Searching AACR under 'pgp inhibitor' (I've got a few XNVA) came across these. Don't know if they mean anything, but parking anyhow...
Enhancement of oral bioavailability of taxanes and CNS penetration of loperamide by the P-glycoprotein inhibitor OC144-093
Michael J. Newman, Miguel Lujan, Jeffrey A. Silverman, Amy O. Chan, Paulina Tran-Tau, Barry Toyonaga, Ross Dixon, Ontogen Corporation, Carlsbad, CA; Unit of Clinical Pharmacology, Hospital Espanol, Mexico City, Mexico; AvMax, Inc., South San Francisco, CA.
OC144-093 is an orally bioavailable third generation P-glycoprotein (P-gp) inhibitor (Mr 495) that reverses P-gp-mediated multidrug resistance (MDR) in a wide variety of tumor models in vitro and in vivo. It is currently under clinical development as adjuvant therapy in the prevention and treatment of multidrug resistant cancer. P-gp expression in normal tissues, such as the intestinal mucosa and endothelium of the blood brain barrier prevents oral absorption and CNS penetration of numerous important therapeutic agents, including HIV-protease inhibitors and chemotherapeutics such as the taxanes, vinca alkaloids and anthracyclines. Conversion of parenteral chemotherapeutics to oral formulations and expansion of the utility of existing agents to CNS indications might be achieved via the coadministration of a P-gp inhibitor. We have now demonstrated that oral coadministration of OC144-093 enhances paclitaxel oral bioavailability from 21% to 100% and docetaxel oral bioavailabilty from 2% to 84% in a rat model. Therapeutic blood levels of paclitaxel were also achieved after oral coadministration of OC144-093 and paclitaxel to human subjects. Enhancement of the CNS penetration of P-gp substrates by OC144-093 was investigated using loperamide, an opiate lacking CNS activity due to P-gp activity in the blood brain barrier. Significant antinociceptive activity was produced by intravenous coadministration of loperamide with OC144-093 in a mouse hot plate model. Our results demonstrate that OC144-093 can be used to convert therapeutics, which are P-gp substrates, into orally bioavailable and CNS active agents, as well as to prevent and treat multidrug resistance associated with cancer chemotherapy.
S-8184 paclitaxel emulsion: Preclinical and phase 1 data
S. Jones, Ha Burris III, J. Hainsworth, N. Willcutt, S. Calvert, F. Greco, J. Pratt, Gordon Brandt, Sarah Cannon Cancer Center, Nashville, TN; Sonus Pharmaceuticals, Bothell, WA.
Background: S 8184 is a cremophor free, vitamin E-based paclitaxel emulsion incorporating a p glycoprotein (pgp) inhibitor and particle size-based tumor targeting. Alpha tocopherol polyethylene glycol succinate (TPGS) is used as a surfactant to help control emulsion particle size. In vitro data suggest that TPGS is a potent pgp inhibitor with about 80% the effectiveness of cyclosporin A. The resulting emulsion particles are manufactured to be 60 to 200 nanometers in size and should preferentially target tumor tissue by the Enhanced Permeability and Retention effect. Preclinical studies with S 8184 show a maximum tolerated dose (MTD) three times greater than Taxol; and significantly higher tumor paclitaxel AUCs. S-8184 can be administered at higher doses than Taxol, resulting in increased anti-tumor activity in the models tested. Objectives: S 8184 paclitaxel emulsion has been developed to reduce or eliminate hypersensitivity reactions and premedications, and reduce infusion time, as a result of elimination of cremophor. The inclusion of a pgp inhibitor and passive tumor targeting are designed to increase tumor drug concentrations. Methods: Phase 1 study goals include identification of dose limiting toxicities (DLTs) and MTD, evaluation of the PK profile, and initial evaluation of efficacy. S 8184 is administered every 3 weeks as a 15 minute IV push without premedications to patients with advanced solid malignancies. Results: To date, 41 cycles (range 1-6) of drug have been given to 15 patients with lung, breast, ovarian, colorectal, and pancreatic cancers and mesothelioma at doses from 25 to 225 mg paclitaxel/m2. Ten patients had prior taxane-containing chemotherapy. Compared with published data for 3 hour infusions of Taxol, the whole blood paclitaxel assay for S 8184 shows Cmax 20x higher and AUC 0inf 4x higher. The elimination halflife is 20 hours and is independent of dose. Both Cmax and AUC are linearly related to dose. MTD has not yet been determined. Two DLTs (Grade 4 neutropenia) have been seen, one each at 125 mg/m2 and 225 mg/m2, both in patients with hepatic metastases. There has been no severe (Grade 3 or greater) neuropathy. Two grade 1 hypersensitivity reactions have been seen in patients who had not received any premedications. Six patients enrolled at doses from 125 mg/m2 to 225 mg/m2 with lung, breast, ovarian, and colorectal cancers demonstrate one partial response in NSCLC; three minor responses in colorectal, breast, and ovarian cancers; and two patients with NSCLC in stable disease. Conclusion: S 8184 can be given safely via IV push at doses of 225 mg/m2 with dose escalation continuing. Early indications suggest clinical activity in a range of tumor types. |
