title: Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: A J
authors.initials: AJ
authors.lastname: Gajjar
authors.forename: R L
authors.initials: RL
authors.lastname: Heideman
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.forename: P J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002528:Cerebellar Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D002675:Child, Preschool; D004347:Drug Interactions; D006801:Humans; D007783:Lactones; D008297:Male; D008527:Medulloblastoma / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010672:Phenytoin / Q000627:therapeutic use*; D019772:Topotecan / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D007783:Lactones; C105151:N-desmethyltopotecan; D010672:Phenytoin; D019772:Topotecan