{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T19:41:17Z","timestamp":1760298077400},"reference-count":15,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,5,5]],"date-time":"2009-05-05T00:00:00Z","timestamp":1241481600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2009,8]]},"abstract":"<jats:sec><jats:label \/><jats:p> <jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003PD 0200390 is a ligand for the alpha\u20102\u2010delta protein, an auxiliary subunit of voltage\u2010gated calcium channels, which is the first in a new class being investigated for the treatment of insomnia.<\/jats:p><jats:p>\u2022\u2003Preclinical studies showed that PD 0200390 increases slow\u2010wave sleep in rats; in humans, data in healthy volunteers showed that PD 0200390 is safe and well tolerated, and that renal excretion of unchanged drug is the primary route of elimination of PD 0200390.<\/jats:p><jats:p>\u2022\u2003This study investigated the effect of renal impairment on the single\u2010dose pharmacokinetics and tolerability of PD 0200390, to determine whether dose adjustments may be required in individuals with renal dysfunction.<\/jats:p><jats:p> <jats:bold>WHAT THIS STUDY ADDS<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003PD 0200390 was well tolerated in subjects with mild, moderate or no renal impairment, whereas the group of patients with severe renal impairment experienced an increased frequency of treatment\u2010associated adverse events.<\/jats:p><jats:p>\u2022\u2003The degree of renal impairment had a predictable effect on the clearance of PD 0200390; correlation between key pharmacokinetic parameters (renal and oral clearance, and drug exposure) and changes in renal function were confirmed by regression analysis.<\/jats:p><jats:p>\u2022\u2003Dose adjustment may be required when PD 0200390 is administered to patients with impaired renal function, to compensate for increased exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>AIMS<\/jats:title><jats:p>To investigate the pharmacokinetics and safety of PD 0200390 in healthy subjects and subjects with renal impairment (RI) and to examine the relationship between oral and renal PD\u20030200390 clearance and estimated creatinine clearance (CLcr).<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>In this open\u2010label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr &gt;80\u2003ml\u2003min<jats:sup>\u22121<\/jats:sup>; <jats:italic>n<\/jats:italic>= 6); mild RI (CLcr 51 to \u226480\u2003ml\u2003min<jats:sup>\u22121<\/jats:sup>; <jats:italic>n<\/jats:italic>= 6); moderate RI (CLcr &gt;30 to 50\u2003ml\u2003min<jats:sup>\u22121<\/jats:sup>; <jats:italic>n<\/jats:italic>= 6); and severe RI (CLcr \u226430\u2003ml\u2003min<jats:sup>\u22121<\/jats:sup>; <jats:italic>n<\/jats:italic>= 8). Subjects received a single, oral dose of PD\u20030200390 25\u2003mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration\u2013time data.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>PD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66\u20133.24\u2003h. Mean half\u2010life in subjects with normal renal function was 5.36\u2003h, and increased with worsening RI. Oral (CL\/<jats:italic>F<\/jats:italic>) and renal (CL<jats:sub><jats:italic>R<\/jats:italic><\/jats:sub>) clearance rates decreased with deteriorating renal function, whereas area under the concentration\u2013time curve (AUC<jats:sub>0\u2013\u221e<\/jats:sub>) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD\u20030200390 exposure. Regression analysis demonstrated that CL\/<jats:italic>F<\/jats:italic> and CL<jats:sub><jats:italic>R<\/jats:italic><\/jats:sub> correlated with CLcr (<jats:italic>r<\/jats:italic>= 0.953 and 0.961, respectively). PD\u20030200390 was well tolerated in subjects with mild, moderate or no RI. The most common adverse events were somnolence, dizziness and headache; these occurred with greatest intensity in the severe RI group.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>PD 0200390 pharmacokinetic parameters (CL\/<jats:italic>F<\/jats:italic>, CL<jats:sub><jats:italic>R<\/jats:italic><\/jats:sub> and AUC<jats:sub>0\u2013\u221e<\/jats:sub>) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2009.03444.x","type":"journal-article","created":{"date-parts":[[2009,5,5]],"date-time":"2009-05-05T11:36:53Z","timestamp":1241523413000},"page":"174-180","source":"Crossref","is-referenced-by-count":6,"title":["Effect of renal impairment on the pharmacokinetics of PD 0200390, a novel ligand for the voltage\u2010gated calcium channel alpha\u20102\u2010delta subunit"],"prefix":"10.1111","volume":"68","author":[{"given":"Brian","family":"Corrigan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas E.","family":"Feltner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Ouellet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John L.","family":"Werth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allen E.","family":"Moton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon","family":"Gibson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,8,7]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.2174\/187152707779940754"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.171.4.382"},{"key":"e_1_2_7_4_2","first-page":"274","article-title":"Epidemiology of insomnia: a longitudinal study in a UK population","volume":"30","author":"Morphy H","year":"2007","journal-title":"Sleep"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.154.10.1417"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/25.6.621"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2006.12.006"},{"issue":"1","key":"e_1_2_7_8_2","first-page":"s102","article-title":"PD 0200390, a novel \u03b12\u03b4 ligand, enhances slow wave sleep [abstract","volume":"63","author":"Donevan S","year":"2008","journal-title":"Biol Psychiatry"},{"issue":"1","key":"e_1_2_7_9_2","first-page":"S29","article-title":"Pharmacokinetics and pharmacodynamics of PD 0200390 following single\u2010dose administration to healthy volunteers","volume":"83","author":"Corrigan B","year":"2008","journal-title":"Clin Pharmacol Ther"},{"issue":"1","key":"e_1_2_7_10_2","first-page":"S30","article-title":"Pharmacokinetics of PD 0200390 following multiple dose administration to healthy volunteers","volume":"83","author":"Corrigan B","year":"2008","journal-title":"Clin Pharmacol Ther"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1159\/000180580"},{"key":"e_1_2_7_12_2","unstructured":"Pfizer Inc. 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