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The efficacy and safety of valproic acid medications with controlled active ingredient release in adults in real clinical practice from the position of pharmacokinetic and pharmacogenetic approaches

https://doi.org/10.14412/2074-2711-2017-1S-11-20

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Abstract

Objective: to analyze the efficacy and tolerability of sustained-release sodium valproate (SV) in adult patients with focal or generalized epilepsy in real clinical practice in three regions (Krasnoyarsk, Moscow, and Samara) of the Russian Federation.

Patients and methods. The investigation enrolled adult patients with focal (n=63) or generalized (n=31) epilepsy who had received a stable dose of the drug alone (n=64 (68%)) or in combination with one of the antiepileptic drugs (AEDs): levetiracetam, lamotrigine, topiramate, or perampanel (n=30 (31.9%)) for at least one year. According to the brand name of drugs, their use frequency was as follows: Depakine® Chrono (61.7%), Convulex® (16%), Depakine® Chronosphere (9.6%), Valparine® XP (8.5%), and Encorate® Chrono (4.3%).

Results. For a period of over one year, most patients with focal epilepsy (FE) (49.2%) and idiopathic generalized epilepsy (IGE) (67.7%) achieved a remission of seizures when they used moderate (1000 mg) and low (<1000 mg) daily doses of SV. Among the PE and IGE patients taking Depakine Chronosphere, the remission rate was highest, amounting to 100 and 75%, respectively. The efficacy of SV in both FE and IGE decreased in the following order: Depakine Chrono, Convulex, and Valparine XP. Clinical remission was achieved in none of the patients taking Encorate Chrono.

The most common unwanted side reactions (USRs) were weight gain, menstrual disorders, tremor, and hair loss; however, their total frequency (16%) proved to be substantially lower than previously considered. The side effects were observed in one-half of the patients receiving a daily SV dose of 1000 mg and more, USRs were noted during combination therapy with SV medications and topiramate (n=5) or lamotrigine (n=2). USRs were frequently observed in the heterozygous carriers of the single nucleotide polymorphisms (SNPs) CYP2C9*3 (27.3%) versus those who had the common (wild-type) allele variant CYP2C9*1, but USRs were recorded mainly in the heterozygous carriers of CYP2C9*3 and CYP2C9*2 who received low daily doses of SV.

The frequency of the CYP2C9 gene among SNPs proved to be highest: CYP2C9*1/*1 in 68 (72.3%) patients, CYP2C9*2 in 14 (14.9%), and CYP2C9*3 in 11 (11.7%). The compound heterozygous CYP2C9*2/*3 genotype was recorded in one (1.06%) case.

The inadequate effect of AEDs requires therapeutic drug monitoring (TDM); and to rule out USRs calls for pharmacogenetic studies before or at the early stages of titration of SV, by determining its starting dosage, titration rate, and therapeutic dose. TDM and a pharmacogenetics study allow optimization of the personalized choice of AEDs. 

About the Authors

P. N. Vlasov
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia
Russian Federation
20, Delegatskaya St., Build. 1, Moscow 127473


N. V. Orekhova
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia
Russian Federation
20, Delegatskaya St., Build. 1, Moscow 127473


M. V. Antonyuk
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia
Russian Federation
20, Delegatskaya St., Build. 1, Moscow 127473


N. V. Filatova
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia
Russian Federation
20, Delegatskaya St., Build. 1, Moscow 127473


N. A. Schnaider
Professor V.F. VoynoYasenetsky Krasnoyarsk State Medical University, Ministry of Health of Russia
Russian Federation
1, Partisan Zheleznyak St., Krasnoyarsk 660022


D. V. Dmitrenko
Professor V.F. VoynoYasenetsky Krasnoyarsk State Medical University, Ministry of Health of Russia
Russian Federation
1, Partisan Zheleznyak St., Krasnoyarsk 660022


S. N. Zobova
Professor V.F. VoynoYasenetsky Krasnoyarsk State Medical University, Ministry of Health of Russia; Federal Research Center «Krasnoyarsk Research Center, Siberian Branch, Russian Academy of Sciences»
Russian Federation

1, Partisan Zheleznyak St., Krasnoyarsk 660022;

50, Akademgorodok St., Krasnoyarsk 660036



I. E. Poverennova
Samara State Medical University, Ministry of Health of Russia
Russian Federation
89, Chapaevskaya St., Samara 443099


A. V. Yakunina
Samara State Medical University, Ministry of Health of Russia
Russian Federation
89, Chapaevskaya St., Samara 443099


V. A. Kalinin
Samara State Medical University, Ministry of Health of Russia
Russian Federation
89, Chapaevskaya St., Samara 443099


S. K. Zyryanov
RUDN University of Russia
Russian Federation
6, Miklukho-Maklai St., Moscow 117198


I. F. Tishchenkova
N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia
Russian Federation
1, Ostrovityanov St., Moscow 119977


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For citation:


Vlasov P.N., Orekhova N.V., Antonyuk M.V., Filatova N.V., Schnaider N.A., Dmitrenko D.V., Zobova S.N., Poverennova I.E., Yakunina A.V., Kalinin V.A., Zyryanov S.K., Tishchenkova I.F. The efficacy and safety of valproic acid medications with controlled active ingredient release in adults in real clinical practice from the position of pharmacokinetic and pharmacogenetic approaches. Neurology, Neuropsychiatry, Psychosomatics. 2017;9(1S):11-20. (In Russ.) https://doi.org/10.14412/2074-2711-2017-1S-11-20

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