Pharmacokinetic and Tumor Distribution Characteristics of Temsirolimus in Patients with Recurrent Malignant Glioma

Abstract

Purpose: To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue. Experimental Design: Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection.Whole blood and tumor tissue were obtained for analysis.Results: Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus. Conclusions: Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70 S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.Temsirolimus Torisel) is an ester of sirolimus (rapamycin). Both temsirolimus and its major metabolite, sirolimus, bind with equipotency to the cytosolic protein FKBP-12 (1). This protein-drug complex inhibits mammalian target of rapamycin -mediated phosphorylation of p70 S6 kinase and the eukaryotic initiation factor 4E-binding protein 1, which are involved in the regulation of key molecules involved in cell cycle control and apoptosis (2, 3). Phosphatidylinositol 3-kinase and AKT are the upstream key regulators of the phosphorylation and activation of mammalian target of

A New Pharmacologic Action of CCI-779 Involves FKBP12-Independent Inhibition of mTOR Kinase Activity and Profound Repression of Global Protein Synthesis

“…Whereas it remains an open question whether this newly described mechanism of CCI-779 action contributes to antitumor efficacy in the clinic, a number of recent clinical studies suggest that micromolar drug levels are present in blood of CCI-779-treated patients with breast cancer (1), advanced renal cancer (15), and malignant glioma (16). Therefore, the high-dose drug concentrations that are used in our work are well within the clinically relevant drug concentrations.…”

“…However, the growth inhibitory effects at these same drug concentrations are generally modest and selective against certain tumor cell lines, including brain, breast, prostate, rhabdomyosarcoma cells. Recent clinical studies in patients with various solid malignancies showed that concentrations of CCI-779 in whole blood generally reach micromolar levels (1,(14)(15)(16). Although most of the in vitro studies that investigate CCI-779 and/or rapamycin action in cancer cells use nanomolar drug concentrations, they do not address the inhibitory response and underlying cellular mechanism(s) to the drug at the clinically relevant micromolar doses.…”

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

“…As both CCI-779 and sirolimus display similar effects on mTORC1, the respective roles of the parental drug and its main metabolite sirolimus on the overall activity of temsirolimus in renal cancer remain unknown. Pharmacokinetic data demonstrated that exposure to rapalogues is strongly increased by the concomitant administration of drugs that are substrates, activators, and inhibitors of CYP3A4 such as rifampicin, anticonvulsants, and immunosuppressive drugs such as cyclosporine (Boni et al, 2007;Kuhn et al, 2007).…”

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

“…2A). The model is based on established pharmacodynamics and known effects of each of the agents [21][22][23][24][25][26][27][28][29] on the cell cycle for 10 tumor types [31][32][33][34][35][36][37][38] and for erythroblasts 39 (erythroblasts have the highest proliferative index of marrow (Fig. 2B).…”

“…f(t) is a probability of effect based on the individual [16][17][18][19][20] or combined [21][22][23][24][25][26][27][28][29] effects of temsirolimus, topotecan, and bortezomib which have been previously described.…”