Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin.
OBJECTIVE
To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of (99m)Tc-sestamibi, a P-gp and MRP1 substrate, was also evaluated.


METHODS
Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m(2)/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m(2) was administered. Cycles were repeated every 21 to 28 days. (99m)Tc-sestamibi scans were performed before and during administration of VX-710 alone.


RESULTS
Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m(2)/h or less. Among seven patients receiving VX-710 160 mg/m(2)/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m(2)/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of (99m)Tc-sestamibi in all patients.


CONCLUSIONS
A 96-hour infusion of VX-710 at 120 mg/m(2)/h plus doxorubicin 45 mg/m(2) has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.
Peck
R A
RA
Vincent T. Lombardi Cancer Research Center and Department of Nuclear Medicine, Georgetown University, Washington, DC, USA.
Hewett
J
J
Harding
M W
MW
Wang
Y M
YM
Chaturvedi
P R
PR
Bhatnagar
A
A
Ziessman
H
H
Atkins
F
F
Hawkins
M J
MJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D010880:Piperidines; D011725:Pyridines; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi; C078444:MSH3 protein, human; C106077:biricodar; C421109:multidrug resistance-associated protein 1