Cancer Chemotherapy and Pharmacology

, Volume 80, Issue 1, pp 165–175 | Cite as

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

  • Cody J. Peer
  • Jung-Min Lee
  • Jeffrey Roth
  • Louis Rodgers
  • Jeffers Nguyen
  • Christina M. Annunziata
  • Lori Minasian
  • Elise C. Kohn
  • William D. Figg
Original Article

Abstract

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.

Keywords

Olaparib Population pharmacokinetics Carboplatin Drug interaction 

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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2017

Authors and Affiliations

  • Cody J. Peer
    • 1
  • Jung-Min Lee
    • 2
  • Jeffrey Roth
    • 1
  • Louis Rodgers
    • 1
  • Jeffers Nguyen
    • 1
  • Christina M. Annunziata
    • 2
  • Lori Minasian
    • 3
  • Elise C. Kohn
    • 2
  • William D. Figg
    • 1
  1. 1.Clinical Pharmacology ProgramCCR, National Cancer Institute, NIHBethesdaUSA
  2. 2.Women’s Malignancies BranchNational Cancer Institute, NIHBethesdaUSA
  3. 3.Division of Cancer PreventionNational Cancer Institute, NIHBethesdaUSA

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