title: Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer.
abstract: OBJECTIVE
  We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer.
  
  
  METHODS
  Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who had not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy.
  
  
  RESULTS
  The MTD of the combination was 225 mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 micromol/L (range, 1.9 to 6.3), respectively, which are within the range necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitxel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations.
  
  
  CONCLUSIONS
  r-Verapamil at 225 mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3-hour infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.
authors.affiliation: Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: K H
authors.initials: KH
authors.lastname: Cowan
authors.forename: D
authors.initials: D
authors.lastname: Solomon
authors.forename: F
authors.initials: F
authors.lastname: Ognibene
authors.forename: B
authors.initials: B
authors.lastname: Goldspiel
authors.forename: R
authors.initials: R
authors.lastname: Chang
authors.forename: M H
authors.initials: MH
authors.lastname: Noone
authors.forename: A M
authors.initials: AM
authors.lastname: Denicoff
authors.forename: C S
authors.initials: CS
authors.lastname: Barnes
authors.forename: M R
authors.initials: MR
authors.lastname: Gossard
authors.forename: P A
authors.initials: PA
authors.lastname: Fetsch
authors.forename: S L
authors.initials: SL
authors.lastname: Berg
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
authors.forename: D J
authors.initials: DJ
authors.lastname: Venzon
authors.forename: J A
authors.initials: JA
authors.lastname: O'Shaughnessy
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000187:drug effects; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001706:Biopsy; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018592:Cross-Over Studies; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014700:Verapamil / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D014700:Verapamil; D017239:Paclitaxel