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.