title: Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) and toxicity of PSC 833 infusion administered with etoposide for 5 days in patients with cancer, and to determine the effect of PSC 833 on etoposide pharmacokinetics.
  
  
  METHODS
  Thirty-five patients were entered onto the study, one of whom was ineligible. Etoposide was delivered from day 1 as a 2-hour infusion over 5 consecutive days at a dose of 75 to 100 mg/m2/d. PSC 833 was administered from day 2 as a 2-hour loading dose and as a 5-day continuous infusion. Doses were escalated from 1 to 2 mg/kg (loading dose) and 1 to 15 mg/kg/d (continuous infusion).
  
  
  RESULTS
  Thirty-four patients were treated with 53 cycles of PSC 833 and etoposide. Steady-state blood PSC 833 levels more than 1,000 ng/mL were achieved in all patients treated at PSC 833 doses > or = 6.6 mg/kg/d by continuous infusion. Myelosuppression was the most common toxicity. The major dose-related toxicity of PSC 833 was reversible hyperbilirubinemia, which occurred in 83% of cycles. The dose-limiting toxicity of PSC 833 was severe ataxia, which occurred in two of nine patients treated at 12 mg/kg/d and in both of the single patients treated at 13.5 and 15 mg/kg/d. PSC 833 concentrations more than 2,000 ng/mL resulted in an increase in etoposide area under the curve (AUC) of 89%, a decrease in etoposide clearance (Cl) of 45%, a decrease in volume of steady-state distribution (Vss) of 41%, and an insignificant increase in alpha half-life (t 1/2 alpha) and significant increase of beta half-life (t 1/2 beta) of 19% and 77%, respectively.
  
  
  CONCLUSIONS
  PSC 833 can be administered in combination with etoposide with acceptable toxicity. The recommended continuous infusion dose of PSC 833 for this schedule is 10 mg/kg/d over 5 days. PSC 833 results in an increase in etoposide exposure and etoposide doses should be reduced in patients receiving PSC 833.
authors.affiliation: Medical Research Council Unit, Medical Research Council Centre, Cambridge, United Kingdom.
authors.forename: D J
authors.initials: DJ
authors.lastname: Boote
authors.forename: I F
authors.initials: IF
authors.lastname: Dennis
authors.forename: P R
authors.initials: PR
authors.lastname: Twentyman
authors.forename: R J
authors.initials: RJ
authors.lastname: Osborne
authors.forename: C
authors.initials: C
authors.lastname: Laburte
authors.forename: S
authors.initials: S
authors.lastname: Hensel
authors.forename: J F
authors.initials: JF
authors.lastname: Smyth
authors.forename: M H
authors.initials: MH
authors.lastname: Brampton
authors.forename: N M
authors.initials: NM
authors.lastname: Bleehen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003524:Cyclosporins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003524:Cyclosporins; D005047:Etoposide; C070272:valspodar