Therapeutic carbamazepine (CBZ) and valproic acid (VPA) monitoring in children using saliva as a biologic fluid

Abstract

Objective: The aim of the study was to analyze retrospectively carbamazepine (CBZ) and valproic acid (VPA) salivary data collected from epileptic children during a 3-year period. Methods: Saliva samples stimulated by citric acid were assayed by FPIA method. One hundred and three patients (aged 1-14 years) were in CBZ or VPA monotherapy or in CBZ-VPA combined therapy. Results: VPA salivary levels were linearly related with daily dose, but a non-linear relationship was found for CBZ, in patients under monotherapy. VPA did not alter saliva CBZ concentration. Conversely, CBZ reduced VPA salivary levels. Non-responsive children displayed higher VPA concentrations. CBZ levels in uncontrolled patients showed non-significant difference in relation with controlled subjects even though their daily doses were higher. Conclusion: Citric acid stimulated saliva is reliable enough to perform therapeutic drug monitoring. Saliva drug levels in non-responsive patients would be explained according to the generalized efflux transporter overexpression hypothesis.Keywords: Saliva concentration, carbamazepine, valproic acid, refractory epilepsy, efflux transporters. RESUMO Monitoramento terapêutico de carbamazepina e ácido valproico em saliva de criançasObjetivo: O objetivo deste estudo foi avaliar retrospectivamente por 3 anos a partir de dados salivares, as terapias com carbamacepina (CBZ) e ácido valproico (VPA) em pacientes pediátricos. Métodos: Foram avaliadas amostras de saliva estimuladas com ácido cítrico por método FPIA em 103 pacientes (idades 1-14 anos) em monoterapia com CBZ ou VPA ou terapia combinada CBZ-VPA. Resultados: Níveis salivares de VPA se relacionaram linearmente com a dose diária, e a relação não linear foi encontrada em pacientes com CBZ. VPA não alterou as concentrações salivares de CBZ, porém a CBZ reduziu os níveis salivares de VPA em pacientes com terapia combinada. Pacientes refratários apresentaram altas concentrações de VPA. Os níveis de CBZ em pacientes não controlados não apresentaram diferenças significativas em relação aos pacientes controlados quando as doses diárias foram mais elevadas. Conclusão: Saliva estimulada com ácido cítrico é adequada para o monitoramento terapêutico. Níveis da droga na saliva em pacientes que não responderam ao tratamento pode ser explicado pelo transporte de efluxo generalizado.Unitermos: Concentração em saliva, carbamacepina, ácido valproico, epilepsia refratária, transportadores de efluxo.

Hyperammonemia Associated with Valproic Acid Concentrations

“…Our group has been working intensively with salivary concentrations of anticonvulsants [ 24 – 26 ]. For a number of drugs, mainly those which are lipophilic and nonionized at salivary pH range (i.e., phenytoin or carbamazepine), studies have demonstrated that salivary concentrations highly correlate with free drug concentration in plasma and therefore are more reflective of the concentration in the biophase [ 24 , 25 ]. If drug diffusion into saliva is only passive, the factors involved in drug excretion to this fluid are its lipophilicity and the degree of ionization.…”

Zopiclone concentrations in oral fluid and blood after, administration of therapeutic doses of zopiclone

“…In a study of patients (27 children and 9 adults) with attention-deficit/hyperactivity disorder (ADHD) a significant correlation between concentrations of methylphenidate in serum and saliva was found (167). Some studies have tried to document the potential of measuring different psychoactive substances in OF, such as antipsychotics (168,169), antidepressants (170) and antiepileptic drugs (171).…”

Active Pharmacovigilance in Epileptic Patients: A Deep Insight into Phenytoin Behaviour

“…But, free drug monitoring is rather expensive for routine practice. Our research group has been working for several years using saliva as biological fluid [4][5][6]. Saliva is not only useful for being a simple and noninvasive collection method but also for the information it gives.…”