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.
Centre de Bioanalyse et Pharmacocinétique, Laboratories Ciba-Geigy, Rueil-Malmaison, France.
M C
MC
Rouan
J B
JB
Lecaillon
J
J
Godbillon
F
F
Menard
T
T
Darragon
P
P
Meyer
O
O
Kourilsky
D
D
Hillion
J C
JC
Aldigier
P
P
Jungers
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