A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy
- 52 Downloads
The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50–100 mg/L).
Ninety-eight children (1–17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg.
A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a Ctrough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%.
If the present study supports the current dose recommendations of 20–30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.
KeywordsChildhood epilepsy Valproate Population pharmacokinetics Protein binding
The authors would like to thank Dr. Mathilde Chipaux (Fondation Ophtalmologic Rothschild) for her participation in patient inclusion of the VAPOP study.
CR drafted the original manuscript; CR and VJ performed the PK modelling analysis; SC and ER realized the analytical dosages; SC, CC, OD, ER, GP and VJ conceptualized the study and revised the manuscript.
Compliance with ethical standards
Conflicts of interest
CR reports personal fees from Biocodex, outside the submitted work. CC reports personal fees and non-financial support from Biocodex; personal fees from Brabant, UCB-Pharma, Bial, Zogenix, and Viropharma, outside the submitted work; and declare that she was the PI of the two clinical studies mentioned in the paper. As clinical principal investigator, CC recruited and followed the patients during the studies. That did not influence what is written in the submitted work. VJ, SC, ER, GP, and OD have nothing to disclose.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 5.Patsalos PN, Berry DJ, Bourgeois BFD, Cloyd JC, Glauser TA, Johannessen SI, Leppik IE, Tomson T, Perucca E (2008) Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 49:1239–1276CrossRefPubMedGoogle Scholar
- 8.ANSM (2013) Micropakine L.P - Résumé des caractéristiques du produit (SCP) Available at: http://agence-prd.ansm.sante.fr/php/ecodex/rcp/R0224686.htm. Accessed 3 May 2017
- 10.Medicines.org.uk (2015) Epilim Chronosphere - Summary of product characteristics (SPC) Available at: https://www.medicines.org.uk/emc/files/pil.3988.pdf. Accessed 3 May 2017
- 14.Holford N. Protein binding model 2011. http://www.cognigencorp.com/nonmem/current/2011-May/2497.html. Accessed 20 Jun 2017
- 22.Dhillon S, Gill K (2006) Basic pharmacokinetics. In: Dhillon S, Kostrzewski A (eds) Clinical Pharmacokinetics, 1st edn. Pharmaceutical Press, p 1–44Google Scholar
- 32.Buck ML (1997) Valproic acid in the treatment of pediatric seizures. Pediatr Pharmacother 3:1–4Google Scholar
- 33.Shen DD, Levy RH (1999) Valproate. In: Eadie MJ, Vajda FJE (eds). Handb. Exp. Pharmacol. Antiepileptic Drugs, Pharmacol. Ther. Springer, p 359–374Google Scholar
- 47.Levy RH, Rettenmeier AW, Anderson GD, Wilensky AJ, Friel PN, Baillie TA, Acheampong A, Tor J, Guyot M, Loiseau P (1990) Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatoxic metabolite of valproic acid. Clin Pharmacol Ther 48:225–235CrossRefPubMedGoogle Scholar
- 51.Landmark CJ, Patsalos PN (2010) Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev 10:119–140Google Scholar
- 53.Anderson GD, Rho JM (2008) AEDs Eliminated by Mixed CYP, UGT, and other metabolic pathways. In: Chapman K, Rho JM (eds) Pediatr. epilepsy case stud. From infancy child. Through Adolesc. CRC Press, Boca Raton, pp 20–21Google Scholar