Skip to main content
SpringerLink
Log in

A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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).

Methods

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.

Results

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%.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Meunier H, Carraz G, Meunier Y, Eymard P, Aimard M (1963) Propriétés pharmacodynamiques de l’acide N-dipropylacétique. Therapie 18:435–438

    CAS  PubMed  Google Scholar 

  2. Johannessen CU, Johannessen SI (2003) Valproate: past, present, and future. CNS Drug Rev 9:199–216

    Article  CAS  PubMed  Google Scholar 

  3. Perucca E (2002) Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 16:695–714

    Article  CAS  PubMed  Google Scholar 

  4. Neels HM, Sierens AC, Naelaerts K, Scharpe SL, Hatfield GM, Lambert WE (2004) Therapeutic drug monitoring of old and newer anti-epileptic drugs. Clin Chem Lab Med 42:1228–1255

    Article  CAS  PubMed  Google Scholar 

  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 49:1239–1276

    Article  CAS  PubMed  Google Scholar 

  6. Herngren L, Lundberg B (1991) Pharmacokinetics of total and free valproic acid during monotherapy in infants. J Neurol 238:315–319

    Article  CAS  PubMed  Google Scholar 

  7. Kodama Y, Kodama H, Kuranari M, Tsutsumi K, Ono S, Fujimura A (1999) No effect of gender or age on binding characteristics of valproic acid to serum proteins in pediatric patients with epilepsy. J Clin Pharmacol 39:1070–1076

    Article  CAS  PubMed  Google 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

  9. Klotz U, Antonin KH (1977) Pharmacokinetics and bioavailability of sodium valproate. Clin Pharmacol Ther 21:736–743

    Article  CAS  PubMed  Google Scholar 

  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

  11. Turnbull DM, Rawlins MD, Weightman D, Chadwick DW (1983) Plasma concentrations of sodium valproate: their clinical value. Ann Neurol 14:38–42

    Article  CAS  PubMed  Google Scholar 

  12. Yáñez JA, Remsberg CM, Sayre CL, Forrest ML, Davies NM (2012) Flip-flop pharmacokinetics—delivering a reversal of disposition: challenges and opportunities during drug development. Ther Deliv 2:643–672

    Article  Google Scholar 

  13. Ding J, Wang Y, Lin W, Wang C, Zhao L, Li X, Zhao Z, Miao L, Jiao Z (2015) A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy : a non-linear pharmacokinetic model based on protein-binding saturation. Clin Pharmacokinet 54:305–317

    Article  CAS  PubMed  Google Scholar 

  14. Holford N. Protein binding model 2011. http://www.cognigencorp.com/nonmem/current/2011-May/2497.html. Accessed 20 Jun 2017

  15. Ueshima S, Aiba T, Makita T, Nishihara S, Kitamura Y, Kurosaki Y, Kawasaki H, Sendo T, Ohtsuka Y, Gomita Y (2008) Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children. J Clin Pharm Ther 33:31–38

    Article  CAS  PubMed  Google Scholar 

  16. Bailey BJ, Briars GL (1996) Estimating the surface area of the human body. Stat Med 15:1325–1332

    Article  CAS  PubMed  Google Scholar 

  17. Anderson BJ, Holford NHG (2008) Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48:303–332

    Article  CAS  PubMed  Google Scholar 

  18. Tod M, Jullien V, Pons G (2008) Facilitation of drug evaluation in children by population methods and modelling. Clin Pharmacokinet 47:231–243

    Article  CAS  PubMed  Google Scholar 

  19. Comets E, Brendel K, Mentré F (2008) Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Prog Biomed 90:154–166

    Article  Google Scholar 

  20. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO (2011) Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J 13:143–151

    Article  PubMed  PubMed Central  Google Scholar 

  21. Parke J, Holford NHG, Charles BG (1999) A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Prog Biomed 59:19–29

    Article  CAS  Google Scholar 

  22. Dhillon S, Gill K (2006) Basic pharmacokinetics. In: Dhillon S, Kostrzewski A (eds) Clinical Pharmacokinetics, 1st edn. Pharmaceutical Press, p 1–44

  23. Holford N, Heo Y-A, Anderson B (2013) A pharmacokinetic standard for babies and adults. J Pharm Sci 102:2941–2952

    Article  CAS  PubMed  Google Scholar 

  24. Dulac O, Alvarez J (2005) Bioequivalence of a new sustained-release formulation of sodium valproate , valproate modified-release granules , compared with existing sustained-release formulations after once- or twice-daily administration. Pharmacotherapy 25:35–41

    Article  CAS  PubMed  Google Scholar 

  25. Ayudhya PDN, Suwanmanee J, Visudtibhan A (2006) Pharmacokinetic parameters of total and unbound valproic acid and their relationships to seizure control in epileptic children. Am J Ther 13:211–217

    Article  Google Scholar 

  26. Cloyd JC, Fisher JH, Kriel RL, Kraus DM (1993) Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther 53:22–29

    Article  CAS  PubMed  Google Scholar 

  27. Schapel GJ, Beran RG, Doecke CJ, O’Reilly WJ, Reece PA, Rischbieth RHC et al (1980) Pharmacokinetics of sodium valproate in epileptic patients : prediction of maintenance dosage by single-dose study. Eur J Clin Pharmacol 17:71–77

    Article  CAS  PubMed  Google Scholar 

  28. Nitsche V, Mascher H (1982) The pharmacokinetics of valproic acid after oral and parenteral administration in healthy volunteers. Epilepsia 23:153–162

    Article  CAS  PubMed  Google Scholar 

  29. Jiang D, Wang L, Wang Y, Li L, Lu W, Bai X (2007) Population pharmacokinetics of valproate in Chinese children with epilepsy. Acta Pharmacol Sin 28:1677–1684

    Article  CAS  PubMed  Google Scholar 

  30. Cook AM, Zafar MS, Mathias S, Stewart AM, Albuja AC, Bensalem-Owen M, Kapoor S, Baumann RJ (2016) Pharmacokinetics and clinical utility of valproic acid administered via continuous infusion. CNS Drugs 30:71–77

    Article  CAS  PubMed  Google Scholar 

  31. Hall K, Otten N, Johnston B, Irvine-Meel J, Leroux M, Seshia S (1985) A multivariable analysis of factors governing the steady-state pharmacokinetics of valproic acid in 52 young epileptics. J Clin Pharmacol 25:261–268

    Article  CAS  PubMed  Google Scholar 

  32. Buck ML (1997) Valproic acid in the treatment of pediatric seizures. Pediatr Pharmacother 3:1–4

    Google Scholar 

  33. Shen DD, Levy RH (1999) Valproate. In: Eadie MJ, Vajda FJE (eds). Handb. Exp. Pharmacol. Antiepileptic Drugs, Pharmacol. Ther. Springer, p 359–374

  34. Benet LZ, Hoener B (2002) Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71:115–121

    Article  CAS  PubMed  Google Scholar 

  35. Blanco-Serrano B, García-Sánchez MJ, Otero MJ, Buelga DS, Serrano J, Domínguez-Gil A (1999) Valproate population pharmacokinetics in children. J Clin Pharm Ther 24:73–80. https://doi.org/10.1046/j.1365-2710.1999.00202.x

    Article  Google Scholar 

  36. Blanco-serrano B, Otero MJ, Santos-buelga D, García Sánchez MJ, Serrano J, Domínguez-Gil A (1999) Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data. Biopharm Drug Dispos 20:233–240

    Article  CAS  PubMed  Google Scholar 

  37. Correa T, Rodriguez I, Romano S (2008) Population pharmacokinetics of valproate in Mexican children with epilepsy. Biopharm Drug Dispos 29:511–520

    Article  CAS  PubMed  Google Scholar 

  38. Desoky ESEL, Fuseau E, Amry SED, Cosson V (2004) Pharmacokinetic modelling of valproic acid from routine clinical data in Egyptian epileptic patients. Eur J Clin Pharmacol 59:783–790. https://doi.org/10.1007/s00228-003-0699-7

    Article  Google Scholar 

  39. Lin W, Jiao Z, Wang C, Wang H, Ma C, Huang P, Guo XZ, Liu YW (2015) Population pharmacokinetics of valproic acid in adult Chinese epileptic patients and its application in an individualized dosage regimen. Ther Drug Monit 37:76–83

    Article  CAS  PubMed  Google Scholar 

  40. Ahn JE, Birnbaum AK, Brundage RC (2005) Inherent correlation between dose and clearance in therapeutic drug monitoring settings : possible misinterpretation in population pharmacokinetic analyses. J Pharmacokinet Pharmacodyn 32:703–718

    Article  PubMed  Google Scholar 

  41. Sriboonruang T, Panomvana D, Chamchitchun S, Silpakit O (2011) The impact of dosage of sustained-release formulation on valproate clearance and plasma concentration in psychiatric patients. J Clin Psychopharmacol 31:115–119. https://doi.org/10.1097/JCP.0b013e318203b405

    Article  CAS  PubMed  Google Scholar 

  42. Wallenburg E, Klok B, de Jong K, de Maat M, Van EN, Stalpers-Konijnenburg S et al (2017) Monitoring protein-unbound valproic acid serum concentrations in clinical practice. Ther Drug Monit 39:269–272

    Article  CAS  PubMed  Google Scholar 

  43. Zaccara G, Messori A, Moroni F (1988) Clinical pharmacokinetics of valproic acid—1988. Clin Pharmacokinet 15:367–389

    Article  CAS  PubMed  Google Scholar 

  44. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med 349:1157–1167

    Article  CAS  PubMed  Google Scholar 

  45. Chiba K, Suganuma T, Ishizaki T, Iriki T, Shirai Y, Naitoh H, Hori M (1985) Comparison of steady-state pharmacokinetics of valproic acid in children between monotherapy and multiple antiepileptic drug treatment. J Pediatr 106:653–658

    Article  CAS  PubMed  Google Scholar 

  46. Theis JGW, Koren G, Daneman R, Sherwin AL, Menzano E, Cortez M, Hwang P (1997) Interactions of clobazam with conventional antiepileptics in children. J Child Neurol 12:208–213

    Article  CAS  PubMed  Google 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 48:225–235

    Article  CAS  PubMed  Google Scholar 

  48. Jogamoto T, Yamamoto Y, Fukuda M, Suzuki Y, Imai K, Takahashi Y, Inoue Y, Ohtsuka Y (2017) Add-on stiripentol elevates serum valproate levels in patients with or without concomitant topiramate therapy. Epilepsy Res 130:7–12

    Article  CAS  PubMed  Google Scholar 

  49. Sennoune S, Mesdjian E, Bonneton J, Genton P, Dravet C, Roger J (1990) Interactions between clobazam and standard antiepileptic drugs in patients with epilepsy. Ther Drug Monit 14:269–274

    Article  Google Scholar 

  50. Walzer M, Bekersky I, Blum RA, Tolbert D (2012) Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes. Pharmacotherapy 32:340–353

    Article  CAS  PubMed  Google Scholar 

  51. Landmark CJ, Patsalos PN (2010) Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev 10:119–140

    Google Scholar 

  52. Farwell JR, Anderson GD, Kerr BM, Tor JA, Levy IH (1993) Stiripentol in atypical absence seizures in children: an open trial. Epilepsia 34:305–311

    Article  CAS  PubMed  Google 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 20–21

    Google Scholar 

  54. Yukawa E, To H, Ohdo S, Higuchi S, Aoyama T (1997) Population-based investigation of valproic acid relative clearance using nonlinear mixed effects modeling: influence of interaction and patient characteristics. J Clin Pharmacol 37:1160–1167

    Article  CAS  PubMed  Google Scholar 

  55. Bondareva IB, Jelliffe RW, Sokolov AV, Tischenkova IF (2004) Nonparametric population modeling of valproate pharmacokinetics in epileptic patients using routine serum monitoring data : implications for dosage. J Clin Pharm Ther 29:105–120

    Article  CAS  PubMed  Google Scholar 

  56. Batchelor HK, Marriott JF (2013) Paediatric pharmacokinetics: key considerations. Br J Clin Pharmacol 79:395–404

    Article  Google Scholar 

  57. Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC, Childhood Absence Epilepsy Study Group (2010) Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 362(9):790–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Mathilde Chipaux (Fondation Ophtalmologic Rothschild) for her participation in patient inclusion of the VAPOP study.

Funding

Study 1 (VAPOP) was funded by Sanofi Aventis France (registration NCT00385411) and study 2 (STIPOP) was funded by Biocodex (EudraCT number: 2007–001784-30). The present work was returned independently from Biocodex.

Author information

Authors and Affiliations

  1. INSERM U1129, Paris Descartes University, CEA, Gif-sur-Yvette, Paris, France

    Christelle Rodrigues, Catherine Chiron, Olivier Dulac, Elisabeth Rey, Gérard Pons & Vincent Jullien

  2. Hôpital Necker-Enfants Malades – Enfants Malades, Inserm U1151, INEM, Laboratoire d’immunologie biologique, Assistance Publique – Hôpitaux de Paris, Paris, France

    Stéphanie Chhun

  3. Service de Pharmacologie, Hôpital Européen Georges Pompidou, 20 Rue Leblanc, 75015, Paris, France

    Vincent Jullien

Authors
  1. Christelle Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stéphanie Chhun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catherine Chiron
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Olivier Dulac
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elisabeth Rey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gérard Pons
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vincent Jullien
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Vincent Jullien.

Ethics declarations

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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

ESM 1

(DOCX 2024 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodrigues, C., Chhun, S., Chiron, C. et al. A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy. Eur J Clin Pharmacol 74, 793–803 (2018). https://doi.org/10.1007/s00228-018-2444-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-018-2444-2

Keywords

Search

Navigation