Optimal sampling of antipsychotic medicines: a pharmacometric approach for clinical practice.
OBJECTIVE
To determine optimal sampling strategies to allow the calculation of clinical pharmacokinetic parameters for selected antipsychotic medicines using a pharmacometric approach.


METHODS
This study utilized previous population pharmacokinetic parameters of the antipsychotic medicines aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone (including 9-OH risperidone) and ziprasidone. d-optimality was utilized to identify time points which accurately predicted the pharmacokinetic parameters (and expected error) of each drug at steady-state. A standard two stage population approach (STS) with MAP-Bayesian estimation was used to compare area under the concentration-time curves (AUC) generated from sparse optimal time points and rich extensive data. Monte Carlo Simulation (MCS) was used to simulate 1000 patients with population variability in pharmacokinetic parameters. Forward stepwise regression analysis was used to determine the most predictive time points of the AUC for each drug at steady-state.


RESULTS
Three optimal sampling times were identified for each antipsychotic medicine. For aripiprazole, clozapine, olanzapine, perphenazine, risperidone, 9-OH risperidone, quetiapine and ziprasidone the CV% of the apparent clearance using optimal sampling strategies were 19.5, 8.6, 9.5, 13.5, 12.9, 10.0, 16.0 and 10.7, respectively. Using the MCS and linear regression approach to predict AUC, the recommended sampling windows were 16.5-17.5 h, 10-11 h, 23-24 h, 19-20 h, 16.5-17.5 h, 22.5-23.5 h, 5-6 h and 5.5-6.5 h, respectively.


CONCLUSIONS
This analysis provides important sampling information for future population pharmacokinetic studies and clinical studies investigating the pharmacokinetics of antipsychotic medicines.
School of Pharmacy and Pharmaceutical Sciences, School of Pharmacy, SUNY at Buffalo, Buffalo, NY, USA; Schizophrenia Research Institute, Sydney, Australia.
Vidya
V
Perera
Robert R
RR
Bies
Gary
G
Mo
Michael J
MJ
Dolton
Vaughan J
VJ
Carr
Andrew J
AJ
McLachlan
Richard O
RO
Day
Thomas M
TM
Polasek
Alan
A
Forrest
D000465:Algorithms; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001499:Bayes Theorem; D006801:Humans; D009010:Monte Carlo Method
D014150:Antipsychotic Agents
antipsychotic medicines; optimal sampling; pharmacometrics; population pharmacokinetics; therapeutic drug monitoring