Intravenous Temsirolimus in Cancer Patients: Clinical Pharmacology and Dosing Considerations
Section snippets
Temsirolimus: A Novel Rapamycin Analog With Intrinsic mTOR Inhibitory Activity
mTOR, an intracellular kinase, acts as a central controller of multiple signaling pathways that regulate mRNA translation of key growth-regulating proteins. A critical role for mTOR in cellular responses to growth factors was first recognized when it was identified as the kinase that is specifically inhibited by the immunosuppressive drug rapamycin (sirolimus), which is used in organ transplantation.4 Subsequently, rapamycin was identified as a potent, mainly cytostatic agent against a wide
Dose Selection
Initial clinical trials were designed to establish the maximum tolerated dose, IV dosing parameters, and safety in patients with advanced solid tumors.7, 8, 15 With cyclic dosing (daily for 5 days every 2 weeks), the maximum tolerated dose of temsirolimus ranged from 15 to 19 mg/m2, depending on the level of previous treatment.8 However, with once-weekly dosing administered as a 30-minute infusion, temsirolimus was well tolerated over a wide range of doses (7.5–220 mg/m2).7 The most frequent
Clinical Pharmacokinetics
In humans, temsirolimus is converted via enzymatic hydrolysis to its major metabolite sirolimus.15, 19, 20 Temsirolimus and sirolimus exhibit equipotent mTOR inhibitory activity.20 Sirolimus is observed in the blood within 15 minutes of temsirolimus administration and reaches a peak concentration by the end of infusion.7 Both temsirolimus and sirolimus undergo oxidative metabolism by cytochrome P450 (CYP) 3A4.21 There is no evidence of accumulation of either temsirolimus or sirolimus with
Recommended Dose in Renal Cell Carcinoma
A phase II trial of temsirolimus in patients with advanced, cytokine-refractory RCC investigated the safety and anti-tumor activity of 3 flat doses (25 mg, 75 mg, and 250 mg) administered once weekly.22 Anti-tumor activity was observed across all doses, but a more frequent need for dose reductions and discontinuations was observed at the higher doses. Therefore, the lowest dose was chosen for further study.2, 22 The recommended clinical dose of once-weekly temsirolimus 25 mg was substantiated
Drug–Drug Interaction Studies
Because temsirolimus and sirolimus are substrates of the CYP3A4 isozyme,21 coadministration of drugs that inhibit, induce, or compete for CYP3A4/5 activity may alter their disposition.1, 19, 20, 21 Thus, a series of drug–drug interaction studies were conducted in healthy subjects. Coadministration of IV temsirolimus 25 mg with the potent CYP3A4-inducing drug rifampin had no significant effect on temsirolimus Cmax or AUC, but decreased sirolimus Cmax and AUC by 65% and 56%, respectively.
Combination of Temsirolimus With Other Agents
Strategies for combining mTOR inhibitors with other agents that target overlapping or parallel pathways may result in additive or synergistic anti-tumor effects. However, it is critical to evaluate the potential for PK drug-drug interactions in combination regimens, as well as overlapping toxicities that, although manageable for either agent alone, become excessive upon combination.
In a feasibility study of the combination of temsirolimus and sorafenib in patients with advanced RCC, preliminary
Conclusions
Temsirolimus is a novel analog of rapamycin and the first mTOR inhibitor to be approved as an anticancer agent. Temsirolimus retains the potent and specific mTOR inhibitor properties of rapamycin but has improved solubility and PK properties and no clinically significant immunosuppressive properties when administered with the once-weekly IV regimen. For treatment of patients with advanced RCC, the recommended dosage of temsirolimus is once-weekly IV 25 mg administered as a 30- to 60-minute
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Targeting ageing with rapamycin and its derivatives in humans: a systematic review
2024, The Lancet Healthy LongevityModel-based precision dosing of sirolimus in pediatric patients with vascular anomalies
2017, European Journal of Pharmaceutical SciencesInsights into drug discovery from natural products through structural modification
2015, FitoterapiaCitation Excerpt :Rapamycin (81), a macrolide initially isolated from Streptomyces hygroscopicushas [123], is a highly specific mTOR inhibitor displaying antifungal, immunosuppressive, anticancer, neuroprotective and antiaging activities [124]. However, the poor aqueous solubility and metabolic instability impeded clinical development of 81 in cancer therapy [125]. Multiple analogues of 81 have been designed for improving its solubility and stability.
Drug interactions with solid tumour-targeted therapies
2014, Critical Reviews in Oncology/HematologyTemsirolimus improves cytotoxic efficacy of cisplatin and gemcitabine against urinary bladder cancer cell lines
2014, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Temsirolimus belongs to the second generation of rapamycin derivatives (rapalogs), which has a better bioavailability than rapamycin, and this facilitates its clinical use [1,2].
Oral and intravenously administered mTOR inhibitors for metastatic renal cell carcinoma: Pharmacokinetic considerations and clinical implications
2013, Cancer Treatment ReviewsCitation Excerpt :The relatively higher half-life of sirolimus is thought to enable weekly dosing with temsirolimus, by contributing to sustained and clinically important exposures for the duration of the weekly dosage interval (Fig. 2). Temsirolimus is cleared from the body predominantly by the liver and eliminated mainly in the faeces.17,33 Following administration of a single dose of radioactively labelled temsirolimus, 83% of the total radioactivity was recovered within 25 days.47
STATEMENT OF CONFLICT OF INTEREST: At the time this supplement was prepared, Drs Boni, Hug, Leister, and Sonnichsen were employees of Wyeth Research, which was acquired by Pfizer Inc in October 2009.