While weight-based dosing (10 mg/kg every 2 weeks) was used in the PACIFIC study for NSCLC, flat dosing has been used in subsequent studies of durvalumab including 4-weekly flat dosing in extensive stage small cell lung cancer.rr
The evidence for flat as opposed to weight-based dosing for durvalumab comes from a population pharmacokinetic (PK) modelling paper by Baverel et al.r This study used pooled data from 1409 patients across two studies: a phase Ib/II study across multiple tumour types, and a phase II study in patients with stage IIIb/IV NSCLC, and aimed to evaluate dosage requirements for special populations and whether a flat-dosing regimen every 2 or every 4 weeks would be comparable to weight-based dosing.r The population included in this PK analysis was predominantly male (56.7%), white (71%) or Asian (19%) with median age 62, and median body weight at baseline of 69.8 kg. Lung cancer patients represented the biggest pool (n = 776).
In this paper the authors developed a PK model of durvalumab based on pooled patient data, and then simulated flat dosing and compared the simulated plasma immune checkpoint inhibitor concentrations to actual concentrations corresponding to a body-weight-based dose. In this study simulations of flat-dosing regimens 750 mg every 2 weeks and 1500 mg every 4 weeks vs 10 mg/kg every 2 weeks suggested that all regimens lead to similar median steady-state exposures and variability, with no increased incidence of extreme concentration values with flat dosing.
While multiple baseline patient demographics including body weight (range: 34 to 149 kg) were found to be statistically significant predictors of durvalumab PK, all caused a magnitude of effect on the durvalumab PK of <30%, which was specified a priori as a threshold for clinical significance.
Simulated PK profiles of durvalumab following weight-based dosing regimens (10 mg/kg q2w) compared with flat dosingr
The area (pink, grey, and green) represents the 90% prediction interval from the semimechanistic time-varying CL model according to three different dosing schemes; they are delimited by the 5th and 95th percentiles of the simulated PK data obtained from a pool of n = 1,000 virtual patients.
© Clin Pharmacol Ther 2018