OSI-420 is an active metabolite of erlotinib which is an orally active EGFR tyrosin kinase inhibitor with IC50 of 2 and 20 nM for the inhibition of human EGFR and EGFR autophosphorylation in tumor cells. Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m2. OSI-420 exposure (AUC) in plasma was 30% (range 12–59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUCCSF:AUCplasma) of erlotinib and OSI-420 was <5% relative to total plasma concentration, but CSF compound exposure was ∼30% of plasma free compound exposure, which was calculated from published plasma protein binding values. The intravenous administration of erlotinib was well tolerated.
|Cell lines||A549, H322, H3255, H358 H661, H1650, H1975, H1299, H596 cells|
|Preparation method||Exponentially growing cells are seeded in 96-well plastic plates and exposed to serial dilutions of erlotinib, pemetrexed, or the combination at a constant concentration ratio of 4:1 in triplicates for 72 h. Using cell count and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to assay cell viability . Expressing growth inhibition as the percentage of surviving cells in drug-treated versus PBS-treated control cells (which is considered as 100% viability). The IC50 value is the concentration resulting in 50% cell growth inhibition by a 72-h exposure to drug(s) compared with untreated control cells and is calculated by the CalcuSyn software|
|Concentrations||30 nM-20 μM|
|Incubation time||72 hour|
|Animal models||Male 5-week-old BALB-nu/nu mice with HPAC|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 80 mg/mL|
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