Population pharmacokinetics of olanzapine in pediatric patients with psychiatric disorders

ABSTRACT

Objective

To develop and validate a population pharmacokinetic (PPK) model of oral olanzapine in pediatric Chinese patients in order to individualize therapy in this population.

Methods

A total of 897 serum concentrations from 269 pediatric patients taking oral olanzapine (ages 8 to 17 years) were collected. Demographic parameters, biological characteristics and concomitant medications were investigated as covariates. The data was analyzed using a nonlinear mixed-effects modeling approach. Bootstrapping (1000 runs), normalized prediction distribution error (NPDE), and external validation of 62 patients were employed. Simulations were performed to explore the individualized dosing regimens in various situations.

Results

The one-compartment model with first-order absorption and elimination had an apparent clearance (CL/F) of 10.38 L/h, a distribution volume (V/F) of 9.41 L/kg and an absorption rate constant (K_a) fixed at 0.3 h⁻¹. The equation was CL∕F (L∕h) = 10.38 × (body weight∕60)^0.25 ×1.33 (if male) × 0.71 (if co-occurrence of infection) × 0.51 (if co-therapy with fluvoxamine) × 1.27 (if co-therapy with sertraline) × 1.43 (if co-therapy with valproate). The final model had satisfactory stability, robustness, and predictive ability. The results from a simulation suggested the oral olanzapine doses required for male and female pediatric patients weighing between 40-60 kg without co-medication were 10–15 mg/day and 7.5-10 mg/day, respectively, and dosage adjustments should be based on sex and body weight; and co-administrated with valproate, sertraline, or fluvoxamine.

Conclusion

This model may help individualize optimum dosing of oral olanzapine for pediatric patients.

KEYWORDS:

• Adolescent
• Asian people
• child
• drug interactions
• drug monitoring
• infections
• models
• olanzapine/*administration &dosage/metabolism/pharmacokinetics
• population pharmacokinetics
• precision medicine

Disclaimer

As a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also.

Article highlights

• Olanzapine, an atypical antipsychotic, is widely used in children and adolescents for the treatment of psychiatric disorders including schizophrenia and bipolar disorder.

• A literature review supports consideration of sex, ethnicity, body weight and co-medications including sertraline, valproate, fluvoxamine and co-occurrence of infection in olanzapine PPK models.

• After considering published models, a new pharmacokinetic population model was developed to assess the pharmacokinetic characteristics of olanzapine in children and adolescents (ages 8-17 years).

• In our final model, sex, co-occurrence of infection and concomitant medications (including fluvoxamine, sertraline, and valproate) were identified as significant covariates of olanzapine’s apparent clearance (CL/F).

• Based on our model, olanzapine dose recommendations in pediatric patients should be based on sex and body weight; co-administrated with valproate, sertraline, or fluvoxamine; and monitored via olanzapine concentrations to maximize patient efficacy and safety.

• Olanzapine dosing for child and adolescent patients with body weights higher than 60 kg appears to be similar to that of adults.

Declaration of interest

C-J Ruan was supported by the program of Beijing Science and Technology Plan Project Z171100001017074. J de Leon personally develops his presentations for lecturing, has never lectured using any pharmaceutical or pharmacogenetic company presentations, and has never been a consultant for pharmacogenetic or pharmaceutical companies. In the past, J de Leon received researcher-initiated grants from Eli Lilly (one ended in 2003 and the other, as co-investigator, ended in 2007); from Roche Molecular Systems, Inc. (ended in 2007); and, in a collaboration with Genomas, Inc., from the NIH Small Business Innovation Research program (ended in 2010). J de Leon has been on the advisory boards of Bristol-Myers Squibb (2003/04) and AstraZeneca (2003). Roche Molecular Systems supported one of his educational presentations, which was published in a peer-reviewed journal (2005). His lectures were supported once by Sandoz (1997), twice by Lundbeck (1999 and 1999), twice by Pfizer (2001 and 2001), three times by Eli Lilly (2003, 2006, and 2006), twice by Janssen (2000 and 2006), once by Bristol-Myers Squibb (2006), and seven times by Roche Molecular Systems, Inc. (once in 2005 and six times in 2006). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author Contributions

C-J Ruan and G Wang had a leading role in the design of the study. C-J Ruan, Y-N Zang, Z Wan, F Jia, Q Yang, C-G Liu, Q Wang, S-S Liu, F Dong, and A-N Li contributed to the acquisition of patient data. Y-N Zang and C-J Ruan conducted the statistical analyses. Y-N Zang wrote the first draft of the article and C-J Ruan and J de Leon modified it based on the journal’s style. All the co-authors critically reviewed the article, provided modifications, approved the first and final versions and any significant changes at the proofreading stage, approved the submission to this journal and agreed to take responsibility and be accountable for the contents of the article and to share responsibility in resolving any questions raised about the accuracy or integrity of the published work.

Data Availability Statement

The data of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This manuscript was funded by the Beijing Municipal Commission of Science and Technology/Beijing Science and Technology Plan Project Z171100001017074.