Published population pharmacokinetic models of valproic acid in adult patients: a systematic review and external validation in a Chinese sample of inpatients with bipolar disorder

ABSTRACT

Background

This study reviewed all published valproic acid (VPA) population pharmacokinetic (PPK) models in adult patients and assessed them using external validation methods to determine predictive performance.

Methods

Thirteen published PPK models (labeled with letters A to M) not restricted to children were identified in PubMed, Embase, and Web of Science databases. They were evaluated in a sample totaling 411 serum concentrations from 146 adult inpatients diagnosed with bipolar disorder in a Chinese hospital. Serum concentrations of VPA were analyzed by validated ultra-performance liquid chromatography-tandem mass spectrometry. Performance was assessed by four tests (prediction-based diagnostics, visual predictive checks, normalized prediction distribution error, and Bayesian forecasting).

Results

Models K and L, developed in large samples of Chinese and Thai patients, showed good performance in our Chinese dataset. Models H and J demonstrated good performance in 2 and 3 of the 4 tests, respectively. Another seven models exhibited intermediate performance. The models with the worst performance, F and M, could not be improved by Bayesian forecasting.

Conclusion

In our validation study, the most important factors contributing to good performance were absence of children, Asian ethnicity, one-compartment models, and inclusion of body weight and VPA dose in previously published models.

KEYWORDS:

• Asian continental ancestry group
• bipolar disorder
• drug monitoring
• population pharmacokinetics
• systematic review
• valproic acid/administration and dosage
• valproic acid/blood
• valproic acid/metabolism
• valproic acid/pharmacokinetics

Article highlights

• Population pharmacokinetics of valproic acid have previously been developed in healthy subjects, epileptic patients, or manic patients to investigate pharmacokinetic characteristics and identify covariates for personalized dosing. The predictability of these models when extrapolated to other clinical samples remains to be established.

• The predictive performances of all published population pharmacokinetic models of valproic acid not restricted to children were evaluated in an independent external adult cohort with inpatients diagnosed with bipolar disorder in a Chinese hospital.

• Model K, using Chinese adult patients with epilepsy, and Model L, using Thai patients with mania, produced the best performances.

• Our literature review and results suggest that the variable factors influencing model predictability in these valproic acid models may include absence of children, ethnicity, type of model structure, and covariates involved (bodyweight and valproic acid daily dose

Acknowledgments

The authors wish to thank Lorraine Maw, MA, at the Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA, for editorial assistance.

Author contributions

C-J Ruan had a leading role in the design of the study. Y-N Zang and W Guo extracted the published PPK information from the literature independently, and C-J Ruan checked the information and provided help in case of doubt. F Dong and A-N Li contributed to the acquisition of patient data. Y-N Zang and C-J Ruan conducted the statistical analyses while J de Leon suggested modifications. 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 authors contributed to the analysis and interpretation of the data, completed a critical revision for important intellectual content and approved the final submitted version of the article.

Data availability statement

The data of this study are available from the corresponding author (email: [email protected]) upon reasonable request.

Declaration of interest

J de Leon has previously 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). He 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 apart from those disclosed.

Reviewer disclosures

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

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

Y-N Zang received support from the Capital’s Funds for Health Improvement and Research (No.2018-4-2124) and A-N Li was supported by Beijing Hospitals Authority Youth Program (No. QMS20201903) and Beijing Municipal Administration of Hospitals Incubating Program (No. PX2019070), which promoted this study.