The disposition of aprindine following a single oral dose can best be described by a two-compartment open model. The mean plasma half-life (t 1/2 beta) increased from 8.0 +/- 2.1 h (SD) after a 25 mg dose of 9.4 +/- 2.9 h after 50 mg and to 15.8 +/- 2.6 h after 100 mg, with a decrease in total plasma clearance (Cl/F) and volume of distribution at steady state (V dss/F) and during beta-phase (V d beta/F). The area under plasma concentration-time curve (AUC), maximum plasma concentration (C max) and the amount of unchanged aprindine excreted in the urine increased in a non-linear fashion with the increase in dose. The t 1/2 beta after multiple oral doses showed a 3-fold increase over the single dose value. These results indicate that aprindine shows dose-dependent non-linear kinetics.
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in some cancers, due to gene alterations such as chromosomal translocation, amplification, or point mutation. It has been recognized as an attractive solid tumor target since the discovery in 2007 of the fusion gene, comprised of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene, which is detected in ca. 6.7% of non-small-cell lung cancer (NSCLC) patients. We have identified a lead compound as an ALK inhibitor through kinase panel screening of in-house kinase-oriented library. The lead compound had a unique scaffold but showed a rather broad kinase inhibition profile. Therefore, we examined structure-activity relationship from the viewpoint of the kinase selectivity as well as ALK inhibition potency. Finally, we identified CH5424802 as a clinical candidate having high selectivity over other kinases including c-Met, c-Kit and KDR. CH5424802 has a preferable PK profile and good oral bioavailability in rats and monkeys. CH5424802 showed preferential antitumor activity against cancers with gene alterations of ALK, such as non-small cell lung cancer (NSCLC) cells expressing EML4-ALK fusion both in vitro and in vivo. CH5424802 is currently being investigated in Phase I/II clinical trials for patients with ALK-positive NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3593. doi:10.1158/1538-7445.AM2011-3593
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