Pharmacokinetic and exploratory exposure–response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study

• DOI: 10.1007/s00280-019-03826-1
• Publication Date: 2019-04-11T10:28:36Z
• Authors: Whitney P. Kirsch...; Matts Kågedal; Bei Wang; Lars Lindbom; Adam Knott; Rachelle Mack; Sharareh Monemi; Ihsan Nijem; Sandhya Girish; Christie Freeman; Debora Fumagalli; Robin McConnell; Guy Jerusalem; Chris Twelves; José Baselga; Gunter von Minckwitz; José Bines; Amit Garg
• Keywords: Pertuzumab; Cmin

To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure-response (E-R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within APHINITY study (NCT01358877, BIG 4-11/BO25126/TOC4939G).A previously developed two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation examine appropriateness for describing concentrations from study. Pharmacokinetic drug-drug interactions (DDIs) between pertuzumab, trastuzumab, chemotherapy were assessed by comparing observed serum or plasma Cmax, Cmin, AUClast geometric mean ratios 90% CIs. Predictions of Cmax,ss, Cmin,ss, AUCss derived individual parameter estimates used E-R analysis.Using data 72 patients, based on goodness-of-fit, popPK deemed appropriate predictions exposures subsequent comparisons historical data, assessment DDIs, analyses. No evidence DDIs trastuzumab PK observed. Analyses differences exposure without invasive disease-free survival events did not indicate improved efficacy increased exposure. Overall Grade ≥ 3 diarrhea prevalence higher versus placebo, but greater increasing apparent relationship suggested respect other grade AEs.Overall, limited available this suggest that no dose adjustments are needed when administered combination EBC regimen.