxford University Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-6ea9c4ff5361614ef81bc9d94cdfe8136808da887c4d45fc3f247ccb6390b8343</citedby><cites>FETCH-LOGICAL-c483t-6ea9c4ff5361614ef81bc9d94cdfe8136808da887c4d45fc3f247ccb6390b8343</cites><orcidid>0000-0001-6078-6170 ; 0000-0003-4026-5129</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832229/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832229/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1598,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34534292$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Watanabe, Mai</creatorcontrib><creatorcontrib>Marcy, Brian</creatorcontrib><creatorcontrib>Hiroki, Ayano</creatorcontrib><creatorcontrib>Watase, Hirotaka</creatorcontrib><creatorcontrib>Kinoshita, Kohnosuke</creatorcontrib><creatorcontrib>Iijima, Michihiko</creatorcontrib><creatorcontrib>Marumo, Toshiyuki</creatorcontrib><creatorcontrib>Zarate, Carlos A</creatorcontrib><creatorcontrib>Chaki, Shigeyuki</creatorcontrib><title>Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents</title><title>The international journal of neuropsychopharmacology</title><addtitle>Int J Neuropsychopharmacol</addtitle><description>Abstract
Background
TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects.
Methods
This was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15–400 mg TS-161) and 10-day multiple-ascending dose (50–150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161.
Results
Following single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a Cmax of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC50 values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness.
Conclusions
The mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects, and is a promising candidate for further clinical development in treatment of patients with depression.</description><subject>Administration, Oral</subject><subject>Adolescent</subject><subject>Adult</subject><subject>AMPA receptors</subject><subject>Animals</subject><subject>Antidepressants</subject><subject>Antidepressive Agents - therapeutic use</subject><subject>Area Under Curve</subject><subject>Depression - drug therapy</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Female</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Physiological aspects</subject><subject>Prodrugs</subject><subject>Receptors, Metabotropic Glutamate - administration & dosage</subject><subject>Regular s</subject><subject>Rodentia</subject><subject>Testing</subject><subject>Young Adult</subject><issn>1461-1457</issn><issn>1469-5111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9klFr2zAQx83YWLtub3segj1sg7ixLMWWXwqhZG0hrKHJno0sn2KltmQkOZAvvM8xOenKCmPo4ST0-__vTroo-oiTS5wUZKp2up_2B14lWfoqOsc0K-IZxvj1cY9jTGf5WfTOuV2SpHRGsrfRGQmRpkV6Hv1a7Hk7cK-MRkYi3wBacwn-MEEb04LllWrVeOK6RquG244L86g0eCXQyhqpWnCjcrNKaE6CJ_q6Wcc4w98maD4StR22I8DRD7OHFt1b3xjnwQaD7qYd0ilBDyCg98aiufZ8a7RyfjTEOWMFnSCl0S3w1jcHtB6qHQjvjvXchRgUqobegnNc-3ipHgEtpDwyQfdgatDevY_eSN46-PAUL6Kf3xeb69t4eX9zdz1fxoIy4uMMeCGolOGVQgcUJMOVKOqCiloCwyRjCas5Y7mgNZ1JQWRKcyGqjBRJxQglF9HVybcfqg5qEXJb3pa9VR23h9JwVb680aopt2ZfMkbSNC2CweeTwZa3UCotTcBEp5wo5znG4YGzbExz-Q8qrBo6JYyG8VteCiYngbDGOQvyuSSclOMYleMYlU9jFPBPf7fxDP-ZmwB8OQFm6P9v9RvFrNLC</recordid><startdate>20220211</startdate><enddate>20220211</enddate><creator>Watanabe, Mai</creator><creator>Marcy, Brian</creator><creator>Hiroki, Ayano</creator><creator>Watase, Hirotaka</creator><creator>Kinoshita, Kohnosuke</creator><creator>Iijima, Michihiko</creator><creator>Marumo, Toshiyuki</creator><creator>Zarate, Carlos A</creator><creator>Chaki, Shigeyuki</creator><general>Oxford University Press</general><scope>TOX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6078-6170</orcidid><orcidid>https://orcid.org/0000-0003-4026-5129</orcidid></search><sort><creationdate>20220211</creationdate><title>Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents</title><author>Watanabe, Mai ; Marcy, Brian ; Hiroki, Ayano ; Watase, Hirotaka ; Kinoshita, Kohnosuke ; Iijima, Michihiko ; Marumo, Toshiyuki ; Zarate, Carlos A ; Chaki, Shigeyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-6ea9c4ff5361614ef81bc9d94cdfe8136808da887c4d45fc3f247ccb6390b8343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Administration, Oral</topic><topic>Adolescent</topic><topic>Adult</topic><topic>AMPA receptors</topic><topic>Animals</topic><topic>Antidepressants</topic><topic>Antidepressive Agents - therapeutic use</topic><topic>Area Under Curve</topic><topic>Depression - drug therapy</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Female</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Physiological aspects</topic><topic>Prodrugs</topic><topic>Receptors, Metabotropic Glutamate - administration & dosage</topic><topic>Regular s</topic><topic>Rodentia</topic><topic>Testing</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Watanabe, Mai</creatorcontrib><creatorcontrib>Marcy, Brian</creatorcontrib><creatorcontrib>Hiroki, Ayano</creatorcontrib><creatorcontrib>Watase, Hirotaka</creatorcontrib><creatorcontrib>Kinoshita, Kohnosuke</creatorcontrib><creatorcontrib>Iijima, Michihiko</creatorcontrib><creatorcontrib>Marumo, Toshiyuki</creatorcontrib><creatorcontrib>Zarate, Carlos A</creatorcontrib><creatorcontrib>Chaki, Shigeyuki</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The international journal of neuropsychopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Watanabe, Mai</au><au>Marcy, Brian</au><au>Hiroki, Ayano</au><au>Watase, Hirotaka</au><au>Kinoshita, Kohnosuke</au><au>Iijima, Michihiko</au><au>Marumo, Toshiyuki</au><au>Zarate, Carlos A</au><au>Chaki, Shigeyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents</atitle><jtitle>The international journal of neuropsychopharmacology</jtitle><addtitle>Int J Neuropsychopharmacol</addtitle><date>2022-02-11</date><risdate>2022</risdate><volume>25</volume><issue>2</issue><spage>106</spage><epage>117</epage><pages>106-117</pages><issn>1461-1457</issn><eissn>1469-5111</eissn><abstract>Abstract
Background
TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects.
Methods
This was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15–400 mg TS-161) and 10-day multiple-ascending dose (50–150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161.
Results
Following single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a Cmax of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC50 values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness.
Conclusions
The mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects, and is a promising candidate for further clinical development in treatment of patients with depression.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>34534292</pmid><doi>10.1093/ijnp/pyab062</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-6078-6170</orcidid><orcidid>https://orcid.org/0000-0003-4026-5129</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1461-1457 |
| ispartof | The international journal of neuropsychopharmacology, 2022-02, Vol.25 (2), p.106-117 |
| issn | 1461-1457 1469-5111 |
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| source | Oxford Journals Open Access Collection; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Administration, Oral Adolescent Adult AMPA receptors Animals Antidepressants Antidepressive Agents - therapeutic use Area Under Curve Depression - drug therapy Dose-Response Relationship, Drug Double-Blind Method Female Health aspects Humans Male Middle Aged Physiological aspects Prodrugs Receptors, Metabotropic Glutamate - administration & dosage Regular s Rodentia Testing Young Adult |
| title | Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents |
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