Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers

Purpose: Combining olaparib with carboplatin was recently shown to be active in both BRCA and non-BRCA mutant cancers in a recent phase I/Ib combination trial. The optimal drug sequence recommended was carboplatin 1-day before olaparib. However, carboplatin pre-treatment induced a ~50% faster olaparib clearance. Methods: To further explore this drug interaction, a population pharmacokinetic (PK) model was designed that included a lag time parameter, a second absorption compartment from tablet formulation, a single distribution/elimination compartment, and covariance among the clearance and volume parameters. Results: Clearance (6.8 L/h) and volume (33 L) estimates were comparable with literature. The only significant covariate was the presence of carboplatin on olaparib clearance, consistent with published noncompartmental PK and in vitro data. Conclusions: Simulations predicted lower steady-state peak/trough olaparib exposure through 24–36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.