The G2677T T and C3435T T alleles as well as the TT, CTT and TTT haplotypes seemed to be significantly associated with drug-resistance epilepsy in our population. Genetic predisposition, involved in this resistance, may contribute to the establishment of a personal optimized therapy for newly diagnosed epileptic patients.

Context: Acyclovir is an antiviral currently used for prevention and treatment of herpes simplex virus (HSV) and varicella-zona virus (VZV) infections. This study aimed to characterize pharmacokinetics of acyclovir and its oral prodrug valacyclovir to optimize dosing in children. Method: Children receiving acyclovir or valacyclovir were included in this study. Pharmacokinetics (PK) were described using the non-linear mixed-effect modelling. Dosing simulations were used to obtain trough concentrations above 50% inhibitory concentration for HSV or VZV (0.56mg/L and 1.125mg/L respectively) and maximal peak concentrations below 25 mg/L. Results: A total of 79 children (212 concentration-time observations) were included, 50 were taking IV acyclovir, 22 oral and 7 both IV and oral, 57 for preventive and 22 for curative purposes. A one-compartment model with first-order elimination best described the data. An allometric model was used to describe body weight effect and estimated glomerular filtration rate (eGFR) was significantly associated with acyclovir elimination Conclusion: To obtain target maximal and trough concentrations, the more suitable initial acyclovir IV dose was 10 mg/kg/6h for children with normal renal function (eGFR ≤ 250 mL/min/1.73m2) and 15 to 20 mg/kg/6h for children with ARC. (eGFR > 250 mL/min/1.73m2) The 20 mg/kg/8h for acyclovir and valacyclovir produced effective concentrations in more than 75% of children, however a 15 mg/kg/6h, if possible, should be preferred. These doses should be prospectively confirmed and a therapeutic drug monitoring could be used to refine them individually.

Context: Ganciclovir is indicated for curative or preventive treatment of cytomegalovirus (CMV) infections. This study aimed to characterize ganciclovir pharmacokinetics, following intravenous ganciclovir and oral valganciclovir administration, in order to optimize dosing scheme.Method: All children aged <18 years receiving ganciclovir or valganciclovir were included in this study. Pharmacokinetics were described using non-linear mixed-effect modelling. Monte Carlo simulations were used to optimize dosing regimen in order to maintain area under the concentration curve (AUC) in the preventive or therapeutic target.Results: Among the 105 children (374 concentration-time observations) included, 78 received intravenous (IV) ganciclovir, 19 oral valganciclovir and 6 both drugs. A two-compartment model with first-order absorption for valganciclovir and first-order elimination best described the data. An allometric model was used to describe bodyweight (BW) effect. Estimated glomerular filtration rate (eGFR) and critically-ill children medical status were significantly associated with ganciclovir elimination.Conclusion: Recommended doses were adapted for prophylactic treatment. To obtain a therapeutic exposure, doses should be increased to 40 mg/kg/day oral or 15-20 mg/kg/day IV in children with normal eGFR and to 56 mg/kg/day oral or 20-25 mg/kg/day IV in children with augmented eGFR. These doses should be prospectively confirmed and a therapeutic drug monitoring could be used to refine them individually.