Population pharmacokinetics of CAP7.1 and the effect on total target lesion size in adult patients with biliary tract cancer.

e15602 Background: The aim of this study was to describe the population pharmacokinietics (PK) of CAP7.1, the prodrug of etoposide, and to describe how changes in total target lesion (TTL) size in biliary tract cancer (BTC) patients depend on treatment with CAP7.1. Methods: Non linear mixed effects modeling with Monolix was used to develop a population PK model. Data for the population PK model was from an open label, dose escalation phase I study and the ongoing randomized, multicenter phase II trial in BTC patients. Data from a total of 39 patients with 434 observations was available for PK modeling. Variability in CAP7.1 plasma concentrations exeeded those of etoposide; for this reason a dose-etoposide PK model was developed without taking into account CAP7.1 concentrations. The individual a posteriori PK model parameter estimates were then used with Simulx to simulate etoposide AUC0-24h , cmax and cmin for each BTC patient and compared with the individual changes in TTL size. Results: Etoposide PK was best described with a two compartmental model with a first order metabolic conversion rate and with linear clearance from the central compartment. The metabolic rate was 0.39 1/h (CV 44%), the clearance 3.2 L/h (CV 56%), the first volume 6.2 L (CV 37%), and the two exchange rates between the two compartments were k12 = 0.53 and k21 = 0.2 1/h. The calculated terminal half life of etoposide was 7.9 h. Linear regression analysis between the simulated AUC0-24h and change in TTL size showed that a higher AUC0-24h was associated with a lower increase in TTL size (R2= 0.172). For an AUC0-24h larger than 100 h ug/mL six out of eight BTC patients had an increase in TTL size of less than 20%. Similarly, a higher cmax (R2= 0.177) or cmin (R2= 0.11) were associated with a larger effect on TTL size although less pronounced for cmin . Conclusions: While the PK of CAP7.1 was variable the dose-etoposide population PK could be well described. The emerging pattern from the data analysis showed that for a higher etoposide AUC0-24h a larger fraction of patients could maintain the increase in TTL size below 20% for the observational period in the phase II study in BTC Clinical trial information: NCT02094560.