Population pharmacokinetics analysis of olanzapine for Chinese psychotic patients based on clinical therapeutic drug monitoring data with assistance of meta-analysis
Anyue Yin (1), Dewei Shang (4), Yuguan Wen (4), Liang Li (1)(2)(3), Tianyan Zhou (1)(2)(3), Wei Lu (1)(2)(3)(5)
(1) School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China; (2) Peking University/Pfizer Pharmacometrics Education Center, Peking University Health Science Center, Beijing 100191, China (3) State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China (4) Guangzhou Brain Hospital (Guangzhou Huiai Hospital, the Affiliated Brain Hospital of Guangzhou Medical University), Guangzhou 510370, China (5) Beijing Institute for Brain Disorders, Beijing 100088, China
Objectives: The aim of this study was to build an eligible population pharmacokinetic (PK) model for olanzapine in Chinese psychotic patients based on therapeutic drug monitoring (TDM) data, with assistance of model-based meta-analysis [1], to facilitate individualized therapy.
Methods: Population PK analysis for olanzapine was performed using NONMEM software (version 7.3.0). TDM data were collected from Guangzhou Brain Hospital (China). Because of the limitations of TDM data, model-based meta-analysis was performed to construct a structural model to assist the modeling of TDM data as prior estimates. After analyzing related covariates in a stepwise manner [2], a simulation was performed to predict concentrations for different types of patients under common dose regimens.
Results: A two-compartment model with first-order absorption and elimination was developed for olanzapine oral tablets, based on 23 articles with 390 data points, and was well applied on the TDM data. The apparent systematic clearance (CL/F) and apparent volume of distribution for the central compartment (V2/F) were found be correlated and the correlation was as high as 98.2 %. Predictability and stability of the model were confirmed to be acceptable. Gender and smoking habits influenced the clearance of olanzapine significantly. To achieve a blood concentration of 20 ng/mL (the lower boundary of the recommended therapeutic range) [3], simulation results indicated that the dose regimen of olanzapine should be 5 mg BID (twice a day), ≥ 5 mg QD (every day) plus 10 mg QN (every night), or >10 mg BID for female nonsmokers, male nonsmokers and male smokers, respectively.
Conclusions: The population PK model, built using meta-analysis, could facilitate the modeling of TDM data collected from Chinese psychotic patients. The factors that significantly influence olanzapine disposition were determined and the final model could be utilized for individualized treatment.
References:
[1] Mandema JW, Gibbs M, Boyd RA, Wada DR, Pfister M. Model-based meta-analysis for comparative efficacy and safety: application in drug development and beyond. Clin Pharmacol Ther (2011) 90(6):766–769.
[2] Wählby U, Jonsson EN, Karlsson MO. Comparison of stepwise covariate model building strategies in population pharmacokinetic- pharmacodynamic analysis. AAPS PharmSci (2002) 4(4):E27.
[3] Hiemke C, Dragicevic A, Gründer G, Hätter S, Sachse J, Vernaleken I et al. Therapeutic monitoring of new antipsychotic drugs. Ther Drug Monit (2004) 26(2):156–160.
