Abstract
Background and Objective: Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK model in Chinese adult psychiatric patients also investigated the influence of comedications and co-occurrence of infections on olanzapine clearance, and explored how to personalize oral olanzapine dosage in the clinical setting. Methods: A total of 1546 serum concentrations from 354 patients were collected in this study. A one-compartment model with first-order absorption was employed to develop the PPK model using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, co-occurrence of infection and concomitant medications (including dangguilonghui tablets, a Chinese herbal medicine for constipation). Bootstrap validation (1000 runs) and external validation of 50 patients were employed to evaluate the final model. Simulations were performed to explore the personalization of olanzapine dosing after stratification by sex, smoking, and comedication with valproate. Results: Typical estimates for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) were 0.30 h−1, 12.88 L/h, and 754.41 L, respectively. Olanzapine clearance was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine clearance was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. The model evaluation indicated that the final model’s performance was good, stable, and precise. Conclusion: This study contributes to the personalization of oral olanzapine dosing, but further studies should be performed to verify the effects of infection and comedications, including valproate and dangguilonghui.
| Original language | English |
|---|---|
| Pages (from-to) | 353-371 |
| Number of pages | 19 |
| Journal | European Journal of Drug Metabolism and Pharmacokinetics |
| Volume | 46 |
| Issue number | 3 |
| DOIs | |
| State | Published - May 2021 |
Bibliographical note
Funding Information:The writing of this article was completed without any external funding. The study was financed by two grants to Beijing Anding Hospital: one with Dr. Ruan as the principal investigator (Beijing Science and Technology Plan Project Z171100001017074), and another from the National Natural Youth Fund (81801322) with Dr. Li as the principal investigator.
Funding Information:
The authors wish to thank all investigators and medical, nursing, and laboratory staff who participated in this study. They would also like to thank Lorraine Maw, MA, at the Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA, for editorial assistance. Can-Jun Ruan is supported by a 2019 NARSAD Young Investigator Award from the Brain & Behavior Research Foundation on clozapine and CYP1A2 gene variants. The authors are grateful to the reviewers who provided important suggestions for improving the article.
Funding Information:
The authors wish to thank all investigators and medical, nursing, and laboratory staff who participated in this study. They would also like to thank Lorraine Maw, MA, at the Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA, for editorial assistance. Can-Jun Ruan is supported by a 2019 NARSAD Young Investigator Award from the Brain & Behavior Research Foundation on clozapine and CYP1A2 gene variants. The authors are grateful to the reviewers who provided important suggestions for improving the article.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)