PHENYTOIN ALTERS THE DISPOSITION OF TOPOTECAN AND N-DESMETHYL TOPOTECAN IN A PATIENT WITH MEDULLOBLASTOMA

Topotecan undergoes both renal and hepatic elimination, with topotecan urinary recovery ranging from 60 to 70%, We evaluated the potential o f phenytoin to alter the disposition of topotecan and its N-desmethyl metabolite, A 5-year-old child with high-risk medulloblastoma received the first course of topotecan with phenytoin and the second course wi thout phenytoin, For both courses, topotecan doses were adjusted to ac hieve a target topotecan lactone plasma area under the curve (AUG), Se rial plasma samples were obtained, and lactone and total plasma concen trations of topotecan, as well as total plasma and cerebrospinal fluid concentrations of N-desmethyl topotecan, were measured by high-perfor mance liquid chromatography. Phenytoin coadministration increased lact one and total topotecan clearance from 43.4 +/- 1.9 L/h/m(2) to 62.9 /- 6.4 L/h/m(2), and 20.8 +/- 2.8 L/h/m(2) to 30.6 +/- 4.1 L/h/m(2), r espectively (P < 0.05), Concomitant phenytoin increased the plasma AUC of total N-desmethyl topotecan from 7.5 +/- 0.68 ng/ml.h to 16.3 +/- 0.53 ng/ml.h (P < 0.05) at plasma AUC of total topotecan of 226.0 +/- 5.5 ng/ml.h and 240.9 +/- 39.8 ng/ml.h, respectively. N-Desmethyl topo tecan penetrated into the cerebrospinal fluid (0.12 +/- 0.01), The pat ient experienced no grade 3 or 4 toxicity, These are the first data do cumenting altered topotecan and N-desmethyl topotecan disposition when coadministered with phenytoin and suggests that topotecan may undergo further hepatic metabolism, Although there is an increase in exposure to the active N-desmethyl topotecan metabolite, it is less than the d ecrease in exposure to topotecan lactone, Therefore, patients concomit antly administered phenytoin may require an increase in topotecan dose to achieve a similar pharmacological effect as a patient not receivin g phenytoin.