title: Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study.
abstract: OBJECTIVE
  To characterize pharmacokinetic (PK) variability of risperidone and 9-OH risperidone using sparse sampling and to evaluate the effect of covariates on PK parameters.
  
  
  METHODS
  PK analysis used plasma samples collected from the Clinical Antipsychotic Trials of Intervention Effectiveness. A nonlinear mixed-effects model was developed using NONMEM to describe simultaneously the risperidone and 9-OH risperidone concentration-time profile. Covariate effects on risperidone and 9-OH risperidone PK parameters were assessed, including age, weight, sex, smoking status, race and concomitant medications.
  
  
  RESULTS
  PK samples comprised 1236 risperidone and 1236 9-OH risperidone concentrations from 490 subjects that were available for analysis. Ages ranged from 18 to 93 years. Population PK submodels for both risperidone and 9-OH risperidone with first-order absorption were selected to describe the concentration-time profile of risperidone and 9-OH risperidone. A mixture model was incorporated with risperidone clearance (CL) separately estimated for three subpopulations [poor metabolizer (PM), extensive metabolizer (EM) and intermediate metabolizer (IM)]. Age significantly affected 9-OH risperidone clearance. Population parameter estimates for CL in PM, IM and EM were 12.9, 36 and 65.4 l h(-1) and parameter estimates for risperidone half-life in PM, IM and EM were 25, 8.5 and 4.7 h, respectively.
  
  
  CONCLUSIONS
  A one-compartment mixture model with first-order absorption adequately described the risperidone and 9-OH risperidone concentrations. Age was identified as a significant covariate on 9-OH risperidone clearance in this study.
authors.affiliation: Strategic Modeling and Simulation Group, Bristol-Myers Squibb Co., Princeton, NJ, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
authors.forename: Kim
authors.initials: K
authors.lastname: Coley
authors.forename: Stephen
authors.initials: S
authors.lastname: Marder
authors.forename: Del
authors.initials: D
authors.lastname: Miller
authors.forename: Margaret
authors.initials: M
authors.lastname: Kirshner
authors.forename: Manickam
authors.initials: M
authors.lastname: Aravagiri
authors.forename: Lon
authors.initials: L
authors.lastname: Schneider
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D001835:Body Weight; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D008956:Models, Chemical; D015233:Models, Statistical; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D018967:Risperidone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018401:Sample Size; D012494:Sampling Studies; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D018967:Risperidone; D000068882:Paliperidone Palmitate
references.citation: Pharmacogenomics. 2002 Mar;3(2):229-43
references.pmid: 11972444
references.citation: J Pharm Sci. 1993 May;82(5):447-9
references.pmid: 7689651
references.citation: Schizophr Bull. 2003;29(1):33-43
references.pmid: 12908659
references.citation: Clin Pharmacol Ther. 2003 Jan;73(1):31-40
references.pmid: 12545141
references.citation: J Clin Psychiatry. 2005 Jan;66(1):15-27
references.pmid: 15669884
references.citation: J Pharmacokinet Pharmacodyn. 2001 Jun;28(3):231-52
references.pmid: 11468939
references.citation: Br J Clin Pharmacol. 2003 Jul;56(1):96-103
references.pmid: 12848781
references.citation: Br J Clin Pharmacol. 2006 May;61(5):558-69
references.pmid: 16669849
references.citation: Can J Psychiatry. 1993 Sep;38 Suppl 3:S89-95
references.pmid: 7504574
references.citation: J Pharmacokinet Biopharm. 1977 Oct;5(5):445-79
references.pmid: 925881
references.citation: JAMA. 2005 Oct 19;294(15):1934-43
references.pmid: 16234500
references.citation: J Pharmacokinet Pharmacodyn. 2007 Apr;34(2):183-206
references.pmid: 17136449
references.citation: Psychopharmacology (Berl). 2006 Jan;183(4):490-9
references.pmid: 16283256
references.citation: Clin Pharmacol Ther. 2000 Aug;68(2):130-42
references.pmid: 10976544
references.citation: J Pharmacol Exp Ther. 1988 Nov;247(2):661-70
references.pmid: 2460616
references.citation: Drug Metab Dispos. 1993 Nov-Dec;21(6):1134-41
references.pmid: 7507814
references.citation: Schizophr Bull. 2003;29(1):15-31
references.pmid: 12908658
references.citation: J Biol Chem. 1990 Oct 5;265(28):17209-14
references.pmid: 2211621
references.citation: J Clin Psychopharmacol. 2005 Dec;25(6):527-32
references.pmid: 16282832
references.citation: Br J Clin Pharmacol. 1991 Dec;32(6):669-70
references.pmid: 1768557
references.citation: Int Clin Psychopharmacol. 1995 Mar;10(1):19-30
references.pmid: 7542676
references.citation: J Psychopharmacol. 2005 Jul;19(4):395-401
references.pmid: 15982995
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1999 Feb;359(2):147-51
references.pmid: 10048600
references.citation: Pharm Res. 1995 Dec;12(12):1845-55
references.pmid: 8786955
references.citation: J Clin Psychopharmacol. 2002 Aug;22(4):419-23
references.pmid: 12172343
references.citation: Psychopharmacology (Berl). 1995 Dec;122(3):223-9
references.pmid: 8748391
references.citation: Psychopharmacology (Berl). 2001 Jan 1;153(2):238-43
references.pmid: 11205425
references.citation: J Clin Pharmacol. 2004 Dec;44(12):1352-9
references.pmid: 15545305
references.citation: N Engl J Med. 2006 Oct 12;355(15):1525-38
references.pmid: 17035647