Effects of Concomitant Antiepileptic Drugs on Serum Carbamazepine Concentration in Epileptic Patients: Quantitative Analysis Based on Extracellular Water Volume as a Transforming Factor

Abstract

The eŠects of concomitant antiepileptic drugs on the serum carbamazepine concentration (C t ) were analyzed quantitatively. Primidone (PRM), phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), zonisamide (ZNS), clonazepam (CZP), and ethosuximide (ETS) were coadministered with carbamazepine (CBZ). Routine therapeutic drug monitoring data, obtained from epileptic patients who were treated with the repetitive oral administration of CBẐ ne granules/tablets, were used for the analysis. A total of 119 patients were administered CBZ alone, and 91, 39, 19, and 6 patients were coadministered one, two, three, and more than four diŠerent antiepileptic drugs, respectively. Using the data obtained from the patients administered CBZ alone, C t could be expressed approximately as a function of the daily dose per extracellular water volume (D/V ECW ) as C t ＝A(D/V ECW ) B (A, B: parameter). By comparing the regression line on log C t vs. log(D/V ECW ) for CBZ alone with that for CBZ plus another concomitant drug, C t was thus found to be aŠected at each deˆnite ratio by PB and PHT, but not by VPA and ZNS. We postulated a model showing that C t is aŠected by each concomitant antiepileptic drug i at each deˆnite ratio. We deˆned the parameter R i (i＝1, 2, …, 7) representing the eŠect of each concomitant antiepileptic drug on C t . A linear polynomial expression, in which both members of this model are converted into common logarithms, was used for a multiple regression analysis. The analysis claried that PB and PHT lowered C t to 0.770 and 0.710 the value of CBZ alone, respectively. On the other hand, VPA and ZNS did not aŠect C t . The number of patients coadministered PRM, CZP, and/or ETS was not su‹cient to detect the eŠect on C t based on a test of signiˆcance. In the case of the addition or discontinuation of concomitant antiepileptic drugs in the same patient, the estimated C t values were calculated using the value of each R i and compared with the measured C t values. Both values were in good agreement, and thus our results appear valid.

Influence of Coadministered Antiepileptic Drugs on Serum Zonisamide Concentrations in Epileptic Patients: Quantitative Analysis Based on Suitable Transforming Factor

“…The influences of concomitant drug use on the serum concentration were evaluated quantitatively in all the patients without them being grouped by other confounding factors. 6,7) In this paper, V ECW also affected the L/D ratio of ZNS independent of confounding factors. Then the authors detected the drug affecting the L/D ratio and investigated its influence quantitatively.…”

Factors Influencing Plasma Concentrations of Phenytoin, Phenobarbitone, Carbamazepine and Sodium Valproate in Epileptic Patients Attending a Tertiary Care Hospital

“…However, V ECW has shown to be a good transforming factor to calculate plasma concentrations of AEDs. 8,9 Future studies with a larger sample size may be helpful in evaluating this factor.…”

“…TDM for Phenytoin, Phenobarbitone, Carbamazepine and/ or Sodium Valproate as per the requisition of the clinician was done by High Performance Liquid Chromatography (HPLC) method which is standardized and performed for routine patient care. V ECW was calculated using the formula: 8 V ECW = 0.068 x body weight [kg] 0.40 x height[cm] 0.633 Clinical response was assessed as per the International League Against Epilepsy Guidelines 2 and was classified into either Category 1 Outcome (Seizure Freedom), Category 2 Outcome (Treatment Failure), or Category 3 Outcome (Undetermined). Seizure Freedom is defined as freedom from seizures for a minimum of three times the longest pre-intervention inter-seizure interval (determined from seizures occurring within the past 12 months) or 12 months, whichever is longer.…”

“…Studies have shown that daily dose of carbamazepine and phenobarbitone expressed in terms of extracellular water volume was found to correlate better with their serum concentrations. 8,9 Other studies reported from India have found that in many patients, the plasma levels do not correlate with the clinical response. 10 Studies discussing the effects of combination therapy on the plasma concentrations of carbamazepine, phenytoin and sodium valproate found that carbamazepine and phenytoin decreased the levels of concomitantly administered drugs.…”

Suivi thérapeutique pharmacologique de trois médicaments antiépileptiques: retour sur vingt années d’expérience

“…Les interactions médicamenteuses qui peuvent avoir lieu en cas bi ou trithérapie avec ces MAE, justifient les demandes de STP de ces molécules [ 38 – 41 ]. En effet, Fukuoka et al [ 42 ] ont réalisé une étude chez 119 patients épileptiques sous carbamazépine seule, 91 patients en bithérapie soit avec le phénobarbital ou avec la phénytoine et 64 malades en polythérapie avec les 3 antiépileptiques. Ces auteurs ont montré que le phénobarbital fait diminuer la concentration de la carbamazépine d'un facteur de 0,77.…”