Infante, Jennifer Nishioka Collection and/or assembly of data:Antoinette R. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate. == Results. == Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m2paclitaxel. Dose-limiting toxicities included a MKI67 grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration (S)-Amlodipine of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a (S)-Amlodipine 31% higher paclitaxel maximal concentration than with administration (S)-Amlodipine of paclitaxel alone at 15, 50, and 80 mg/m2. At the MTR, coadministration of 800 mg pazopanib and 80 mg/m2paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve. == Conclusion. == Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m2when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8. == Introduction == Angiogenesis plays an essential role in the growth and progression of cancer [1]. Small-molecule tyrosine kinase inhibitors represent a novel approach to targeting angiogenesis. These multitargeted compounds may overcome redundancies in signaling pathways and result in more effective (S)-Amlodipine inhibition of tumor growth than with single targeted agents. Pazopanib (Votrient; GlaxoSmithKline, Research Triangle Park, NC) was approved by the U.S. Food and Drug Administration (FDA) in October 2009 for the treatment of patients with advanced renal cell carcinoma [2]. It is an oral, small-molecule inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-, PDGFR-, and c-Kit tyrosine kinases [3]. In preclinical experiments, pazopanib has shown significant inhibition of VEGF-induced VEGFR-2 phosphorylation with a half-maximal inhibition concentration (IC50) of 30 nM, and is three- to 400-fold selective for VEGFRs compared with other kinases. It also inhibits VEGF-induced proliferation of human umbilical vein endothelial cells with an IC50of 8 nM. Studies in mice also showed that a plasma concentration 40 M (17.5 g/ml) is required for optimal inhibition of VEGF-induced VEGFR-2 phosphorylation in mice. Additionally, pazopanib shows growth inhibition in a variety of human tumor xenografts in mice including breast, renal, lung, colon, and prostate tumors, and melanoma, and also inhibits angiogenesis in vivo [4]. In a phase I study, single-agent pazopanib was administered to 63 patients with advanced solid tumors at doses of 50 mg three times weekly to 2,000 mg once daily. Steady-state plasma pazopanib concentrations appeared to plateau at doses 800 mg daily [5]. At a daily dose of 800 mg pazopanib, the majority of patients achieved a target trough concentration of 15 g/ml, which is similar to that required to inhibit VEGFR-2 phosphorylation in vivo. Of the 14 patients treated with pazopanib at a dose of 800 mg once daily, one patient had dose-limiting toxicities of grade 3 hypertension and grade 3 proteinuria. Based on these observations, the recommended phase II dose of single-agent pazopanib is 800 mg orally once daily. The combination of an angiogenesis inhibitor with chemotherapy is a common treatment approach for several solid tumor types. Bevacizumab (Avastin; Genentech, South San Francisco, CA), a humanized monoclonal antibody directed against VEGF, combined with chemotherapy has indications for the treatment of patients with metastatic colon cancer and non-small cell lung cancer (NSCLC) as first-line therapy [6,7]. Cytotoxic agents, such as paclitaxel, when administered at low doses and frequent intervals, may exert antiangiogenic effects, thereby enhancing anticancer activity [8,9]. Patients with metastatic human epidermal growth factor receptor (HER)-2negative breast cancer who received treatment with weekly paclitaxel on days 1, 8, and 15 every 28 days in combination with bevacizumab on days 1 and 15 experienced a longer progression-free survival interval and higher response rate than patients treated with paclitaxel alone, which led to the FDA approval of this combination in the first-line setting [10]. On the basis of preclinical evidence of the antiangiogenic activity of pazopanib, the activity of paclitaxel in the treatment of solid tumors, and the observation that weekly paclitaxel has antiangiogenic effects, we investigated the combination of once-daily pazopanib with paclitaxel given once weekly for three consecutive weeks every 28 days. Paclitaxel is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8 [11,12]. In vitro data suggest that pazopanib is a potential inhibitor of the CYP3A4 and CYP2C8 isoenzymes and may decrease the clearance of paclitaxel [4]. Therefore, this study also was designed to determine the potential effect of pazopanib on the pharmacokinetics of paclitaxel. The specific objectives of this phase I study were to.