Misleading valproate dose-related reference ranges calculated by AGNP consensus guidelines 2017 Short running title : Valproate AGNP dose-related reference range

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology 2017 were recently published. In particular, definition and calculation of drug dose-related reference ranges (DRRR) were updated. However, calculation of DRRR with newly published dose-related concentration factors (DRC) for valproate lead to misleading, too high DRRR. Future pharmacokinetic studies that strongly control for confounding factors that may impact the pharmacokinetics of valproate were needed to receive appropriate pharmacokinetic data for the calculation of DRRR of valproate. We suggest for the next consensus update a DRCmean of approximately 52 ng/mL/mg. Thus, an approximately 50% reduction in DRCmean is recommended, as the DRCmean in the 2017 guidelines amounts 98.5 ng/ mL/mg. Currently, DRRR of valproate should be used with caution in clinical practice. Correspondence to: Gudrun Hefner, Vitos Klinik Hochtaunus, Emil-Sioli-Weg 1-3 61081 Friedrichsdorf, Germany, Tel: +49 (0)6123 602 7686 , Fax: +49 (0)6123 602 – 666, E-Mail: Gudrun.Hefner@vitos-rheingau.de


Letter to the editor
Recently, the Therapeutic Drug Monitoring (TDM) task force of the working group on neuropsychopharmacology and pharmacopsychiatry (AGNP) issued actualized Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 [1]. In particular, definition and calculation of drug dose-related reference ranges (DRRR) [2] were updated. While the 2011 guidelines [3] list dose-related plasma concentration factors (C/D) for the calculation of DRRR, new guidelines 2017 [1] list dose-related concentration factors (DRC). In the guidelines 2011 [3], C/D low and C/D high factors were multiplied by the daily dose for the calculation of DRRR. After the update [1], these factors were replaced by DRC low and DRC high .
In the 2011 guidelines [3], C/D factors for valproate were only given for a dosing interval of 24h, while the new guidelines [1] additionally list DRC factors for a dosing interval of 12h. Furthermore, as presented in the updated guidelines, the new calculation of DRC factors considered the short elimination half-life of valproate, that should lead to more reliable DRRR [1].
As only patients without pharmacokinetic abnormalities (e.g. liver or kidney disease, age ≥65 years) that were adherent to medication (dosing interval 12h) were included in the study, reliable results were expected [4].
C/D factors of the guidelines 2011 [3] and DRC factors (dosing interval 12h) of the updated guidelines [1]  C/D factors of the 2011 guidelines [3] were solely based on data obtained from a pharmacokinetic study by Vasudev and colleagues [5]. Small sample size (n=9) of patients with bipolar disorder limited the power of this study. DRC factors [1] of the 2017 guidelines were also based on data of this small study [5], and additionally on data of Chu and colleagues [6]. These authors investigated the influence of genetic polymorphisms on the pharmacokinetics of valproic acid in Chinese epilepsy patients (n=225). The authors detected that allelic distribution in these patients differed significantly from that in a control group [6]. Results of both studies [5,6] were limited for the calculation of C/D and DRC factors, as patients with pharmacokinetic abnormalities were not strictly excluded from analysis.
Thus, calculating DRRR with the C/D or DRC factors could not lead to ranges that would be expected in "normal" patients, as specified in the guidelines [1,3]. In contrast, Chu et al.
[6] intentionally examined the influence of a pharmacokinetic peculiarity and resulting data were therefore not suitable for the updated guidelines. Selection bias may have occurred, leading to confounding pharmacokinetic values. Johannessen Landmark and colleagues detected a 10-fold pharmacokinetic variability in valproate C/D for doses <700mg/day in women of childbearing age. The variability decreased with increasing dose to 4-fold for doses ≥1500mg/day [7]. Because of this large interindividual variability in C/D, valproate serum concentrations should be obtained in strongly selected patients without pharmacokinetic abnormalities to receive reliable pharmacokinetic data, as much lower interindividual variabilities were given in these patients. As no area under the concentration curve (AUC) values were available, no new DRC of valproate could be calculated from the data of Hefner and colleagues [4]. Nevertheless, based on calculated C/D, we recommend for the next consensus update a DRC mean of approximately Copyright: ©2018 Hefner G. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.