title: Combination metronomic oral topotecan and pazopanib: a pharmacokinetic study in patients with gynecological cancer.
abstract: BACKGROUND
  Combination metronomic topotecan plus pazopanib is active against preclinical models of gynecological cancer. Both agents are substrates for ATP-binding cassette family transporters so there is an increased likelihood for pharmacokinetic (PK) drug-drug interactions.
  
  
  METHODS
  PK analyses of topotecan were performed during three cycles of a phase I dose-escalation study of metronomic topotecan and pazopanib in consenting adult patients with gynecological cancer. Concentration time data were analyzed using a population PK approach.
  
  
  RESULTS
  Twenty-one patients were evaluable for serial PK studies. Considerable inter- and intra-patient variability was observed in the PK parameters, attributable primarily to highly variable oral bioavailability. No difference in topotecan disposition was detected between administration cycles, nor between the off- versus on-pazopanib studies.
  
  
  CONCLUSIONS
  The lack of a statistically significant drug-drug interaction agrees with preclinical findings suggesting that pazopanib does not influence the PK of metronomic topotecan. No adjustment of low dose metronomic topotecan dosing is merited when used in conjunction with pazopanib.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, U.S.A. clinton.stewart@stjude.org.
authors.forename: David C
authors.initials: DC
authors.lastname: Turner
authors.forename: Todd D
authors.initials: TD
authors.lastname: Tillmanns
authors.forename: K Elaine
authors.initials: KE
authors.lastname: Harstead
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Throm
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000284:Administration, Oral; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy*; D006801:Humans; D007191:Indazoles; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D019772:Topotecan; C516667:pazopanib
keywords: Metronomic topotecan; drug drug interaction; gynecological cancer; pazopanib; pharmacokinetics
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