Topotecan undergoes both renal and hepatic elimination, with
topotecan urinary recovery ranging from 60 to 70%. We evaluated the potential of
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 without
phenytoin. For both courses,
topotecan doses were adjusted to achieve a target
topotecan lactone plasma area under the curve (AUC). Serial plasma samples were obtained, and
lactone and total plasma concentrations of
topotecan, as well as total plasma and cerebrospinal fluid concentrations of
N-desmethyl topotecan, were measured by high-performance liquid chromatography.
Phenytoin coadministration increased
lactone and total
topotecan clearance from 43.4 +/- 1.9 L/h/m2 to 62.9 +/- 6.4 L/h/m2, and 20.8 +/- 2.8 L/h/m2 to 30.6 +/- 4.1 L/h/m2, respectively (P < 0.05). Concomitant
phenytoin increased the plasma AUC of total
N-desmethyl topotecan from 7.5 +/- 0.68 ng/ml x h to 16.3 +/- 0.53 ng/ml x h (P < 0.05) at plasma AUC of total
topotecan of 226.0 +/- 5.5 ng/ml x h and 240.9 +/- 39.8 ng/ml x h, respectively.
N-Desmethyl topotecan penetrated into the cerebrospinal fluid (0.12 +/- 0.01). The patient experienced no grade 3 or 4 toxicity. These are the first data documenting 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 decrease in exposure to
topotecan lactone. Therefore, patients concomitantly administered
phenytoin may require an increase in
topotecan dose to achieve a similar pharmacological effect as a patient not receiving
phenytoin.