Oral and intravenously administered mTOR inhibitors for metastatic renal cell carcinoma: Pharmacokinetic considerations and clinical implications

• Published in: Cancer treatment reviews Vol. 39; no. 7; pp. 784 - 792
• Main Authors: Danesi, Romano, Boni, Joseph P, Ravaud, Alain
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01-11-2013; Elsevier
• Subjects: Administration, Intravenous; Administration, Oral; Antineoplastic agents; Biological and medical sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - enzymology; Carcinoma, Renal Cell - pathology; Everolimus; Hematology, Oncology and Palliative Medicine; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - enzymology; Kidney Neoplasms - pathology; Kidneys; Medical sciences; Metastatic renal cell carcinoma; mRCC; mTOR inhibitors; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Nephrology. Urinary tract diseases; Oral Intravenous; Pharmacokinetics; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Signal Transduction - drug effects; Sirolimus - administration & dosage; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; Sirolimus - pharmacokinetics; Sirolimus - therapeutic use; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Tumors; Tumors of the urinary system; Metastatic renal cell carcinoma; mTOR inhibitors; Oral Intravenous; Pharmacokinetics; mRCC; Kidney disease; Urinary system disease; Carcinoma; Intravenous administration; Oral administration; Malignant tumor; Metastasis; Kidney cancer; mTOR inhibitor; Grawitz tumor; Advanced stage; Cancer
• ISSN: 0305-7372; 1532-1967
• DOI: 10.1016/j.ctrv.2012.12.012

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.