Development of a pharmacokinetic (PK) model and assessment of patient (pt) covariate effects on dose-dependent PK following different dosing schedules in two phase I trials of AP23573 (AP), a mTOR inhibitor

Desai, Anjali; Mita, Masayuki; Fetterly, Gerald J.; Chang, Colin; Netsch, M.; Knowles, Heather; Bedrosian, Camille L.; Rowinsky, Eric K.; Tolcher, A. W.; Ratain, Mark J.

doi:10.1200/jco.2005.23.16_suppl.3043

Cited by 5 publications

(3 citation statements)

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“…There are differences in the half‐lives, potentially affecting the optimal dosing schedules. The half‐life of everolimus in stable renal transplant patients was 24–35 h 41 and 13–25 42 , 43 and 45–74 h, 37 respectively, for the intravenous formulations of temsirolimus and deferolimus.…”

Section: Inhibitors Of the Mtor Pathwaymentioning

confidence: 99%

“…35 Similar to sirolimus, CYP3A4 and P-glycoprotein affect its absorption and contribute to wide interpatient variability. 36 The rapalogs share many characteristics with sirolimus, including extensive partitioning into red blood cells, 36,37 metabolism by hepatic CYP3A enzymes, 38,39 and primarily fecal excretion. 35 In a study of patients with liver cirrhosis, the clearance of everolimus was reduced by 53% and the halflife prolonged 84%, showing the need for dose reductions in patients with liver impairment.…”

Section: Inhibitors Of the Mtor Pathway Mechanisms Of Action And Mechmentioning

confidence: 99%

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Rapamycin: Something Old, Something New, Sometimes Borrowed and Now Renewed

Hartford

Ratain

2007

Clin Pharmacol Ther

209

176

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The molecular target of rapamycin (mTOR) is central to a complex intracellular signaling pathway and is involved in diverse processes including cell growth and proliferation, angiogenesis, autophagy, and metabolism. Although sirolimus (rapamycin), the oldest inhibitor of mTOR, was discovered more than 30 years ago, renewed interest in this pathway is evident by the numerous rapalogs recently developed. These newer agents borrow from the structure of sirolimus and, although there are some pharmacokinetic differences, they appear to differ little in terms of pharmacodynamic effects and overall tolerability. Given the multitude of potential applications for this class of agents and the decrease in cost that can be expected upon the expiration of sirolimus patents, renewed focus on this agent is warranted.

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Section: Inhibitors Of the Mtor Pathwaymentioning

confidence: 99%

Section: Inhibitors Of the Mtor Pathway Mechanisms Of Action And Mechmentioning

confidence: 99%

Rapamycin: Something Old, Something New, Sometimes Borrowed and Now Renewed

Hartford

Ratain

2007

Clin Pharmacol Ther

209

176

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“…Pharmacokinetic studies from trials of AP23573 and temsirolimus suggested that the nonlinear pharmacokinetics was consistent with saturation of the red blood cell (RBC) compartment, which contains an abundance of FKBP-12 protein. 49 Sirolimus and the 40-O-(2-hydroxyethyl) ester derivation, everolimus, are orally administered, and the efficiency of absorption is modulated by p-glycoproteins (reviewed in ref. 50).…”

Section: Pharmacology Of Sirolimus and Derivativesmentioning

confidence: 99%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

184

134

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The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

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