PURPOSE: Comparative pharmacokinetic (PK) analysis of the mTOR inhibitor RAD001 (everolimus) in rats and mice. METHODS: Blood cell partitioning, plasma protein binding and PK parameters of RAD001 in blood and tissues (including brain) of both mice and rats were determined. PK modeling predicted plasma/blood and tumor levels from a variety of regimens and these were compared with the known human PK profile. DCE-MRI was used to compare tumor vascularity between mice and rats. Estimation of IC50 values in vitro and ED50 values in vivo were used to provide an indication of anti-tumor activity. RESULTS: The PK properties of RAD001 differed between mice and rats, including erythrocyte partitioning, plasma protein binding, plasma/blood t(1/2), oral bioavailability, volume of distribution, tissue/tumor penetration and elimination. Modeling of tumor and blood/plasma PK suggested that in mice, multiple daily administrations result in a 2-fold increase in tumor levels of RAD001 at steady state, whereas in rats, a 7.9-fold increase would occur. Weekly high-dose regimens were predicted not to facilitate tumor accumulation in either species. Total tumor levels of RAD001 were four- to eight-fold greater in rats than in mice. Rat tumors had a >2-fold greater plasma content and permeability compared to mouse tumors, which could contribute to differences in tumor drug uptake. Maximal antitumor effects (T/C of 0.04-0.35) were observed in both species after daily administration with similar C(max) and AUC values of unbound (free) RAD001. These free levels of RAD001 are exceeded in serum from cancer patients receiving clinically beneficial daily regimens. In rodents, brain penetration of RAD001 was poor, but was dose-dependent and showed over-proportional uptake in rats with a longer t(1/2) compared to the systemic circulation. CONCLUSIONS: The PK of RAD001 differed between mice and rats, with rats having a PK profile closer to that of humans. High intermittent doses of RAD001 may be more appropriate for treatment of brain tumors.
PURPOSE: Comparative pharmacokinetic (PK) analysis of the mTOR inhibitor RAD001 (everolimus) in rats and mice. METHODS: Blood cell partitioning, plasma protein binding and PK parameters of RAD001 in blood and tissues (including brain) of both mice and rats were determined. PK modeling predicted plasma/blood and tumor levels from a variety of regimens and these were compared with the known human PK profile. DCE-MRI was used to compare tumor vascularity between mice and rats. Estimation of IC50 values in vitro and ED50 values in vivo were used to provide an indication of anti-tumor activity. RESULTS: The PK properties of RAD001 differed between mice and rats, including erythrocyte partitioning, plasma protein binding, plasma/blood t(1/2), oral bioavailability, volume of distribution, tissue/tumor penetration and elimination. Modeling of tumor and blood/plasma PK suggested that in mice, multiple daily administrations result in a 2-fold increase in tumor levels of RAD001 at steady state, whereas in rats, a 7.9-fold increase would occur. Weekly high-dose regimens were predicted not to facilitate tumor accumulation in either species. Total tumor levels of RAD001 were four- to eight-fold greater in rats than in mice. Rattumors had a >2-fold greater plasma content and permeability compared to mousetumors, which could contribute to differences in tumor drug uptake. Maximal antitumor effects (T/C of 0.04-0.35) were observed in both species after daily administration with similar C(max) and AUC values of unbound (free) RAD001. These free levels of RAD001 are exceeded in serum from cancerpatients receiving clinically beneficial daily regimens. In rodents, brain penetration of RAD001 was poor, but was dose-dependent and showed over-proportional uptake in rats with a longer t(1/2) compared to the systemic circulation. CONCLUSIONS: The PK of RAD001 differed between mice and rats, with rats having a PK profile closer to that of humans. High intermittent doses of RAD001 may be more appropriate for treatment of brain tumors.
Authors: Fabian Eisa; Robert Brauweiler; Martin Hupfer; Tristan Nowak; Laura Lotz; Inge Hoffmann; David Wachter; Ralf Dittrich; Matthias W Beckmann; Gregor Jost; Hubertus Pietsch; Willi A Kalender Journal: Eur Radiol Date: 2011-11-10 Impact factor: 5.315
Authors: Brad Poore; Ming Yuan; Antje Arnold; Antoinette Price; Jesse Alt; Jeffrey A Rubens; Barbara S Slusher; Charles G Eberhart; Eric H Raabe Journal: Neuro Oncol Date: 2019-02-14 Impact factor: 12.300
Authors: Kristin P Bibee; Ya-Jian Cheng; James K Ching; Jon N Marsh; Allison J Li; Richard M Keeling; Anne M Connolly; Paul T Golumbek; Jacob W Myerson; Grace Hu; Junjie Chen; William D Shannon; Gregory M Lanza; Conrad C Weihl; Samuel A Wickline Journal: FASEB J Date: 2014-02-05 Impact factor: 5.191
Authors: Bernard L Marini; Lydia L Benitez; Andrew H Zureick; Ralph Salloum; Angela C Gauthier; Julia Brown; Yi-Mi Wu; Dan R Robinson; Chandan Kumar; Robert Lonigro; Pankaj Vats; Xuhong Cao; Katayoon Kasaian; Bailey Anderson; Brendan Mullan; Benjamin Chandler; Joseph R Linzey; Sandra I Camelo-Piragua; Sriram Venneti; Paul E McKeever; Kathryn A McFadden; Andrew P Lieberman; Noah Brown; Lina Shao; Marcia A S Leonard; Larry Junck; Erin McKean; Cormac O Maher; Hugh J L Garton; Karin M Muraszko; Shawn Hervey-Jumper; Jean M Mulcahy-Levy; Adam Green; Lindsey M Hoffman; Katie Dorris; Nicholas A Vitanza; Joanne Wang; Jonathan Schwartz; Rishi Lulla; Natasha Pillay Smiley; Miriam Bornhorst; Daphne A Haas-Kogan; Patricia L Robertson; Arul M Chinnaiyan; Rajen Mody; Carl Koschmann Journal: Transl Res Date: 2017-08-10 Impact factor: 7.012
Authors: Dipti K Pawaskar; Robert M Straubinger; Gerald J Fetterly; Bonnie H Hylander; Elizabeth A Repasky; Wen W Ma; William J Jusko Journal: Cancer Chemother Pharmacol Date: 2013-03-03 Impact factor: 3.333