Intravenous temsirolimus in cancer patients: clinical pharmacology and dosing considerations.
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.
Boni
Joseph P
JP
Department of Translational Development, Pfizer Inc., 500 Arcola Rd., Collegeville, PA 19426, USA. BoniJ@wyeth.com
Hug
Bruce
B
Leister
Cathie
C
Sonnichsen
Daryl
D
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; C401859:temsirolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus