title: Phase I pharmacokinetic trial and correlative in vitro phase II tumor kinetic study of Apomine (SR-45023A), a novel oral biphosphonate anticancer drug.
abstract: OBJECTIVE
  To study the human pharmacokinetics and in vitro cytotoxicity of Apomine, an p.o. administered, nonmyelosuppressive agent that selectively inhibits cell proliferation and induces tumor cell apoptosis through the farnesoid X receptor.
  
  
  METHODS
  Seven solid cancer patients who participated in an ongoing Phase I study of Apomine and received the starting dose level of 125 mg/m(2)/day x 14 days every 3 weeks underwent a pharmacokinetic study on day 14 of the first course. Plasma concentrations of Apomine were assayed with a Hewlett Packard gas chromatograph using a nitrogen phosphorus detector and HP-5 15m x 0.32-mm column. Fresh human ovarian cancer tumor samples were obtained during initial exploratory laparotomy from 35 chemotherapy-naive, advanced stage epithelial ovarian cancer patients. Tumor samples were tested for sensitivity to Apomine, carboplatin, cisplatin, paclitaxel, and topotecan using an in vitro clonogenic [(3)H]thymidine end point assay.
  
  
  RESULTS
  Pharmacokinetic analysis revealed a mean Apomine plasma C(max) of 16.4 +/- 9.1 microg/ml (29.1 microM), a mean plasma AUC(0--12 h) of 173.4 +/- 105 microg. h/ml (308 microM. h), and a mean t(1/2 (24--192 h)) of 156.2 +/- 42.9 h. In vitro assay results showed that 63 and 91% of the ovarian cancers were sensitive (i.e., >70% inhibition of tumor cell growth) to Apomine at concentrations of 10 and 20 microM. The sensitivity rates were 91% for carboplatin (270 microM), 88% for cisplatin (33 microM), 41% for paclitaxel (5.9 microM), and 85% for topotecan (2.2 microM).
  
  
  CONCLUSIONS
  These in vitro assay results, taken together with our preliminary plasma pharmacokinetic data, suggest that Apomine should be clinically active at the 125 mg/m(2) dose level.
authors.affiliation: Section of Hematology and Oncology, College of Medicine, University of Arizona, Tucson, Arizona, USA. dalberts@azcc.arizona.edu
authors.forename: D S
authors.initials: DS
authors.lastname: Alberts
authors.forename: A V
authors.initials: AV
authors.lastname: Hallum
authors.forename: M
authors.initials: M
authors.lastname: Stratton-Custis
authors.forename: D J
authors.initials: DJ
authors.lastname: Garcia
authors.forename: M
authors.initials: M
authors.lastname: Gleason-Guzman
authors.forename: S E
authors.initials: SE
authors.lastname: Salmon
authors.forename: P
authors.initials: P
authors.lastname: Santabarbara
authors.forename: E J
authors.initials: EJ
authors.lastname: Niesor
authors.forename: S
authors.initials: S
authors.lastname: Floret
authors.forename: C L
authors.initials: CL
authors.lastname: Bentzen
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D004164:Diphosphonates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; C407151:apomine