Crizotinib (Xalkori) is an orally available potent inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase and mesenchymal-epithelial transition factor. Objectives of the present study were as follows: 1) to characterize crizotinib time-dependent inhibition (TDI) potency for CYP3A in human liver microsomes (HLM) and cryopreserved human hepatocytes suspended in human plasma (HSP); 2) to characterize crizotinib enzyme induction potency on CYP3A4 in cryopreserved human hepatocytes; 3) to predict crizotinib steady-state plasma concentrations in patients (e.g., autoinhibition and autoinduction) using the mechanistic dynamic model, Simcyp population-based simulator; and 4) to predict a clinical crizotinib-midazolam interaction using the dynamic model as well as the static mathematical model. Crizotinib inactivation constant (K I ) and maximum inactivation rate constant (k inact ) for TDI were estimated as, respectively, 0.37 mM and 6.9 h 21 in HLM and 0.89 mM and 0.78 h 21 in HSP.Thus, crizotinib inactivation efficiency (k inact /K I ) was ∼20-fold lower in HSP relative to HLM. Crizotinib E max and EC 50 for CYP3A4 induction (measured as mRNA expression) were estimated as 6.4-to 29-fold and 0.47 to 3.1 mM, respectively. Based on these in vitro parameters, the predicted crizotinib steady-state area under plasma concentration-time curve (AUC) with HLM-TDI was 2.1-fold higher than the observed AUC, whereas that with HSP-TDI was consistent with the observed result (£1.1-fold). The increase in midazolam AUC with coadministration of crizotinib (21-fold) was significantly overpredicted using HLM-TDI, whereas the prediction using HSP-TDI (3.6-fold) was consistent with the observed result (3.7-fold). Collectively, the present study demonstrated the value of HSP to predict in vivo CYP3A-mediated drugdrug interaction.

The relative effectiveness of incentive and minimal justification techniques in promoting electrical energy conservation among 90 homeowners was investigated. Subjects in the Questionnaire condition were asked to complete a short energy conservation survey. Those in the Commitment condition were asked to curtail their consumption of electricity by 15%. In the Questionnaire + Commitment condition, subjects received both requests. These three groups were compared to an Incentive condition, where individuals were offered a highly attractive monetary incentive for conserving electricity, a Questionnaire + Commitment + Incentive condition, and a Control condition. The groups did not differ in electricity consumption during baseline, initial request, or follow-up periods. However, during the conservation period, homeowners in the Commitment and the combined treatment groups conserved more electricity and contained more conservers than either of the remaining groups. These outcomes were discussed in terms of the comparative effectiveness of minimal justification and incentive strategies for inducing behavioral change.How can the likelihood that an individual will engage in prosocial behavior be increased? Recent research on this question (Piliavin, Dovidio, Gaertner, & Clark, 1981;Staub, 1978Staub, , 1979 Wispe, 1978) has shown clearly how a number of factors can inhibit the occurrence of such behavior. For example, in spite of their attitudes, intentions, and moral convictions about the importance of acting in a socially responsible way, individuals are often confronted with powerful social inhibitors-for example, diffusion of responsibility, evaluation apprehension, and pluralisitc ignorance-which precent them from doing so. This study explores the conditions under which individuals can effectively 'Requests for reprints should be sent to Richard Katzev,

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A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model was used for preclinical to clinical translation of inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate (ADC) for B cell malignancies including non-Hodgkin's lymphoma (NHL) and acute lymphocytic leukemia (ALL). Preclinical data was integrated in a PK/PD model which included (1) a plasma PK model characterizing disposition and clearance of inotuzumab ozogamicin and its released payload N-Ac-γ-calicheamicin DMH, (2) a tumor disposition model describing ADC diffusion into the tumor extracellular environment, (3) a cellular model describing inotuzumab ozogamicin binding to CD22, internalization, intracellular N-Ac-γ-calicheamicin DMH release, binding to DNA, or efflux from the tumor cell, and (4) tumor growth and inhibition in mouse xenograft models. The preclinical model was translated to the clinic by incorporating human PK for inotuzumab ozogamicin and clinically relevant tumor volumes, tumor growth rates, and values for CD22 expression in the relevant patient populations. The resulting stochastic models predicted progression-free survival (PFS) rates for inotuzumab ozogamicin in patients comparable to the observed clinical results. The model suggested that a fractionated dosing regimen is superior to a conventional dosing regimen for ALL but not for NHL. Simulations indicated that tumor growth is a highly sensitive parameter and predictive of successful outcome. Inotuzumab ozogamicin PK and N-Ac-γ-calicheamicin DMH efflux are also sensitive parameters and would be considered more useful predictors of outcome than CD22 receptor expression. In summary, a multiscale, mechanism-based model has been developed for inotuzumab ozogamicin, which can integrate preclinical biomeasures and PK/PD data to predict clinical response.