Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100

Administration of BAS 100, a novel mechanism-based CYP3A4 inhibitor isolated from grapefruit juice, resulted in a 2.1-fold increase in erlotinib exposure following oral administration to wild-type and humanised CYP3A4 transgenic mice. This study illustrates the potential of BAS 100 to increase the low and variable oral bioavailability of erlotinib in cancer patients

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 in Healthy Subjects: A Placebo-Controlled, Randomized Phase 1 Study

David Gordon,1 Edward T Hellriegel,1 Heidi Rath Hope,2 David Burt,1 Joseph B Monahan2 1Research and Development, Aclaris Therapeutics, Inc., Wayne, PA, USA; 2Research and Development, Aclaris Therapeutics, Inc., and Confluence Discovery Technologies, Inc., St. Louis, MO, USACorrespondence: David GordonChief Medical Officer, Research and Development, Aclaris Therapeutics, Inc., 640 Lee Road, Suite 200, Wayne, PA, 19087, USATel +1 484-540-6273Email [email protected]: ATI-450 is an oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) inflammatory signaling pathway. This phase 1, single and multiple ascending dose (SAD, MAD) study evaluated ATI-450 safety, tolerability, pharmacokinetics, and pharmacodynamics.Patients and Methods: Healthy adults were randomly assigned to SAD (10, 30, 50, 100 mg; n=24) and MAD (10, 30, 50 mg twice daily [BID] for 7 days; n=24) cohorts of ATI-450 or placebo (n=14). Safety and tolerability were evaluated through clinical and laboratory assessments. Pharmacokinetic parameters were evaluated in plasma samples; pharmacodynamic assessments included quantification of cytokine levels (tumor necrosis factor α [TNF-α], interleukin [IL]-1β, IL-6, IL-8) and phosphorylation of the MK2 downstream substrate, heat shock protein 27 (p-HSP27).Results: The most common adverse events were headache (10/48, 20.8%), dizziness (6/48, 12.5%), upper respiratory tract infection (3/48, 6.3%), and constipation (3/48, 6.3%). Pharmacokinetics were dose-proportional, with a terminal half-life of 9‒12 hours in the MAD cohorts on day 7. Dose- and concentration-dependent inhibition of ex vivo stimulated cytokines and target biomarker was observed. On day 7, patients in the 50 mg BID dose cohort recorded mean trough drug levels that were 1.4, 2.2, 2.3, and 2.4 times greater than the IC80 for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. Mean Cmax was 3.5, 5.4, 5.6, and 6.0 times greater than the IC80 for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. IL-6 inhibition > 50% was noted for part of the dosing interval.Conclusion: ATI-450 was well tolerated at the doses investigated, exhibited dose- and time-independent (ie, linear) pharmacokinetics, and dose-related pharmacodynamic effects. These results support further study of ATI-450 in immunoinflammatory diseases in phase 2 trials.Keywords: immunologic diseases, rheumatoid arthritis, serine-threonine kinases, protein kinase inhibitors, pharmacokinetics/pharmacodynamic

Modafinil Blocks Reinstatement of Extinguished Opiate-Seeking in Rats: Mediation by a Glutamate Mechanism

Opiate addiction is characterized by high rates of relapse even after long periods of abstinence, requiring new relapse-prevention treatments that do not have abuse potential. Recently, clinical studies suggested that the wake-promoting drug modafinil might decrease relapse in cocaine addicts. In addition, group II metabotropic glutamate receptors (mGlu2/3R) have been suggested as a new therapeutic target for drug addiction. Here, we investigated the ability of modafinil to prevent the acute morphine to promote reinstatement of extinguished preference for morphine, and the involvement of mGlu2/3Rs in this effect. Conditioned place preference (CPP) for morphine was induced in Sprague–Dawley rats, followed by extinction training. Preference for the morphine-paired side was reinstated following extinction by a morphine-priming injection. The results of our study showed that modafinil (300 mg/kg, i.p., but not 100 mg/kg) 30 min before the morphine-priming injection blocked reinstatement of extinguished CPP. The anti-reinstatement effect of modafinil was completely prevented by pretreatment with the selective mGlu2/3 antagonist LY341495. Additional experiments indicated that modafinil alone did not produce a preference, and that modafinil did not alter the expression of morphine CPP or the cueing properties of morphine either 1 or 14 days after morphine CPP conditioning. These data reveal a novel mechanism for modafinil actions, a role for mGlu2/3 receptors in reinstatement of opiate-seeking, and a new therapeutic option to treat relapse in opiate addiction