Effect of progabide on serum phenytoin and carbamazepine concentrations.
Progabide (PGB) is a gamma-aminobutyric acid (GABA)-agonist drug undergoing clinical evaluation for the treatment of spasticity, movement disorders, and epilepsy. Drug interactions were studied during a randomized, double-blind, crossover trial of the efficacy and toxicity of PGB in patients with partial seizures taking phenytoin (PHT) and carbamazepine (CBZ). In twenty-two of 32 patients (69%) receiving PGB, PHT dosage was reduced, while only four patients (12%) had their dosage reduced during placebo treatment (p less than 0.001). Carbamazepine dosage was decreased in five of 32 patients (16%) during the active treatment, while two patients (6%) had a dosage reduction when receiving placebo (p greater than 0.75). The mean PHT concentrations at the end of baseline, PGB, and placebo treatments were significantly different: 17.5, 20.4, and 16.8 mg/L, respectively (p less than 0.05). Nevertheless, careful adjustment of PHT dosage maintained serum concentration within +/- 25% of target values in both the PGB and placebo periods. Among patients who first received PGB and then placebo, PHT concentrations remained elevated relative to dose suggesting that PGB exerts a prolonged effect on PHT disposition. The addition of PGB to regimens including PHT results in a significant increase in serum PHT concentrations. This drug interaction most likely occurs as a result of PGB mediated inhibition of hepatic microsomal enzymes.
Brundage
R C
RC
College of Pharmacy, Medical University of South Carolina, Charleston.
Cloyd
J C
JC
Leppik
I E
IE
Graves
N M
NM
Welty
T E
TE
D000328:Adult; D002220:Carbamazepine / Q000097:blood* / Q000627:therapeutic use; D003292:Convulsants / Q000627:therapeutic use*; D004311:Double-Blind Method; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D010672:Phenytoin / Q000097:blood* / Q000627:therapeutic use; D011897:Random Allocation; D012640:Seizures / Q000097:blood* / Q000188:drug therapy; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use
D003292:Convulsants; D002220:Carbamazepine; C017985:progabide; D005680:gamma-Aminobutyric Acid; D010672:Phenytoin