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.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Rowinsky
E K
EK
Institute for Drug Development, University of Texas Health Science Center, San Antonio 78229, USA. erowinsk@saci.org
Smith
L
L
Wang
Y M
YM
Chaturvedi
P
P
Villalona
M
M
Campbell
E
E
Aylesworth
C
C
Eckhardt
S G
SG
Hammond
L
L
Kraynak
M
M
Drengler
R
R
Stephenson
J
J
Harding
M W
MW
Von Hoff
D D
DD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D007166:Immunosuppressive Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; C106077:biricodar