Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study.
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.
Feng
Yan
Y
Strategic Modeling and Simulation Group, Bristol-Myers Squibb Co., Princeton, NJ, USA.
Pollock
Bruce G
BG
Coley
Kim
K
Marder
Stephen
S
Miller
Del
D
Kirshner
Margaret
M
Aravagiri
Manickam
M
Schneider
Lon
L
Bies
Robert R
RR
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
D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D018967:Risperidone; D000068882:Paliperidone Palmitate
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