oc-144-093 and Neoplasms

oc-144-093 has been researched along with Neoplasms* in 4 studies

Reviews

2 review(s) available for oc-144-093 and Neoplasms

ArticleYear
Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer.
    Current opinion in pharmacology, 2006, Volume: 6, Issue:4

    Early publications using cultured cancer cells immediately recognized the phenomenon of resistance to anticancer agents. However, it was not until 1973 that it was first demonstrated that a major factor in the resistance of cancer cells was that of reduced drug accumulation. This year marks the 30th anniversary of the discovery by Juliano and Ling that P-glycoprotein mediates this active efflux of chemotherapeutic drugs from cancer cells. Since this seminal finding, the investigation of P-glycoprotein (MDR1, ATP binding cassette [ABC]B1) has proceeded with great vigour. However, it soon became apparent that P-glycoprotein was not expressed in all drug-resistant cells that displayed an accumulation deficiency, which led to the discovery of other ABC transporters involved in drug efflux. In 1992, the multidrug resistance-associated protein (MRP1, ABCC1) was identified in small cell lung cancer followed by breast cancer resistance protein (mitoxantrone resistance protein, ABCG2) in 1999. After three decades of research, can we confidently define the contribution of multidrug resistance transporters to chemoresistance and do we have clinically useful drugs to sensitise cancers?

    Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Clinical Trials as Topic; Cyclosporins; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Imidazoles; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Neoplasms; Quinolines; RNA Interference

2006
ONT-093 (Ontogen).
    Current opinion in investigational drugs (London, England : 2000), 2002, Volume: 3, Issue:11

    Ontogen is developing ONT-093 (formerly OC-144-093), a P-glycoprotein pump inhibitor, for the potential reversal of multidrug resistance in patients undergoing cancer chemotherapy. The compound is also being evaluated for its potential enhancement of the oral bioavailability of drugs that are P-glycoprotein substrates requiring either high dosage forms or intravenous administration, and for the potential improvement of central nervous system penetration of P-glycoprotein substrate drugs.

    Topics: Animals; Clinical Trials as Topic; Drug Resistance, Multiple; Humans; Imidazoles; Neoplasms; Technology, Pharmaceutical

2002

Trials

2 trial(s) available for oc-144-093 and Neoplasms

ArticleYear
Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093).
    Cancer chemotherapy and pharmacology, 2005, Volume: 55, Issue:1

    Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement of the oral uptake of docetaxel on combination with orally administered OC144-093, a potent P-gp inhibitor. Furthermore, the safety of combined treatment was determined and whether known functional genetic polymorphisms of the MDR1 gene could be associated with variability in docetaxel pharmacokinetics was also investigated.. A proof of concept study was carried out in 12 patients with advanced solid tumors. Patients were randomized to receive one course of 100 mg oral docetaxel combined with 500 mg OC144-093 followed 2 weeks later by a second i.v. course of docetaxel at a flat dose of 100 mg, without OC144-093, or vice versa. This was followed by standard i.v. docetaxel treatment if indicated.. The apparent relative oral bioavailability of docetaxel was 26+/-8%. Orally administered docetaxel combined with oral OC144-093 resulted in a Cmax of 415+/-255 ng ml(-1), an AUC0-infinity of 844+/-753 ng h ml(-1) and kel of 0.810+/-0.296 h(-1). These values differed significantly from those following i.v. administration of docetaxel, with a Cmax of 2124+/-1054 ng ml(-1), an AUC0-infinity of 2571+/-1598 ng h ml(-1) and a kel of 1.318+/-0.785 h(-1) (P=0.003, P=0.006, P=0.016). The study medication was well tolerated and most of the adverse events possibly or probably related to OC144-093 and docetaxel were of CTC grade 1 and 2. One patient had a homozygous 3435T/T mutation, which is associated with low intestinal P-gp expression, and two other patients had a homozygous mutation on exon 21.. The relative apparent bioavailability of 26% was most likely caused by a significant effect of OC144-093 on the oral uptake of docetaxel. Large intrapatient and interpatient (pharmacokinetic) variation was found after oral as well as after i.v. administration of docetaxel. Higher plasma levels were observed after 100 mg i.v. docetaxel than after 100 mg oral docetaxel plus 500 mg oral OC144-093. The safety of the oral combination was good. More patients should be evaluated to determine the effect of P-gp single nucleotide polymorphisms on oral pharmacokinetic values of docetaxel.

    Topics: Administration, Oral; Aged; Antineoplastic Agents, Phytogenic; Biological Availability; Docetaxel; Drug Administration Schedule; Drug Resistance, Multiple; Female; Humans; Imidazoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Taxoids

2005
A phase I pharmacokinetic study of the P-glycoprotein inhibitor, ONT-093, in combination with paclitaxel in patients with advanced cancer.
    Investigational new drugs, 2005, Volume: 23, Issue:4

    ONT-093 is an orally bioavailable inhibitor of P-glycoprotein (P-gp). In pre-clinical studies, ONT-093 could inhibit P-gp and reverse multidrug resistance at nM concentrations with no effect on paclitaxel pharmacokinetics. Phase I trials of ONT-093 in normal human volunteers showed no dose-limiting toxicities at serum concentrations associated with biologic activity achieved with doses ranging from 300 to 500 mg.. Phase I pharmacokinetic trial of ONT-093 in doses from 300 to 500 mg administered before and after intravenous paclitaxel doses of 150 to 175 mg/m(2) repeated every 21 days. All patients received paclitaxel alone on cycle 1.. 18 patients were enrolled onto 4 dose levels. Toxicity of the combination included neutropenia, arthralgia, myalgia, and peripheral neuropathy. Four of 6 patients receiving 500 mg doses of ONT-093 and paclitaxel at 175 mg/m(2) (dose level 4) had higher-grade neutropenia with cycle 2, with 1 patient experiencing febrile neutropenia. Plasma pharmacokinetic parameters of paclitaxel were unchanged between cycle 1 and 2 for dose levels 1 to 3, but at dose level 4, 45-65% increases in paclitaxel AUC were observed in 4 of the 6 patients. Mean C(max) of ONT-093 was 9 microM (range 5-15 microM) which were 3- to 5-fold higher than in single agent studies of ONT-093.. Doses of ONT-093 achieving serum concentrations associated with biological activity were well tolerated in combination with standard doses of paclitaxel. Toxicities of the combination in this schedule were mainly attributable to paclitaxel and dose-limiting toxicity was limited to febrile neutropenia. There was an apparent pharmacokinetic interaction between paclitaxel and ONT-093, possibly related in part to the excipient, Cremophor, present in the paclitaxel formulation.

    Topics: Adult; Aged; Alopecia; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Arthralgia; ATP Binding Cassette Transporter, Subfamily B, Member 1; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Imidazoles; Male; Middle Aged; Neoplasms; Neutropenia; Paclitaxel; Polyethylene Glycols

2005