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

Yan Nan Zang, Wei Guo, Fang Dong, An Ning Li, Jose de Leon, Can Jun Ruan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish
Pages (from-to)621-635
Number of pages15
JournalExpert Review of Clinical Pharmacology
Issue number5
StatePublished - 2022

Bibliographical note

Funding Information:
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.

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

Publisher Copyright:
© 2022 Informa UK Limited, trading as Taylor & Francis Group.


  • 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

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics (all)
  • Pharmacology (medical)


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