THERAPEUTIC DRUG MONITORING OF ANTICONVULSANTS IN CLINICAL PRACTICS

Abstract: his paper presents the results of therapeutic drug monitoring (TDM) of anticonvulsants (valproats and carbamazepins) in 614 patients with epilepsy in clinical practices. 295 patients were treated with different drugs of valproats and 314 patients were treated with different drugs of carbamazepine. The frequency of achievement the therapeutic concentrations on valproat treatment was 66,4%, the average daily dose was 1325,1 mg. The frequency of achievement the therapeutic concentrations on treatment with drug forms with prolong release (Depakin chrono, Convulex retard) was higher, than on drug forms with immediate release. The frequency of subtherapeutic concentrations on valproat treatment was 16,3% and overtherapeutic concentrations – 1%. In doses of valproats less then 500 mg there was no patients with therapeutic concentrations, in doses 1001-1500 mg/day the therapeutic concentrations have 75% patients, in doses higher than 2000 mg/day – there was a risk of overdose. The frequency of achievement the therapeutic concentrations on carbamazepine treatment was 78,6%, the average daily dose was 922,2 mg. The frequency of achievement the therapeutic concentrations on treatment with drug forms with prolong release (Tedretol CR, Finlepsin retard) was higher, than on drug forms with immediate release. The frequency of subtherapeutic concentrations on carbamazepine treatment was 6,3% and overtherapeutic concentrations – 1,25%. When used initial daily doses (less then 600 mg) 64,3% patients have therapeutic concentrations , when used highly doses (high than 600 mg) 87% patients have therapeutic concentrations. In daily doses of carbamazepine higher then 600 mg and 1200 mg the frequency of the overtherapeutic concentrations were 1,3% and 4,1% both by Cmin and Cmax, only by overtherapeutic Cmax – 8,8% and 18,4%.

therapeutic drug monitoring, anticonvulsants, valproats, carbamazepine, epilepsy

1. Гусев Е.И., Белоусов Ю.Б., Гехт А.Б., Бондарева И.Б., Соколов А.В., Тищенкова И.Ф. Лечение эпилепсии: рациональное дозирование антиконвульсантов. 2000; 203 с.

2. Евтушенко С.К., Иванова Н.Ю., Омельяненко А.А., Евтушенко И.С. Мониторинг уровня антиконвульсантов в крови как протокольная необходимость в контроле терапии больных эпилепсией. Международный неврологический журнал. 2008; 5 (21): 15-21.

3. Сергиенко В.И., Джеллифф Р., Бондарева И.Б. Прикладная фармакокинетика: основные положения и клиническое применение. М.: Издательство РАМН, 2003, 208 с.

4. Шнайдер Н.А., Дмитренко Д.В., Пилюгина М.С. Фармакогенетика антиэпилептических препаратов. Бюллетень сибирской медицины 2008; 4: 111-9.

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

6. Baumann P., Hiemke C., Ulrich S. et. al. AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry. 2004; 37 (6): 243-65.

7. Babaei A., Eslamai M.H. Evaluation of therapeutic drug level monitoring of phenobarbital, phenytoin and carbamazepine in Iranian epileptic patients. Int. J. Clin. Pharmacol. Ther. 2007; 45 (2): 121-5.

8. Brunton L.L., Chabner B.A., Knollmann B.C., Goodman & Gilman’s the Pharmacological Basis of Therapeutics. Pharmacotherapy of the Epilepsies, Valproic Acid. The McGraw-Hill Companies. 2011; 12e: Chapter 21.

9. Duncan J.S., Sander J.W., Sisodiya S.M., Walker M.C. Adult epilepsy. Lancet 2006; 367: 1087-1100.

10. 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.

11. Irshaid Y.M., Hamdi A.A., Al Homrany M. Evaluation of therapeutic drug monitoring of antiepileptic drugs. Int. J. Clin. Pharmacol. Ther. 2003; 41 (3): 126-31.

12. Johannessen S.I., Landmark C.J. Value of therapeutic drug monitoring in epilepsy. Expert Rev. Neurother. 2008; 8 (6): 929-39.

13. Juvany R., Leiva E., Gasol M. et al. Safety of expanded therapeutic range of valproic acid. Eur. J. Hosp. Pharm. 2012; 19: 196-7.

14. Meng H., Ren J., Lv Y. et al. Association study of CYP3A5 genetic polymorphism with serum concentrations of carbamazepine in Chinese epilepsy patients. Neurology Asia. 2011; 16 (1): 39-45.

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

16. Park P.W., Seo Y.H., Ahn J.Y. et al. Effect of CYP3A5*3 genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients. J. Clin. Pharm. Ther. 2009; 34 (5): 569-74.

17. 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.

18. Radeef M.Y., Al-Shamma К., Hammash B.M. Therapeutic drug monitoring and evaluation of therapeutic effectiveness and adverse effects of antiepileptic drugs in Iraqi epileptic patients. Glob. J. Med. Res. 2012; 12 (8): 11-34.

19. Saruwatari J., Ishitsu T., Nakagawa К. Update on the genetic polymorphisms of drug-metabolizing enzymes in antiepileptic drug therapy. Pharmaceuticals 2010;3:2709-32.

20. Shakya G., Malla S., Shakya K.N., Shrestha R. Therapeutic drug monitoring of antiepileptic drugs. J. Nepal. Med. Assoc. 2008; 47 (171): 94-7.

21. Seo T., Nakada N., Ueda N. et al. Effect of CYP3A5*3 on carbamazepine pharmacokinetics in Japanese patients with epilepsy. Clin. Pharmacol. Ther. 2006; 79 (5): 509-10.

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