title: Oral and intravenously administered mTOR inhibitors for metastatic renal cell carcinoma: pharmacokinetic considerations and clinical implications.
abstract: Identification of the role of biological pathways in metastatic renal cell carcinoma (mRCC) has led to the development of targeted agents for its treatment, in particular those that inhibit the vascular endothelial growth factor pathway, and inhibitors of mammalian target of rapamycin (mTOR). mTOR is central to signalling pathways that regulate cellular growth, proliferation and survival, and this paper focuses on the two currently licensed mTOR inhibitors, temsirolimus and everolimus. These agents are administered via different routes (intravenously and orally, respectively), and this has an impact on their pharmacokinetics; intravenous temsirolimus is not affected by variable absorption in the gastrointestinal tract or by food intake, unlike the orally administered mTOR inhibitor everolimus. Temsirolimus is administered weekly, whereas everolimus is currently approved for daily dosing. In general, intravenous administration is likely to ensure better control of plasma drug concentrations, greater treatment adherence, and more regular monitoring of toxicity and therapeutic response, although it can be uncomfortable and inconvenient for patients. Oral administration is preferred by patients for its convenience, but can be associated with suboptimal adherence to treatment, and poor and variable bioavailability. Temsirolimus and everolimus have both been associated with improved outcomes in patients with mRCC but, as reviewed in this paper, the pharmacokinetic characteristics of these agents differ in many respects.
authors: Department of Clinical and Experimental Medicine, University of Pisa, Italy. romano.danesi@med.unipi.it
authors: Romano
authors: R
authors: Danesi
authors: Joseph P
authors: JP
authors: Boni
authors: Alain
authors: A
authors: Ravaud
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D000068338:Everolimus; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Metastatic renal cell carcinoma; Oral Intravenous; Pharmacokinetics; mRCC; mTOR inhibitors