Effect of phenytoin, phenobarbital and valproic acid on carbamazepine clearance and therapeutic out come: derived from routine therapeutic drug monitoring data at Prasat Neurological Institute

Abstract

Background : Pharmacokinetics (PK) of carbamazepine (CBZ) are highly variable and further complicated by concomitant use of other antiepileptic drugs with induction or inhibition properties.

Objective : To determine the pharmacokinetics of CBZ when used as monotherapy or co-administrated with phenytoin (PHT), phenobarbital (PB) or valproic acid (VPA) along with the related therapeutic outcome.

Design : A descriptive study.

Setting : Prasat Neurological Institute, Bangkok.

Patients : Patients aged more than 13 years old with epilepsy or other neurological disease who used CBZ as monotherapy or co-administrated with PHT, PB or VPA and their therapeutic drug monitoring data (TDM) had been recorded and available were included into this study.

Method : Four-year retro-prospective data, August 2006 - August 2010, were collected from electronic database and medical records of the outpatient epilepsy clinic.

Result : Data of 74 patients, 34 men and 40 women, were identified and used in this analysis; 71 were diagnosed with epilepsy while 3 had neuropathic pain. Their age were ranged from 13.87 to 82.05 years (mean = 40.13 ± 15.22). The median level - to - dose ratio of CBZ in patients who used CBZ as monotherapy (10.88 mcg/L/mg, N = 30) was significantly higher (p < 0.001) than those obtained after combination therapy with PHT (6.13 mcg/L/mg, N =15), PB (6.81 mcg/L/mg, N =14) or VPA (8.88 mcg/ L/mg, N =15), even though the median daily dose of CBZ (13.36 VS 16.47, 16.88 and 16.02 mg/kg/day, respectively) was not significantly different (p = 0.184). The median clearance of CBZ in patients who used CBZ in combination with PHT (2.34 L/kg/day) or PB (1.49 L/kg/day) was significantly higher than that observed after CBZ monotherapy (1.09 L/kg/day) (p < 0.001 and p = 0.013, respectively). However, the median clearance of CBZ in patients who used CBZ in combination with VPA (1.34 L/kg/day) was not significantly different from that found after monotherapy (p = 0.118). Seventeen patients (24%) of the 71 epileptic patients participated had uncontrolled seizure while 4 patients (6%) had mild adverse effects.

Conclusion : The clearance of CBZ in patients who used CBZ as monotherapy was significantly lower than in those observed patients who used CBZ in combination with PHT or PB, but it was not significantly different from patients who used CBZ in combination with VPA.