Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers
Abstract The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L‐kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeti...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-04-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.741 |
| _version_ | 1818441433162448896 |
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| author | Mohammad Al‐Mahdi Al‐Karagholi Jakob Møller Hansen Dalia Abou‐Kassem Anna Koldbro Hansted Kumari Ubhayasekera Jonas Bergquist László Vécsei Inger Jansen‐Olesen Messoud Ashina |
| author_facet | Mohammad Al‐Mahdi Al‐Karagholi Jakob Møller Hansen Dalia Abou‐Kassem Anna Koldbro Hansted Kumari Ubhayasekera Jonas Bergquist László Vécsei Inger Jansen‐Olesen Messoud Ashina |
| author_sort | Mohammad Al‐Mahdi Al‐Karagholi |
| collection | DOAJ |
| description | Abstract The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L‐kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open‐label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well‐tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first‐in‐human study of LKYN showed that LKYN was safe and well‐tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed‐back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans. |
| first_indexed | 2024-12-14T18:28:10Z |
| format | Article |
| id | doaj.art-594ff105002f42b18f21c7e12f68f42e |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-12-14T18:28:10Z |
| publishDate | 2021-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-594ff105002f42b18f21c7e12f68f42e2022-12-21T22:51:53ZengWileyPharmacology Research & Perspectives2052-17072021-04-0192n/an/a10.1002/prp2.741Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteersMohammad Al‐Mahdi Al‐Karagholi0Jakob Møller Hansen1Dalia Abou‐Kassem2Anna Koldbro Hansted3Kumari Ubhayasekera4Jonas Bergquist5László Vécsei6Inger Jansen‐Olesen7Messoud Ashina8Danish Headache Center Department of Neurology University of Copenhagen DenmarkDanish Headache Center Department of Neurology University of Copenhagen DenmarkDanish Headache Center Department of Neurology University of Copenhagen DenmarkDanish Headache Center Glostrup Research Institute Rigshospitalet Glostrup Faculty of Health and Medical Sciences University of Copenhagen DenmarkAnalytical Chemistry and Neurochemistry Department of Chemistry ‐ BMC Uppsala University SwedenAnalytical Chemistry and Neurochemistry Department of Chemistry ‐ BMC Uppsala University SwedenDepartment of Neurology and MTA‐SZTE Neuroscience Research Group University of Szeged Szeged HungaryDanish Headache Center Glostrup Research Institute Rigshospitalet Glostrup Faculty of Health and Medical Sciences University of Copenhagen DenmarkDanish Headache Center Department of Neurology University of Copenhagen DenmarkAbstract The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L‐kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open‐label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well‐tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first‐in‐human study of LKYN showed that LKYN was safe and well‐tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed‐back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.https://doi.org/10.1002/prp2.741epilepsyglutamatkynurenic acidmigrainestroke |
| spellingShingle | Mohammad Al‐Mahdi Al‐Karagholi Jakob Møller Hansen Dalia Abou‐Kassem Anna Koldbro Hansted Kumari Ubhayasekera Jonas Bergquist László Vécsei Inger Jansen‐Olesen Messoud Ashina Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers Pharmacology Research & Perspectives epilepsy glutamat kynurenic acid migraine stroke |
| title | Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers |
| title_full | Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers |
| title_fullStr | Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers |
| title_full_unstemmed | Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers |
| title_short | Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers |
| title_sort | phase 1 study to access safety tolerability pharmacokinetics and pharmacodynamics of kynurenine in healthy volunteers |
| topic | epilepsy glutamat kynurenic acid migraine stroke |
| url | https://doi.org/10.1002/prp2.741 |
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