VARIABILITY AND CLINICAL RELEVANCE OF THE INTERACTION BETWEEN SODIUM VALPROATE AND CARBAMAZEPINE IN EPILEPTIC PATIENTS

Twenty-four epileptic patients (16 females, 8 males; aged 13-62 years) were studied before and after the addition of sodium valproate (VPA) 500 mg twice daily for 5 days. All had been established previously on carbamazepine (CBZ) as monotherapy (300-1600 mg daily in divided doses). Sixteen of these patients undertook a battery of cognitive function tests before and after VPA introduction. VPA had no effect on total or free CBZ concentrations. However, median concentrations of the active metabolite, CBZ 10, 11 epoxide (CBZ-E), were significantly increased (CBZ-E before VPA 1.3 mg/l, after VPA 2.1 mg/l, P < 0.01). The median rise was 25%, although the extent of the interaction ranged from a 25% decrease to an increase of 123% in CBZ-E concentrations. This was related to the marked inter-individual variation in circulating VPA (mean 25-69 mg/1), as CBZ-E concentrations correlated significantly with total (r = 0.5, P < 0.05, 95% CI 0 to +0.08) and free (r = 0.7, P < 0.001, 95% CI +0.09 to +0.25) VPA levels in individual patients. Although uncontrolled, no deterioration in performance of any of the cognitive function tests was observed following the addition of VPA. This study does not support immediate clinical relevance for this drug interaction between VPA and CBZ.