Commentary on clinical significance of CYP2C9‐status‐guided valproic acid therapy in children

Abstract

The results of this retrospective study1 suggest a positive effect of cytochrome P450 (CYP)2C9–guided valproate (VPA) treatment when compared with non–CYP2C9-guided treatment, based on the significant lower rate of patients with hyperammonemia in the CYP2C9-guided cohort. Eight of 47 patients in the control group versus one of 51 patients in the CYP2C9-guided group showed hyperammonemia 1 month after the beginning of VPA treatment. We think that the study results should be interpreted with caution, however. In the intervention group, CYP2C9 status was determined, but the incidence of low expressers was higher than expected according to the literature.2 If the expression of the CYP2C9 gene was different in the control group, this could have led to a substantial bias. This potential bias could influence the (significant) higher ratio of patients with a serum VPA concentration outside the therapeutic range. The intervention and control groups also differed with respect to VPA dosing. The control group received a dosing of 20–40 mg/kg. Dosing for the normal expressers in the intervention group was 30–40 mg/kg. The authors did not explain why normal expressers did not receive VPA treatment based on standard clinical protocol, and the mean or average dose in either cohorts were not reported, as could influence outcome. The authors found a higher rate of hyperammonemia in the control group without hepatotoxicity. Literature reports between 100 and 260 clinical apparent cases of hepatotoxicity or hepatotoxicity with a fatal outcome in the period ranging from 1977 until 2013. However, the literature also notes that serious adverse reactions are rare, especially those leading to fatalities.3, 4 One patient with hyperammonemia was observed with secondary symptoms (nausea, vomiting, lack of appetite, fatigue, drowsiness, confusion, cognitive slowing, or loss of consciousness). It is not mentioned if this was in the control or intervention group. Also Segura-Bruna et al.5 have noted that no relationship has been found between the daily doses of VPA and the appearance and severity of valproate-induced hyperammonemic encephalopathy (VHE).6 They also noted no relationship between the development of VHE and serum VPA levels. Others described no correlation between clinical severity of VHE and higher blood ammonium levels when hyperammonemia was confirmed.6 So there does not seem to be a solid relationship between the development of clinically significant VHE and serum VPA levels.5 As is suggested by Monostory et al. In conclusion, in our opinion the authors note this research as a first attempt to establish the influence of CYP2C9 on VPA metabolism. However, based on presented data and given the low prevalence of hepatotoxicity, the study seems to be too small to make firm conclusions such as that CYP2C9-status-guided VPA treatment is preferable to non–CYP2C9-guided treatment and that CYP2C9-guided VPA treatment has demonstrated to improve the safety of VPA treatment. None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.