title: Effect of renal impairment on the pharmacokinetics of PD 0200390, a novel ligand for the voltage-gated calcium channel alpha-2-delta subunit.
abstract: OBJECTIVE
  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 0200390 clearance and estimated creatinine clearance (CLcr).
  
  
  METHODS
  In this open-label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr >80 ml min(-1); n= 6); mild RI (CLcr 51 to < or =80 ml min(-1); n= 6); moderate RI (CLcr >30 to 50 ml min(-1); n= 6); and severe RI (CLcr < or =30 ml min(-1); n= 8). Subjects received a single, oral dose of PD 0200390 25 mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data.
  
  
  RESULTS
  PD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66-3.24 h. Mean half-life in subjects with normal renal function was 5.36 h, and increased with worsening RI. Oral (CL/F) and renal (CL(R)) clearance rates decreased with deteriorating renal function, whereas area under the concentration-time curve (AUC(0-infinity)) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD 0200390 exposure. Regression analysis demonstrated that CL/F and CL(R) correlated with CLcr (r= 0.953 and 0.961, respectively). PD 0200390 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.
  
  
  CONCLUSIONS
  PD 0200390 pharmacokinetic parameters (CL/F, CL(R) and AUC(0-infinity)) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.
authors.affiliation: Department of Neuroscience, Pfizer Global Research and Development, 50 Pequot Avenue, New London, CT 06320, USA. brian.corrigan@pfizer.com
authors.forename: Brian
authors.initials: B
authors.lastname: Corrigan
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Feltner
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: John L
authors.initials: JL
authors.lastname: Werth
authors.forename: Allen E
authors.initials: AE
authors.lastname: Moton
authors.forename: Gordon
authors.initials: G
authors.lastname: Gibson
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015220:Calcium Channels / Q000378:metabolism / Q000493:pharmacokinetics*; D003517:Cyclopentanes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D012016:Reference Values; D012044:Regression Analysis; D012720:Severity of Illness Index; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D055815:Young Adult
chemical_list: C547571:(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid; D000085:Acetates; C425903:CACNA2D1 protein, human; D015220:Calcium Channels; D003517:Cyclopentanes; D010726:Phosphodiesterase Inhibitors
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