Population Pharmacokinetic Modeling and Stochastic Simulations to Support Pediatric Dose Selection of Pimavanserin

Pimavanserin is a selective serotonin-modulating agent with inverse agonist/antagonist activity at the 5-HT2A receptor. Safety and efficacy of pimavanserin 34 mg once daily was studied in adults with hallucinations and delusions associated with Parkinson's disease psychosis and other neuropsych...

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Veröffentlicht in:Journal of clinical pharmacology 2023-12, Vol.63 (12), p.1408-1416
Hauptverfasser: Darwish, Mona, Bugarski-Kirola, Dragana, Jaworowicz, David, Owen, Joel, Qaraghuli, Farah Al, Barry, Alida, DeKarske, Daryl
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container_end_page 1416
container_issue 12
container_start_page 1408
container_title Journal of clinical pharmacology
container_volume 63
creator Darwish, Mona
Bugarski-Kirola, Dragana
Jaworowicz, David
Owen, Joel
Qaraghuli, Farah Al
Barry, Alida
DeKarske, Daryl
description Pimavanserin is a selective serotonin-modulating agent with inverse agonist/antagonist activity at the 5-HT2A receptor. Safety and efficacy of pimavanserin 34 mg once daily was studied in adults with hallucinations and delusions associated with Parkinson's disease psychosis and other neuropsychiatric conditions. This analysis used model-based simulations of pimavanserin steady-state exposures to identify a dose that generated pediatric exposures comparable with adult exposures achieved with 34 mg pimavanserin. A population pharmacokinetics model was developed using pooled plasma drug concentration (i.e., actual) data from 13 clinical studies, including a phase 1 study of adolescent pediatric patients (13-17 years) with various psychiatric conditions. Stochastic simulations were performed to predict exposures in a virtual (i.e., simulated) group of pediatric patients (5-17 years). Steady-state measures of area under the plasma concentration-time curve (AUC) and maximum drug concentration (Cmax) were simulated for relevant age and weight stratifications and compared with simulated exposures in adults (18-49 years). Simulated mean AUC ranged 47.41-54.73 ng·d/mL and mean Cmax ranged 41.13-50.07 ng/mL in adults receiving pimavanserin 34 mg. Simulated mean (SD) Cmax with 34 mg pimavanserin was similar in patients aged 10-17 years (56.54 [24.58] ng/mL) and adults. Pimavanserin 20 mg yielded a mean (SD) Cmax most like the 34-mg adult Cmax in patients aged 5-9 years (45.30 [21.31] ng/mL) and in the 14-25 kg pediatric patient weight group (49.18 [22.91] ng/mL). Pimavanserin 20 and 34 mg in pediatric patients aged 5-9 and 10-17 years, respectively, yielded exposures similar to daily pimavanserin 34 mg in adults aged 18-49 years. This article is protected by copyright. All rights reserved.
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Safety and efficacy of pimavanserin 34 mg once daily was studied in adults with hallucinations and delusions associated with Parkinson's disease psychosis and other neuropsychiatric conditions. This analysis used model-based simulations of pimavanserin steady-state exposures to identify a dose that generated pediatric exposures comparable with adult exposures achieved with 34 mg pimavanserin. A population pharmacokinetics model was developed using pooled plasma drug concentration (i.e., actual) data from 13 clinical studies, including a phase 1 study of adolescent pediatric patients (13-17 years) with various psychiatric conditions. Stochastic simulations were performed to predict exposures in a virtual (i.e., simulated) group of pediatric patients (5-17 years). Steady-state measures of area under the plasma concentration-time curve (AUC) and maximum drug concentration (Cmax) were simulated for relevant age and weight stratifications and compared with simulated exposures in adults (18-49 years). Simulated mean AUC ranged 47.41-54.73 ng·d/mL and mean Cmax ranged 41.13-50.07 ng/mL in adults receiving pimavanserin 34 mg. Simulated mean (SD) Cmax with 34 mg pimavanserin was similar in patients aged 10-17 years (56.54 [24.58] ng/mL) and adults. Pimavanserin 20 mg yielded a mean (SD) Cmax most like the 34-mg adult Cmax in patients aged 5-9 years (45.30 [21.31] ng/mL) and in the 14-25 kg pediatric patient weight group (49.18 [22.91] ng/mL). Pimavanserin 20 and 34 mg in pediatric patients aged 5-9 and 10-17 years, respectively, yielded exposures similar to daily pimavanserin 34 mg in adults aged 18-49 years. This article is protected by copyright. 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All rights reserved.</description><subject>Drug dosages</subject><subject>Inverse agonists</subject><subject>Mental disorders</subject><subject>Movement disorders</subject><subject>Neurodegenerative diseases</subject><subject>Parkinson's disease</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Pharmacokinetics</subject><subject>Psychosis</subject><subject>Simulation</subject><subject>Stochasticity</subject><issn>0091-2700</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNpd0ctKxDAUBuAgio6jC19AAm500fHk0ttSxisoFsZ9SdNTJ2Pb1KQVfHtbHV24Chy-_CTnJ-SEwYIB8MuN7tYLLli4Q2YsDHkgI5C7ZAaQsoDHAAfk0PsNAItkyPbJgYhlzCIRzYjLbDfUqje2pdlauUZp-2Za7I2mT7bE2rSvVLUlXfVWr5Wf5ivTbK942lu6GrrOup5mWBrVuxFcW490hTXq71xb0cw06kO1Hp1pj8hepWqPx9tzTl5ub16W98Hj893D8uox0AKSPih4VQgRFpgqKTEEjYwVpUx0EsaKibRksRinKRQiwTApOTLQPJVVIXWFUszJ-U9s5-z7gL7PG-M11rVq0Q4-54lkwCNIJ3r2j27s4NrxcaNKYh7FPI5GdfGjtLPeO6zyzo3fcp85g3zqIZ96yKceRnu6TRyKBss_-bt48QVGSoS5</recordid><startdate>20231201</startdate><enddate>20231201</enddate><creator>Darwish, Mona</creator><creator>Bugarski-Kirola, Dragana</creator><creator>Jaworowicz, David</creator><creator>Owen, Joel</creator><creator>Qaraghuli, Farah Al</creator><creator>Barry, Alida</creator><creator>DeKarske, Daryl</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20231201</creationdate><title>Population Pharmacokinetic Modeling and Stochastic Simulations to Support Pediatric Dose Selection of Pimavanserin</title><author>Darwish, Mona ; Bugarski-Kirola, Dragana ; Jaworowicz, David ; Owen, Joel ; Qaraghuli, Farah Al ; Barry, Alida ; DeKarske, Daryl</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c308t-b2fb335be9a44e50ce11bd48c857a139d17350c90b38e58d2e10c294fb4cfe43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Drug dosages</topic><topic>Inverse agonists</topic><topic>Mental disorders</topic><topic>Movement disorders</topic><topic>Neurodegenerative diseases</topic><topic>Parkinson's disease</topic><topic>Patients</topic><topic>Pediatrics</topic><topic>Pharmacokinetics</topic><topic>Psychosis</topic><topic>Simulation</topic><topic>Stochasticity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Darwish, Mona</creatorcontrib><creatorcontrib>Bugarski-Kirola, Dragana</creatorcontrib><creatorcontrib>Jaworowicz, David</creatorcontrib><creatorcontrib>Owen, Joel</creatorcontrib><creatorcontrib>Qaraghuli, Farah Al</creatorcontrib><creatorcontrib>Barry, Alida</creatorcontrib><creatorcontrib>DeKarske, Daryl</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Darwish, Mona</au><au>Bugarski-Kirola, Dragana</au><au>Jaworowicz, David</au><au>Owen, Joel</au><au>Qaraghuli, Farah Al</au><au>Barry, Alida</au><au>DeKarske, Daryl</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Population Pharmacokinetic Modeling and Stochastic Simulations to Support Pediatric Dose Selection of Pimavanserin</atitle><jtitle>Journal of clinical pharmacology</jtitle><addtitle>J Clin Pharmacol</addtitle><date>2023-12-01</date><risdate>2023</risdate><volume>63</volume><issue>12</issue><spage>1408</spage><epage>1416</epage><pages>1408-1416</pages><issn>0091-2700</issn><eissn>1552-4604</eissn><abstract>Pimavanserin is a selective serotonin-modulating agent with inverse agonist/antagonist activity at the 5-HT2A receptor. 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Steady-state measures of area under the plasma concentration-time curve (AUC) and maximum drug concentration (Cmax) were simulated for relevant age and weight stratifications and compared with simulated exposures in adults (18-49 years). Simulated mean AUC ranged 47.41-54.73 ng·d/mL and mean Cmax ranged 41.13-50.07 ng/mL in adults receiving pimavanserin 34 mg. Simulated mean (SD) Cmax with 34 mg pimavanserin was similar in patients aged 10-17 years (56.54 [24.58] ng/mL) and adults. Pimavanserin 20 mg yielded a mean (SD) Cmax most like the 34-mg adult Cmax in patients aged 5-9 years (45.30 [21.31] ng/mL) and in the 14-25 kg pediatric patient weight group (49.18 [22.91] ng/mL). Pimavanserin 20 and 34 mg in pediatric patients aged 5-9 and 10-17 years, respectively, yielded exposures similar to daily pimavanserin 34 mg in adults aged 18-49 years. This article is protected by copyright. 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subjects Drug dosages
Inverse agonists
Mental disorders
Movement disorders
Neurodegenerative diseases
Parkinson's disease
Patients
Pediatrics
Pharmacokinetics
Psychosis
Simulation
Stochasticity
title Population Pharmacokinetic Modeling and Stochastic Simulations to Support Pediatric Dose Selection of Pimavanserin
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