Elsevier

Seminars in Oncology

Volume 36, Supplement 3, December 2009, Pages S18-S25
Seminars in Oncology

Intravenous Temsirolimus in Cancer Patients: Clinical Pharmacology and Dosing Considerations

https://doi.org/10.1053/j.seminoncol.2009.10.009Get rights and content

Temsirolimus, a highly specific inhibitor of mammalian target of rapamycin (mTOR), is a novel anticancer targeted therapy with a new mechanism of action. The prototype mTOR inhibitor, oral rapamycin, is poorly soluble and undergoes extensive first-pass metabolism, leading to low and potentially variable absorption and exposure. For some tumors, maximizing the bioavailability and dose intensity via intravenous (IV) administration may provide optimal clinical benefit. Temsirolimus is an ester analog of rapamycin that retains its potent intrinsic mTOR inhibitory activity while exhibiting better solubility for IV formulation. In the treatment of advanced renal cell carcinoma, temsirolimus is administered as a 30- to 60-minute IV infusion once weekly at a flat dose of 25 mg. This dosage results in high peak temsirolimus concentrations and limited immunosuppressive activity. Because temsirolimus is active and well tolerated, different dosages and schedules are being explored for other solid and hematologic malignancies, including mantle cell lymphoma. Temsirolimus exhibits a high volume of distribution that, together with IV administration, leads to extensive distribution into peripheral tissues. In addition, significant and protracted exposures are attained with sirolimus (rapamycin), the major equipotent metabolite of temsirolimus. Whereas temsirolimus and sirolimus are both metabolized by cytochrome P450 (CYP) 3A4, drug interaction studies with agents that induce or inhibit CYP3A4 activity indicate that exposure to the sirolimus metabolite is somewhat sensitive to pharmacokinetic (PK) drug interaction. Therefore, temsirolimus dose adjustments are warranted if coadministration cannot be avoided. Despite its complexity, the PK profile of IV temsirolimus is well characterized in cancer patients and provides a strong basis for its future study as a monotherapy or in combination with other anticancer agents.

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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    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.

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