Journal of Clinical Oncology, Vol 16, 2964-2976, Copyright © 1998 by American Society of Clinical Oncology
Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP
EK Rowinsky, L Smith, YM Wang, P Chaturvedi, M Villalona, E Campbell, C Aylesworth, SG Eckhardt, L Hammond, M Kraynak, R Drengler, J Stephenson Jr, MW Harding and DD Von Hoff
Institute for Drug Development, University of Texas Health Science Center, San Antonio 78229, USA. erowinsk@saci.org
PURPOSE: To evaluate the feasibility of administering biricodar (VX- 710;
Incel, Vertex Pharmaceuticals Inc, Cambridge, MA), an agent that modulates
multidrug resistance (MDR) conferred by overexpression of both the
multidrug resistance gene product (MDR1) P-glycoprotein and the
MDR-associated protein (MRP) in vitro, in combination with paclitaxel. The
study also sought to determine the maximum-tolerated dose (MTD) of
paclitaxel that could be administered with biologically relevant
concentrations of VX-710 and characterize the toxicologic and pharmacologic
profiles of the VX-710/ paclitaxel regimen. PATIENTS AND METHODS: Patients
with solid malignancies were initially treated with VX-710 as a 24-hour
infusion at doses that ranged from 10 to 120 mg/m2 per hour. After a 2-day
washout period, patients were re-treated with VX-710 on an identical dose
schedule followed 8 hours later by paclitaxel as a 3-hour infusion at doses
that ranged from 20 to 80 mg/m2. The pharmacokinetics of both VX-710 and
paclitaxel were studied during treatment with VX-710 alone and VX-710 and
paclitaxel. Thereafter, patients received VX-710 and paclitaxel every 3
weeks. RESULTS: VX-710 alone produced minimal toxicity. The toxicologic
profile of the VX-710/paclitaxel regimen was similar to that reported with
paclitaxel alone; neutropenia that was noncumulative was the principal
dose-limiting toxicity (DLT). The MTD levels of VX-710/ paclitaxel were 120
mg/m2 per hour and 60 mg/m2, respectively, in heavily pretreated patients
and 120/60 to 80 mg/m2 per hour in less heavily pretreated patients. At
these dose levels, VX-710 steady-state plasma concentrations (Css) ranged
from 2.68 to 4.89 microg/mL, which exceeded optimal VX-710 concentrations
required for MDR reversal in vitro. The pharmacokinetics of VX-710 were
dose independent and not influenced by paclitaxel. In contrast, VX-710
reduced paclitaxel clearance. At the two highest dose levels, which
consisted of VX-710 120 mg/m2 per hour and paclitaxel 60 and 80 mg/m2,
pertinent pharacokinetic determinants of paclitaxel effect were similar to
those achieved with paclitaxel as a 3-hour infusion at doses of 135 and 175
mg/m2, respectively. CONCLUSION: VX-710 alone is associated with minimal
toxicity. In combination with paclitaxel, biologically relevant VX-710
plasma concentrations are achieved and sustained for 24 hours, which
simulates optimal pharmacologic conditions required for MDR reversal in
vitro. The acceptable toxicity profile of the VX-710/ paclitaxel
combination and the demonstration that optimal pharmacologic conditions for
MDR reversal are achievable support a rationale for further trials of
VX710/paclitaxel in patients with malignancies that are associated with de
novo or acquired resistance to paclitaxel caused by overexpression of MDR1
and/or MRP.
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