Diurnal Fluctuations in Free and Total Steady‐State Plasma Levels of Carbamazepine and Correlation with Intermittent Side Effects

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Abstract
The relationship between diurnal fluctuations in free (unbound) and total plasma carbamazepine levels and the appearance of intermittent side effects was investigated in 9 epileptic patients receiving chronic therapy with carbamazepine, alone or in combination with phenobarbital. On a 3-times-day or 4-times-daily dosing schedule, both total and free carbamazepine levels fluctuated considerably (on an average, 41 and 45%, respectively, around the mean). Side effects (particularly diplopia and nystagmus) were observed in 5 patients and showed an intermittent pattern in 4. Side effects were never found at total carbamazepine levels < 34 .mu.mol/l but invariably appeared at levels > 38 .mu.mol/1. At levels between 34 and 38 .mu.mol/l adverse effects were inconsistently observed. The correlation between plasma carbamazepine levels and manifestations of toxicity was slightly stronger when free rather than total levels were considered. Side effects were always apparent at free levels > 7.2 .mu.mol/l. These data underline the limitations of relying on a single drug level determination during the monitoring of carbamazepine therapy and emphasize the necessity of carefully adjusting the dosing schedule, to minimize the appearance of intermittent adverse effects.