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Combining radiotherapy with immune checkpoint blockade may offer considerable therapeutic impact if the immunosuppressive nature of the tumor microenvironment (TME) can be relieved. In this study, we used mathematical models, which can illustrate the potential synergism between immune checkpoint inhibitors and radiotherapy. A discrete-time pharmacodynamic model of the combination of radiotherapy with inhibitors of the PD1-PDL1 axis and/or the CTLA4 pathway is described. This mathematical framework describes how a growing tumor first elicits and then inhibits an antitumor immune response. This antitumor immune response is described by a primary and a secondary (or memory) response. The primary immune response appears first and is inhibited by the PD1-PDL1 axis, whereas the secondary immune response happens next and is inhibited by the CTLA4 pathway. The effects of irradiation are described by a modified version of the linearquadratic model. This modeling offers an explanation for the reported biphasic relationship between the size of a tumor and its immunogenicity, as measured by the abscopal effect (an offtarget immune response). Furthermore, it explains why discontinuing immunotherapy may result in either tumor recurrence or a durably sustained response. Finally, it describes how synchronizing immunotherapy and radiotherapy can produce synergies. The ability of the model to forecast pharmacodynamic endpoints was validated retrospectively by checking that it could describe data from experimental studies, which investigated the combination of radiotherapy with immune checkpoint inhibitors. In summary, a model such as this could be further used as a simulation tool to facilitate decision making about optimal scheduling of immunotherapy with radiotherapy and perhaps other types of anticancer therapies. Cancer Res; 76(17); 4931-40. Ó2016 AACR.

ABSTRACT.Early prediction of human clearance is often challenging, in particular for the growing number of low-clearance compounds. Long-term in vitro models have been developed which enable sophisticated hepatic drug disposition studies and improved clearance predictions. Here, the cell line HepG2, iPSC-derived hepatocytes (iCell®), the hepatic stem cell line HepaRG™, and human hepatocyte co-cultures (HμREL™ and HepatoPac®) were compared to primary hepatocyte suspension cultures with respect to their key metabolic activities. Similar metabolic activities were found for the long-term models HepaRG™, HμREL™, and HepatoPac® and the short-term suspension cultures when averaged across all 11 enzyme markers, although differences were seen in the activities of CYP2D6 and non-CYP enzymes. For iCell® and HepG2, the metabolic activity was more than tenfold lower. The micropatterned HepatoPac® model was further evaluated with respect to clearance prediction. To assess the in vitro parameters, pharmacokinetic modeling was applied. The determination of intrinsic clearance by nonlinear mixed-effects modeling in a long-term model significantly increased the confidence in the parameter estimation and extended the sensitive range towards 3% of liver blood flow, i.e., >10-fold lower as compared to suspension cultures. For in vitro to in vivo extrapolation, the well-stirred model was used. The micropatterned model gave rise to clearance prediction in man within a twofold error for the majority of low-clearance compounds. Further research is needed to understand whether transporter activity and drug metabolism by non-CYP enzymes, such as UGTs, SULTs, AO, and FMO, is comparable to the in vivo situation in these long-term culture models.KEY WORDS: in vitro clearance; in vitro liver models; IVIVE; nonlinear mixed-effects modeling.

No abstract

Purpose: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens.Experimental Design: A pharmacokinetic-pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system.Results: RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options.Conclusion: Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing.