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- W2254266499 abstract "C144 Background: Temsirolimus is a selective inhibitor of the mammalian target of rapamycin (mTOR), which has been approved by the US Food and Drug Administration for the treatment of patients with advanced renal cell carcinoma. Temsirolimus binds to intracellular FKBP-12 and the complex inhibits mTOR kinase activity, resulting in inhibition of phosphorylation of proteins downstream of mTOR and subsequent G1 phase cell cycle arrest. The objectives of this study were to define the structure of pharmacokinetic (PK) disposition of temsirolimus and to characterize its pharmacokinetic (PK) and pharmacodynamic (PD) relationship after a single intravenous (IV) dose. Methods: In this open-label, inpatient/outpatient, nonrandomized, sequential group study, healthy adults received single temsirolimus doses of 1, 3, 10, 15, or 25 mg IV over 30 minutes. Venous blood samples were collected over 14 days to measure concentrations of temsirolimus and sirolimus (a major metabolite) in blood and levels of phosphorylated S6 ribosomal protein (S6RP), a cytosolic distal substrate of p70S6 kinase in the mTOR pathway, in CD3+ lymphocytes. A nonlinear compartmental PK model described the maximal binding capacity (Bmax) and dissociation constant (Kd) of binding in red blood cells and peripheral tissues. An indirect response PK/PD model was used to quantify temporal effects of drug concentration on PD response. Results: The study included 30 subjects; 6 received each dose of temsirolimus. In red blood cells, specific temsirolimus binding was dose-dependent, with mean maximal receptor occupancy observed with doses of 3 mg or higher. The mean (10th, 90th percentile) Bmax in red blood cells and tissues was 1.4 (0.47, 2.5) mg and 5.0 (0.94, 9.9) mg, respectively, and 6.4 [1.4, 12.4] mg for whole body. The mean (10th, 90th percentile) Kd was 5.1 (1.3, 8.7) ng/mL and was comparable to active concentrations in preclinical models for tumor growth inhibition. Inhibition of phosphorylation of S6RP was rapid, and extent and duration were dose dependent with median IC50 that ranged from 0.31 ng/mL (1 mg dose) to 5.1 ng/mL (25 mg dose). The duration of 50% maximal inhibition of S6RP phosphorylation was 82 hours.Conclusions: Temsirolimus IV doses greater than 6.4 mg may be required to optimize drug distribution and exposure to maximize clinical benefit. The PK/PD response profile of phosphorylation of S6RP demonstrated substantial modulation and confirmed that a single 25-mg IV dose of temsirolimus suppressed mTOR-mediated signaling for a long duration." @default.
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- W2254266499 date "2007-11-01" @default.
- W2254266499 modified "2023-09-24" @default.
- W2254266499 title "mTOR inhibition following a single intravenous infusion of temsirolimus in healthy individuals" @default.
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