Klinická farmakologie a farmacie – 2/2021

www.klinickafarmakologie.cz / Klin Farmakol Farm 2021; 35(2): 49–53 / KLINICKÁ FARMAKOLOGIE A FARMACIE 53 PŮVODNÍ PRÁCE THE EFFECT OF VALPROIC ACID ON PLASMA LEVEL OF CARBAMAZEPINE AND CARBAMAZEPINE-10, 11-EPOXIDE IN LONG-TERM TREATMENT WITH SLOW-RELEASE DRUG FORMULATIONS IN PEDIATRIC PATIENTS; THE IMPORTANCE OF TDM Conclusion The CBZ-VPA interaction is complicated, both increase and decrease in the CBZ level might occur. When therapeutic drug monito- ring is performed, the dose of CBZ is balanced according to the TDM outcomes, similar CBZ levels are reached, and the clinical effect of the interaction is eliminated. It is important to interpret TDM outcomes in relation with dosage and concomitant therapy. Due to a CBZ level balance, the incidence of adver- se drug reactions remained unchanged in CBZ + VPA. LITERATURA 1. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002; 16: 695–714. 2. Tanaka. Clinically significant pharmacokinetic drug in- teractions between antiepileptic drugs. J Clin Pharm Ther 1999; 24: 87–92. 3. Potter JM, Donnelly A. Carbamazepine-10,11-epoxide in therapeutic drug monitoring. Ther Drug Monit 1998; 20: 652–657. 4. Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug moni- toring of antiepileptic drugs in epilepsy: a 2018 update. Ther Drug Monit. 2018; 40: 526–548. 5. Levy RH, Wurgen CJ. Carbamazepine. Interactions with other drugs. In: Levy RH, Mattson RH, Meldrum BS, eds. Antie- pileptic Drugs. New York: Raven Press; 1995: 543–554. 6. Kerr BM, Levy RH. Carbamazepine. Carbamazepine epoxide. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs. New York: Raven Press; 1995: 529–541. 7. Patsalos PN, Fröscher W, Pisani F et al. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43: 365–385. 8. Spina E, Pisani F, Perucca E. Clinically significant pharma- cokinetic drug interactions with carbamazepine, an update. Clin Pharmacokinet 1996; 31: 198–213. 9. Anderson GD. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 1998; 32: 554–563. 10. Arroyo S, Sander JWAS. Carbamazepine in comparative trials: pharmacokinetic characteristics too often forgotten. Neurology 1999; 53: 1170–1174. 11. Battino D, Estienne M, Avanzini G. Clinical pharmacokine- tics of antiepileptic drugs in pediatric patients. Part I. Pheno- barbital, primidone, valproic acid, ethosuximide and mesuxi- mide. Clin Pharmacokinet 1995; 29: 257–286. 12. Svinarov DA, Pippenger CE. Valproic acid-carbamazepi- ne interaction: Is valproic acid a selective inhibitor of epoxide hydrolase? Ther Drug Monit 1995; 17: 217–220. 13. Liu H, Delgado MR, Browne R. Interactions of valproic acid with carbamazepine and its metabolites’ concentrati- ons, concentration ratios, and level/dose ratios in epileptic children. Clin Neuropharmacol 1995; 18: 1–12. 14. Budakova L, Brozmanova H, Grundmann M et al. Simulta- neous determination of antiepileptic drugs and their two ac- tive metabolites by HPLC. J Sep Sci. 2008; 31: 1–8. 15. Brozmanova H, Grundmann M. First experiences with the- rapeutic monitoring of antiepileptics [abstract]. Cesk Fysiol. 1985; 34: 416 [in Czech]. 16. Epi Info [computer program]. Version 6.04b. Atlanta: Cen- ters for Disease Control and Prevention; 1997. 17. Prism [computer program]. Version 5.0, San Diego: Gra- phPad Software, Inc.; 2007. 18. Levy RH, Moreland TA, Morseli et al. Carbamazepine/ valproic acid interaction in man and rhesus monkey. Epilep- sia 1984; 25: 338–345. 19. Rambeck B, May T, Juergens U. Serum concentrations of carbamazepine and its epoxide and diol metabolites in epi- leptic patients: the influence of dose and comedication. Ther Drug Monit 1987; 9: 298–303. 20. Schoeman JF, Elyas AA, Brett EM et al. Altered ratio of car- bamazepine-10,11-epoxide/carbamazepine in plasma of chil- dren: evidence of anticonvulsant drug interaction. Dev Med Child Neurol 1984; 26: 749–755. 21. Bernus I, Dickinson RG, Hooper WD et al. The mechanism of the carbamazepine-valproate interaction in humans. Br J Clin Pharmacol 1997; 44: 21–27. 22. Koristkova B, Grundmann M. Effect of a drug form change on the utilization of carbamazepine in hospital departments [In Czech]. Klin Farmacol Farmac 2000; 14: 19–22. 23. Morris RG, Black AB, Harris AL et al. Lamotrigine and the- rapeutic drug monitoring: retrospective survey following the introduction of a routine service. Br J Clin Pharmacol. 1998; 46: 547–551. Tab. 10. Level/dose ratios of carbamazepine and carbamazepine-10,11-epoxide in 11 patients treated with both CBZ and CBZ + VPA No CBZ level/dose [mg × L -1 /mg] CBZ-E level/dose [mg × L -1 /mg] CBZ level/DBW [mg × L -1 /mg × kg -1 ] CBZ-E level/DBW [mg × L -1 /mg × kg -1 ] CBZ CBZ + VPA CBZ CBZ + VPA CBZ CBZ + VPA CBZ CBZ + VPA 1 26.0 × 10 -3 19.0 × 10 -3 30 × 10 -3 2.0 × 10 -3 0.676 0.494 78.0 × 10 -3 52.0 × 10 -3 2 23.4 × 10 -3 10.7 × 10 -3 48 × 10 -3 1.8 × 10 -3 0.430 0.298 81.8 × 10 -3 48.8 × 10 -3 3 15.7 × 10 -3 13.3 × 10 -3 30 × 10 -3 1.8 × 10 -3 0.486 0.454 93.0 × 10 -3 61.8 × 10 -3 4 14.5 × 10 -3 6.4 × 10 -3 21 × 10 -3 2.9 × 10 -3 0.352 0.211 51.9 × 10 -3 96.8 × 10 -3 5 17.3 × 10 -3 10.8 × 10 -3 43 × 10 -3 2.9 × 10 -3 0.347 0.321 85.3 × 10 -3 87.5 × 10 -3 6 12.9 × 10 -3 8.3 × 10 -3 07 × 10 -3 1.8 × 10 -3 0.367 0.287 20.2 × 10 -3 60.3 × 10 -3 7 10.4 × 10 -3 13.3 × 10 -3 34 × 10 -3 6.1 × 10 -3 0.215 0.253 69.3 × 10 -3 116.5 × 10 -3 8 11.6 × 10 -3 10.3 × 10 -3 23 × 10 -3 2.6 × 10 -3 0.484 0.458 96.2 × 10 -3 114.7 × 10 -3 9 16.4 × 10 -3 12.8 × 10 -3 17 × 10 -3 2.1 × 10 -3 0.475 0.383 49.7 × 10 -3 62.9 × 10 -3 10 7.6 × 10 -3 6.1 × 10 -3 15 × 10 -3 1.1 × 10 -3 0.373 0.307 74.7 × 10 -3 53.3 × 10 -3 11 8.8 × 10 -3 8.3 × 10 -3 28 × 10 -3 1.1 × 10 -3 0.168 0.217 53.8 × 10 -3 29.1 × 10 -3 mean ± SD 15.0 × 10 -3 ± 5.7 × 10 -3 10.9 × 10 -3 ± 3.7 × 10 -3 ** 27 × 10 -3 ± 12 × 10 -3 2.4 × 10 -3 ± 1.4 × 10 -3 0.397 ± 0.139 0.345 ± 0.099* 68.5 × 10 -3 ± 22.7 × 10 -3 71.3 × 10 -3 ± 28.5 × 10 -3 DBW – dose related to body weight, ** p < 0.01, * p < 0.05     Fig. 1. Histogram of CBZ plasma levels. The therapeutic range is given by box