Daniel P Radin, Rok Cerne, Jeffrey M Witkin, Arnold Lippa
{"title":"年轻健康志愿者服用低冲击安帕金 CX1739 的安全性、耐受性和药代动力学特征","authors":"Daniel P Radin, Rok Cerne, Jeffrey M Witkin, Arnold Lippa","doi":"10.1002/cpdd.1475","DOIUrl":null,"url":null,"abstract":"<p><p>AMPA-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the mammalian brain. Ampakines, positive allosteric modulators of AMPAR, hold significant potential for the treatment of a wide range of neurological/neuropsychiatric disorders in which excitatory synaptic transmission is compromised. Low-impact ampakines are a distinct subset of ampakines that accelerate channel opening yet minimally affect receptor desensitization, which may explain their lack of seizurogenic effects at therapeutic doses in preclinical models. CX1739 is a low-impact ampakine that has shown efficacy in preclinical studies. The current clinical study examined the tolerability and pharmacokinetics of CX1739 in healthy male volunteers in a 2-part study. Part A was a single dose escalation study (100-1200 mg, 48 patients) and Part B was a multiple dose ascending study (300-600 mg BID for 7-10 days, 32 patients). CX1739 was well tolerated up to 900 mg once daily (QD) and 450 mg twice a day, with the prominent side effects being headache and nausea. Importantly, the half-life of CX1739 was 6-9 hours, and T<sub>max</sub> was 1-5 hours. CX1739 C<sub>max</sub> and AUC were dose-proportional. These findings thus set the stage for further explorations of this drug candidate in phase 2 clinical studies.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5000,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Safety, Tolerability, and Pharmacokinetic Profile of the Low-Impact Ampakine CX1739 in Young Healthy Volunteers.\",\"authors\":\"Daniel P Radin, Rok Cerne, Jeffrey M Witkin, Arnold Lippa\",\"doi\":\"10.1002/cpdd.1475\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>AMPA-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the mammalian brain. Ampakines, positive allosteric modulators of AMPAR, hold significant potential for the treatment of a wide range of neurological/neuropsychiatric disorders in which excitatory synaptic transmission is compromised. Low-impact ampakines are a distinct subset of ampakines that accelerate channel opening yet minimally affect receptor desensitization, which may explain their lack of seizurogenic effects at therapeutic doses in preclinical models. CX1739 is a low-impact ampakine that has shown efficacy in preclinical studies. The current clinical study examined the tolerability and pharmacokinetics of CX1739 in healthy male volunteers in a 2-part study. Part A was a single dose escalation study (100-1200 mg, 48 patients) and Part B was a multiple dose ascending study (300-600 mg BID for 7-10 days, 32 patients). CX1739 was well tolerated up to 900 mg once daily (QD) and 450 mg twice a day, with the prominent side effects being headache and nausea. Importantly, the half-life of CX1739 was 6-9 hours, and T<sub>max</sub> was 1-5 hours. CX1739 C<sub>max</sub> and AUC were dose-proportional. These findings thus set the stage for further explorations of this drug candidate in phase 2 clinical studies.</p>\",\"PeriodicalId\":10495,\"journal\":{\"name\":\"Clinical Pharmacology in Drug Development\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":1.5000,\"publicationDate\":\"2024-09-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Pharmacology in Drug Development\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/cpdd.1475\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Pharmacology in Drug Development","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cpdd.1475","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Safety, Tolerability, and Pharmacokinetic Profile of the Low-Impact Ampakine CX1739 in Young Healthy Volunteers.
AMPA-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the mammalian brain. Ampakines, positive allosteric modulators of AMPAR, hold significant potential for the treatment of a wide range of neurological/neuropsychiatric disorders in which excitatory synaptic transmission is compromised. Low-impact ampakines are a distinct subset of ampakines that accelerate channel opening yet minimally affect receptor desensitization, which may explain their lack of seizurogenic effects at therapeutic doses in preclinical models. CX1739 is a low-impact ampakine that has shown efficacy in preclinical studies. The current clinical study examined the tolerability and pharmacokinetics of CX1739 in healthy male volunteers in a 2-part study. Part A was a single dose escalation study (100-1200 mg, 48 patients) and Part B was a multiple dose ascending study (300-600 mg BID for 7-10 days, 32 patients). CX1739 was well tolerated up to 900 mg once daily (QD) and 450 mg twice a day, with the prominent side effects being headache and nausea. Importantly, the half-life of CX1739 was 6-9 hours, and Tmax was 1-5 hours. CX1739 Cmax and AUC were dose-proportional. These findings thus set the stage for further explorations of this drug candidate in phase 2 clinical studies.
期刊介绍:
Clinical Pharmacology in Drug Development is an international, peer-reviewed, online publication focused on publishing high-quality clinical pharmacology studies in drug development which are primarily (but not exclusively) performed in early development phases in healthy subjects.