A rational approach to dose optimisation of pembrolizumab using cost analysis and pharmacokinetic modelling and simulation.

Background: Pembrolizumab is a PDL1 inhibitor licensed for the treatment of unresectable melanoma at a dose of 2mg/kg every three weeks. A population pharmacokinetic model based on two compartment first order elimination model has been used to describe the pharmacokinetics of pembrolizumab in advanced malignancies. Dose banding or the standardisation of doses into a defined set of ranges offers an alternative approach to precise dosing. The aim of this work is to evaluate using a simulated study and data from 43 patients treated at one UK centre the change in cost, drug exposure and target engagement between precise dosing (2mg/kg), banded and fixed dosing (150mg and 200mg) strategies.

Methods: Data from 43 consecutive patients who received pembrolizumab with a median weight of 79.5kg (range 44-130kg). 5 cycles of treatment based on median time on treatment of Keynote-002 trial was assumed for cost evaluation. 1000 random individuals were evaluated in a simulated study for pharmacokinetic and pharmacodynamic assessment. The published population PK model were used to simulate change in exposure and probability of achieving reported trough level (10mg/L) required for maximum target engagement for different dosing strategies.

Results: Based on 43 patients receiving 5 cycles of pembrolizumab, the costs of different strategies are illustrated in Table 1. The table also includes simulated area under the curve and mean probability of achieving a trough level of 10mg/L required for maximum target engagement before the second cycle of treatment for the different dosing strategies.

Conclusions: Significant cost reduction can be achieved by banded and fixed dose strategies compared to precise dosing strategy while maintaining comparable level of exposure and target engagement.