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Purpose: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. Experimental Design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day1) and on the third day (day 4).The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes. Results: In 11evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days1and 4 were 42.6 (33.0-54.9) AgÁh/mL and 41.2 (32.1-53.1) AgÁh/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 Amol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro. Conclusion: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically.The first rationally designed inhibitor of a signal transduction pathway, imatinib, is a competitive inhibitor of Bcr-Abl, platelet-derived growth factor receptors (a and h), and c-KIT receptor tyrosine kinases (1 -4). It was first approved for the treatment of Philadelphia chromosome -positive chronic myelogenous leukemia and, shortly thereafter, for c-KITpositive metastatic and unresectable gastrointestinal stromal tumor (5, 6).The pharmacokinetic properties of imatinib have been investigated in healthy volunteers and in patients with chronic myelogenous leukemia, gastrointestinal stromal tumor, and other tumors (7,8). Imatinib is well absorbed after oral administration with a bioavailability exceeding 90% (9). It is extensively metabolized, with up to 80% of the administered dose being recovered in feces, predominantly as metabolites (10). Imatinib is metabolized in vitro principally by cytochrome P450 (CYP) 3A4 and CYP3A5, with CYP1A2, CYP2C9, CYP2C19, and CYP2D6 playing a minor role (8). The main circulating metabolite of imatinib is an N-desmethyl derivative, CGP74588, which has in vitro activity similar to that of imatinib, and the systemic exposure represents approximately 10% to 15% of that for imatinib (10). The pharmacokinetic profile of a single dose of imatinib is sensitive to CYP3A4 modulation, with a 74% and 30% reduction in imatinib area under the curve (AUC) observed with coadministrati...

We investigated the risk factors for venous thrombosis in cancer patients with implantable ports undergoing chemotherapy. One hundred and seventy one ports were placed in a central (''chest ports'') and 84 in a peripheral vein (''arm ports''), 181 received prophylactic nadroparin and 10 coumarin. Clinically overt thrombosis was confirmed by ultrasound or angiography. Catheter-related thrombosis incidence without anticoagulants was 28% in arm and 33% in chest ports, but with anticoagulants this was 32% in arm and only 1% in chest ports (odds ratio (OR) 34.8 95% confidence interval (CI) 7.3-165). Left-sided placement compared with rightsided and catheter tip position in the superior vena cava compared with right atrium were associated with a 3.5 respectively 2.6-fold increased risk. Thrombosis was associated with elevated homocysteine levels (OR = 3.8, 95% CI 1.3-11.3), but not with factor V Leiden or prothrombin 20210A gene mutations, or high concentration of factor VIII, IX or XI. Prophylaxis with anticoagulants is recommended for chest, but not for arm ports. Determination of plasma homocysteine levels may identify patients at an increased risk for thrombosis.

Regorafenib is an oral multikinase inhibitor that has shown antitumor activity in a range of solid tumors. Based on data from phase III clinical trials, regorafenib is indicated for the treatment of adult patients with metastatic colorectal cancer who have previously been treated with, or are not considered candidates for, other available therapies, and in patients with advanced gastrointestinal stromal tumors that cannot be surgically removed and no longer respond to other appropriate treatments. A panel of oncology nurses, research coordinators, and other medical oncology experts, experienced in the care of patients treated with regorafenib, met to discuss the best practice for the management of regorafenib-associated adverse events (AEs). The panel agreed that, in clinical trials and daily practice with regorafenib, AEs are common but mostly manageable. The most common and/or important AEs associated with regorafenib were considered to be hand–foot skin reaction, rash or desquamation, stomatitis, diarrhea, hypertension, liver abnormalities, and fatigue. This manuscript describes the experience and recommendations of the panel for managing these AEs in everyday clinical practice. Appropriate education, monitoring, and management are considered essential for reducing the incidence, duration, and severity of regorafenib-associated AEs.

After completing this course, the reader will be able to:1. Describe the oral manifestations that can appear with TKI/mTORI.2. Describe the limitations of the current oral assessment tools in assessing these novel presentations and list items needed to assess the presentations properly.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CMECorrespondence: Christine Boers-Doets, R.N., C.N.S., M. ABSTRACTBackground. Oral adverse events (OAEs) associated with multitargeted tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORIs) are underestimated but frequent and novel presentations of mucosal manifestations. Because optimal antitumor activity requires maintaining the optimal dose, it is essential to avoid unintended treatment delays or interruptions. Methods. We review the reported prevalence and appearance of OAEs with TKIs and mTORIs and the current oral assessment tools commonly used in clinical trials. We discuss the correlations between OAEs and hand-foot skin reaction (HFSR) and rash.Results. The reported prevalence of oral mucositis/stomatitis of any grade is 4% for pazopanib, 28% for sorafenib, 38% for sunitinib, 41% for temsirolimus, and 44% for everolimus. Oral lesions associated with these agents have