THERAPEUTIC DRUG MONITORING OF ANTICONVULSANTS IN CHILDREN IN CLINICAL PRACTICE

Objective. To study concentration of valproats in children with epilepsy, newborns  and infants with episyndrome  using therapeutic drug monitoring (TDM) in routine clinical practice.

Materials and  methods. 75 children aged 1-18 years and 59 preterm newborns aged 0-90 days receiving valproic acid drugs were included in the study. Valproic acid concentration was measured using high performance liquid chromatography (HРLC).

Results. Therapeutic concentration was achieved in 77.3%  of  children  aged  1-18  years  with  an  average  daily dose  of  25.94  mg/kg  (1021.4  mg);  overtherapeutic concentrations  were registered  in 9.3%  of the cases.  Concentration of valproic acid tended  to decrease  along with children’s age. Among children aged 1-18, a direct correlation between the daily dose (in mg/kg) and concentrations  of  valproates was observed: r=0.42 for C_min and r=0.50 for C_max. There was no correlation between age and concentration. In newborns,  therapeutic concentration  was achieved only in 33.9% of the cases  with an average daily dose  of 43.4 mg/kg  (82.6  mg); overtherapeutic  concentrations  were registered  in 11.9%  of the  cases.  Significant  differences  in average daily doses  and concentrations of valproic acid were found in newborns under 1 month of age; overtherapeutic concentrations  in the group of preterm newborns  under 1 month were observed  in 23.5% of the cases versus 9.5% in the group of newborns  of 2-3 months  of age (p=0.07).  Weak inverse  correlation between  age and concentration  of valproic acid was seen in newborns: r=-0.25 for C_min and r=-0.24 for C_max. There was no correlation between the dose and concentration of valproic acid, this explains unpredictability of the dose response  in the group of preterm newborns and low rates of achieving therapeutic concentrations. 

Conclusion. Specific features of valproic acid pharmacokinetics  in newborns  and children are associated  with specific TDM parameters identified within the study; these  findings show high value of TDM.

1. Patsalos P. N., Berry D. J., Bourgeois B. F. et al. 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. 2008; 49 (7): 1239-76.

2. Johannessen S. I., L andmark C. J. Value of therapeutic drug monitoring in epi-lepsy. Exper t Rev Neurother. 2008; 8 (6): 929 -39.

3. Milsap R. L., Jusko W. J. Pharmacokinetics in the Infant. Environ Health Perspect. 1994; 102 (11): 107-110.

4. Morselli P. L., Franco-Morselli R., Bossi L. Clinical Pharmacokinetics in New-borns and Infants: Age-related Differences and Therapeutic Implications. Clinical Pharmacokinetics.1980; 5: 485-527.

5. Gilmall J. T. Therapeutic Drug Monitoring in the Neonate and Paediatric Age Group: Problems and Clinical Pharmacokinetic Implications. Clin Pharmacokinet. 1990; 19: 1-10.

6. Walson P. D. Role of Therapeutic Drug Monitoring (TDM) in Pediatric AntiConvulsant Drug Dosing. Brain Dev. 1994; 16 (1): 23-26.

7. Aldaz A., Ferriols R., Aumente D. et al. Pharmacokinetic Monitoring of Antiepileptic Drugs. Farm Hosp. 2011; 35: 326-39.

8. Ghodke-Puranik Y., Thorn C. F., Lamba J. K. et al. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics. 2013; 23 (4): 236-41.

9. Neels H. M., Sierens A. C., Naelaerts K. et al. Therapeutic drug monitoring of old and newer antiepileptic Lab Med. 2004; 42 (11): 1228-55.

10. Warner A., Privitera M., David B. Standards of laboratory practice: antiepilep-tic drug monitoring. Clinical Chemistry. 1998; 44 (5): 1085-95.

11. Gusev E. I., Belousov Yu. B., Gekht A. B., Bondareva I. B., Sokolov A. V., Tishchenkova I. F. Treatment of epilepsy: rational dosing of anticonvulsants [Lechenie epilepsii: ratsional’noe dozirovanie antikonvul’-santov (in russian)]. SPb. 2000; 203 s.

12. Belousov Yu. B., Leonova M. V., Shteinberg L. L., Tishchenkova I. F., Soko-lov A. V. Epilepsiya i paroksizmal’nye sostoyaniya / Epilepsy and paroxysmal conditions. 2013; 5 (3): 6-16.

13. Evtushenko S. K., Ivanova N. Yu., Omel’yanenko A. A., Evtushenko I. S. Mezhdunarodnyi nevrologicheskii zhurnal. 2008; 5 (21): 15-21.