biricodar and Neoplasms

Modulation of P glycoprotein (Pgp) in clinical oncology has had limited success. Contributing factors have included the limitation in our understanding of the tumours in which Pgp overexpression is mechanistically important in clinical drug resistance; the failure to prove that concentrations of modulators achieved in patients were sufficient to inhibit Pgp; and the inability to conclusively prove that Pgp modulation was occurring in tumours in patients. New approaches are needed to determine the clinical settings in which Pgp overexpression plays a major role in resistance. (Clinical trials with third generation modulators are ongoing, including trials with the compounds LY335979, R101933 and XR9576. Using the Pgp substrate Tc-99m Sestamibi as an imaging agent, increased uptake has been seen in normal liver and kidney after administration of PSC 833, VX710 and XR9576. These studies confirm that the concentrations of modulator achieved in patients are able to increase uptake of a Pgp substrate. Furthermore, CD56+ cells obtained from patients treated with PSC 833 demonstrate enhanced rhodamine retention in an ex vivo assay after administration of the antagonist. Finally, a subset of patients treated with Pgp antagonists show enhanced Sestamibi retention in imaged tumours. These results suggest that Pgp modulators can increase drug accumulation in Pgp-expressing tumours and normal tissues in patients. Using third generation Pgp antagonists and properly designed clinical trials, it should be possible to determine the contribution of modulators to the reversal of clinical drug resistance.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzazepines; Clinical Trials as Topic; Cyclosporins; Dibenzocycloheptenes; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitors; Fluorescent Dyes; Gene Expression Regulation, Neoplastic; Genes, MDR; Humans; Mice; Mice, Knockout; Neoplasm Proteins; Neoplasms; Piperidines; Pyridines; Quinolines; Radionuclide Imaging; Radiopharmaceuticals; Rhodamines; Technetium Tc 99m Sestamibi; Tissue Distribution; Tumor Cells, Cultured

Vertex is developing biricodar as a chemosensitizing agent designed to restore the effectiveness of chemotherapeutic agents in tumor multidrug resistance. By November 1998, phase II trials had commenced for biricodar, in combination with chemotherapy, for five common cancer indications: breast, ovarian, soft-tissue sarcomas, small cell lung cancer and prostate cancer. Phase II trials were ongoing in January 2002. By March 2000, Vertex was the sole developer of biricodar, as an agreement made in 1996 with BioChem Pharma (now Shire Pharmaceuticals), for the development and marketing of biricodar in Canada was terminated. Biricodar is the free base compound, which also has a citrate salt analog known as VX-710-3. Vertex has published three patents, WO-09615101, WO-09636630 and WO-09736869, disclosing derivatives of biricodar that are claimed for the treatment of multidrug resistant protein and P-glycoprotein-mediated multidrug resistant tumors. In January 2002, a Banc of America analyst report forecast that biricodar had a 30% chance of reaching the market with a launch date in the second half of 2005, with peak sales estimated at $250 million.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Piperidines; Pyridines; Structure-Activity Relationship

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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; DNA-Binding Proteins; Dose-Response Relationship, Drug; Doxorubicin; Drug Interactions; Female; Half-Life; Humans; Infusions, Intravenous; Liver; Male; Maximum Tolerated Dose; Middle Aged; Multidrug Resistance-Associated Proteins; MutS Homolog 3 Protein; Neoplasms; Piperidines; Pyridines; Radionuclide Imaging; Radiopharmaceuticals; Technetium Tc 99m Sestamibi; Tissue Distribution

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 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Resistance, Multiple; Female; Humans; Immunosuppressive Agents; Infusions, Intravenous; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Neoplasms; Paclitaxel; Piperidines; Pyridines

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Cyclosporins; Dibenzocycloheptenes; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs, Investigational; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; National Institutes of Health (U.S.); Neoplasms; Piperidines; Pyridines; Quinolines; United States