The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites.
We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated. The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2-2.5-times higher in patients with severe renal impairment (CLCR < 10 ml.min-1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects. The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance. The maximum target dose in patients with slight renal impairment (CLCR > 30 ml.min-1) should not be changed. In patients with moderate renal impairment (CLCR 10-30 ml.min-1) it should be reduced by 50%. In patients with severe renal impairment (CLCR < 10 ml.min-1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.
Rouan
M C
MC
Centre de Bioanalyse et Pharmacocinétique, Laboratories Ciba-Geigy, Rueil-Malmaison, France.
Lecaillon
J B
JB
Godbillon
J
J
Menard
F
F
Darragon
T
T
Meyer
P
P
Kourilsky
O
O
Hillion
D
D
Aldigier
J C
JC
Jungers
P
P
D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000078330:Oxcarbazepine
D000927:Anticonvulsants; D002220:Carbamazepine; C004822:10,11-dihydro-10,11-dihydroxy-5H-dibenzazepine-5-carboxamide; D000078330:Oxcarbazepine