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Published on 29 April 2009

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Phenytoin-inducing effect related to carbamazepine in epileptic patients

teaser

In polytherapy treatment, the percentage of patients with carbamazepine plasma concentration above the therapeutic range decreases compared with monotherapy

Maria Criado Daza
PhD, Resident Pharmacist

Fernández Feijoo
PhD, Chief Pharmacist
Cytostatics Section

Calleja Hernández
MRPharmS, Chief Pharmacist
Clinic Management Unit
Pharmacy Service
Virgen de las Nieves
University Hospital
Granada, Spain

Epilepsy is a chronic disease characterised by the presence of episodes referred to as “epileptic crises”. Such a crisis is defined as an “excessive discharge of a hyperexcitable neuronal formation”.[1] Some 60% of epilepsy patients control their symptoms with monotherapy. Ten per cent of patients who are not controlled with monotherapy (40%) will be well controlled with the combination of two drugs with different mechanisms of action: since epilepsy is a heterogeneous disease, acting on two different mechanisms of action may increase the chances of
affecting control.[1,4]

It is, therefore, important to study the most frequent drug interactions or those which would occur in daily practice. In this piece of research we studied the interaction between two antiepileptic drugs, carbamazepine and phenytoin, because among all possible combinations of antiepileptic drugs, this one is very common in daily practice because of the synergies
shown when they are taken together.[4,6] In addition, the small therapeutic margin of both drugs means that both therapeutic efficiency and potential toxicity might well be affected.[2,7,9]

Phenytoin in small doses follows linear kinetics, but in higher doses given to achieve and maintain a stationary state, the kinetics are not linear. Phenytoin is metabolised in the liver to a limited degree, which means that at the moment that metabolic enzymes are saturated, the kinetics are not linear. Therefore, slight changes in maintenance doses are associated with major changes in plasma concentration.[9,10] In patients who have liver insufficiency, phenytoin plasma concentration rises sufficiently to reach toxic levels.

Regarding carbamazepine, the other antiepileptic drug studied here, elimination takes place via the liver, as with phenytoin, being a powerful inductor of metabolism of cytochrome P-450 (even increasing its own metabolism). An epileptic patient treated with carbamazepine and phenytoin but who stops
treatment with phenytoin via medical prescription will probably suffer carbamazepine intoxication, as phenytoin will no longer act as an inductor of hepatic metabolism, decreasing metabolism and clearance of carbamazepine, and increasing plasma concentration to toxic levels.[9,11]

Method: descriptive observational prospective research
The research focused on all patients in our hospital in whom carbamazepine plasma concentration had been determined in monotherapy or in relation to phenytoin.

The study was undertaken between 1 October 2006 and 31 January 2007. In total, 79 applications were filled, 57 of them to determine carbamazepine in monotherapy and 22 to determine carbamazepine and phenytoin concentration. Antiepileptic drug plasma concentration was determined using the AxSYM PLUS 5.1 analyser (Abbott), which is based on immunoassay technology by fluorescence polarisation. Immunoassays use a selective antibody to find analytes of interest (in this case, antiepileptic drugs). Using observed dose and concentration data, elimination constants (Ke) of patients with an estimated concentration of carbamazepine within a range were calculated.

With Ke data, average elimination constants of patients treated using monotherapy with carbamazepine were compared with average elimination constants of carbamazepine in patients treated with both carbamazepine and phenytoin. Statistic analysis was undertaken if the average Ke was lower in
patients treated using monotherapy rather than polytherapy. Statistical analysis was carried out with SPSS for Windows version 12.0. Student’s t-test was used to compare the averages of frequency. The reliability interval was 95%. Units of Ke are 1/h.

Results
As indicated in Figures 1 and 2, 35% of patients using monotherapy presented concentrations within the therapeutic range; in 24% of patients this was higher and in 18% lower. No data were available for 23% of patients.

In total, 73% of the polytherapy group presented concentrations within the therapeutic range; and in 27% this was lower.

Table 1 indicates that 21 adult patients treated using monotherapy with carbamazepine, and 16 patients treated with carbamazepine plus phenytoin showed carbamazepine plasma concentrations within therapeutic range. The average of elimination constants seen in patients treated with carbamazepine (Ke = 0.031885714/ h) is lower than the average of elimination constants in patients treated with carbamazepine plus phenytoin (Ke = 0.0405125/ h). When
calculating Student’s t-test, a significant statistical result was attained with a reliable interval of 95%, with significance at 0.0041927.

[[HPE42_33a]]

Conclusion
The use of more than one antiepileptic drug is common or patients resistant to monotherapy.1,3 The combination of phenytoin and carbamazepine means the presence of pharmacokinetic interactions in most patients who are treated with both drugs, as these drugs have a common metabolism. This can affect the efficiency and toxicity of antiepileptic therapy, as outlined in several articles.[12,15]

We have seen that plasma clearance rises significantly in patients treated with carbamazepine plus phenytoin, compared with patients treated solely with carbamazepine.[15,17] This is due to the induction of hepatic metabolism produced by phenytoin, hastening the elimination of carbamazepine from the body.

Enzymatic induction of both drugs (phenytoin and carbamazepine) means no patient treated with polytherapy showed concentrations of antiepileptic drug above therapeutic range, so there is no risk of toxicity in any of these patients, but there is a lack of efficiency as therapeutic levels are not reached.[10,11]

[[HPE42_33b]]

References
1. Epilepsy. In: DiPiro JT, et al, editors. Pharmacotherapy: a pathophysiologic approach. 6th ed. New York: McGraw Hill; 2005.
2. Status epilepticus. In: DiPiro JT, et al , editors. Pharmacotherapy: a pathophysiologic approach. 6th ed. New York: McGraw Hill; 2005.
3. Casas Fernandez C, et al. Evidencia cientifica en epilepsia: manual de actuacin. Madrid; 2006.
4. Mateos Marcos V, Salas Puig J. Epilepsia caso a caso. Madrid; Luzán 5: 2006.
5. Suñe Arbussá JM, et al. Manual de interacciones medicamentosas. Barcelona: Edit Medica Jims; 1997.
6. Braumann P, et al. Dialogues Clin Neurosci 005;7(3):231-47.
7. COF. Manual de interacciones de los medicamentos. Madrid:
Edit Gráficas Fl; 1993.
8. Torres M, et al. Med UIS 1996;10(1):4-6.
9.
Stockley I. Interacciones farmacolgicas. Barcelona: Pharma; 2004.
10. Phenitoin. In: DRUGDEXÃ’.System (Internet database). Greenwood Village (Co): Thompson Healthcare. Updated periodically.
11. Clin Pharmacokinet 1995;29:442-50.
12. Am J Hosp Pharm 1993;50(12):S23-9.
13. Eur J Clin Pharmacol 1992;43:201-3.
14. Lancet Neurol 2003;2(6):347-56.
15. Drug Saf 1998;19(6):495-510.
16. Ann Pharmacother 1993;27:708-11.
17. Eur J Clin Pharmacol 1998;54(4):359-62.



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