Coadministration of phenytoin and felbamate: evidence of additional phenytoin dose-reduction requirements based on pharmacokinetics and tolerability with increasing doses of felbamate.
OBJECTIVE
This open-label study investigated the pharmacokinetic interaction of phenytoin (PHT) and felbamate (FBM).


METHODS
Ten subjects with epilepsy receiving PHT monotherapy were administered increasing doses of FBM (1,200, 1,800, 2,400-3,600 mg/day) at 2-week intervals. PHT doses were reduced by 20% on an individual basis when evidence of clinically significant intolerance was present. With intolerance, the PHT dose was reduced before the next incremental FBM dose. Blood samples were analyzed for FBM, PHT, and PHT metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH).


RESULTS
Total PHT plasma concentrations increased with coadministered FBM. PHT Cmax increased from 15.9 microg/ml at baseline to 20.9 microg/ml after 1,200 mg/day FBM and to 26.8 microg/ml after 1,800 mg/day FBM. Four subjects required a 20% PHT dose reduction after 1,800 mg/day FBM and six after the administration of 2,400 mg/day FBM. All subjects required further 20% PHT reductions before 3,600 mg/day FBM. FBM Cmax and AUCT were reduced, and apparent clearance increased compared with data from FBM monotherapy.


CONCLUSIONS
With the initiation of FBM therapy in subjects receiving PHT, the PHT dosage should be reduced by 20%. Further PHT dose reductions are likely to be necessary if the FBM dose is increased. The requirements for reductions in dose might be predicted by clinical signs of PHT intolerance.
Sachdeo
R
R
Robert Wood Johnson Medical School, Department of Neurology, New Brunswick, New Jersey 08903, USA.
Wagner
M L
ML
Sachdeo
S
S
Shumaker
R C
RC
Lyness
W H
WH
Rosenberg
A
A
Ward
D
D
Perhach
J L
JL
D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy*; D000078328:Felbamate; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D048448:Phenylcarbamates; D010672:Phenytoin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011409:Propylene Glycols / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D010672:Phenytoin; D000078328:Felbamate