title: Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous "manual syringe" injection or intravenously in women with HER2-positive early breast cancer.
abstract: OBJECTIVE
  To characterize the population pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) trastuzumab in early breast cancer (EBC), assess the impact of covariates on trastuzumab PK, and evaluate fixed (nonweight-based) dosing for the SC regimen administrated via handheld syringe.
  
  
  METHODS
  Serum trastuzumab concentrations from 595 patients with HER2-positive EBC in the HannaH study (fixed 600 mg SC trastuzumab or weight-based IV trastuzumab) were analyzed using nonlinear mixed-effects modeling. Multiple logistic regression was used to assess the exposure-response relationships between PK, efficacy [pathologic complete response (pCR)], and safety [grade ≥3 adverse events (AEs)].
  
  
  RESULTS
  Trastuzumab PK was described by a two-compartment model with parallel linear and nonlinear elimination and first-order SC absorption, with a bioavailability of 77 %. Estimated total clearance (CL) values were 0.18-0.22 L/day for steady-state trough/peak concentrations of 75-148 µg/mL; the estimate for central volume of distribution was 2.9 L. Body weight and alanine transaminase, while showing significant effects on PK, only explained 8% of the variability in CL. Exposure-response analyses showed no relationship between PK, pCR, and grade ≥3 AEs for either regimen.
  
  
  CONCLUSIONS
  A fixed 600 mg SC dose of trastuzumab provides the desired exposure, with steady-state trough concentrations (35-123 μg/mL for the 5th-95th percentiles) above the historical target concentration of 20 μg/mL for efficacy. Fixed dosing is further supported by lack of an exposure-response relationship between PK, pCR, and grade ≥3 AEs. No dose adjustment per patient factors is required within the ranges studied.
authors.affiliation: Genentech, Inc., California, CA, USA.
authors.forename: Angelica L
authors.initials: AL
authors.lastname: Quartino
authors.affiliation: Roche, Basel, Switzerland.
authors.forename: Carina
authors.initials: C
authors.lastname: Hillenbach
authors.affiliation: Genentech, Inc., California, CA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Quantitative Solutions, Inc., Menlo Park, CA, USA.
authors.forename: Hanbin
authors.initials: H
authors.lastname: Li
authors.affiliation: Quantitative Solutions, Inc., Menlo Park, CA, USA.
authors.forename: Russell D
authors.initials: RD
authors.lastname: Wada
authors.affiliation: Genentech, Inc., California, CA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Visich
authors.affiliation: Genentech, Inc., California, CA, USA.
authors.forename: Chunze
authors.initials: C
authors.lastname: Li
authors.affiliation: Roche, Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Heinzmann
authors.affiliation: Genentech, Inc., California, CA, USA.
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Jin
authors.affiliation: Genentech, Inc., California, CA, USA. blum@gene.com.
authors.forename: Bert L
authors.initials: BL
authors.lastname: Lum
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D016015:Logistic Models; D017711:Nonlinear Dynamics; D018719:Erb-b2 Receptor Tyrosine Kinases; D013594:Syringes; D014018:Tissue Distribution; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
keywords: Early breast cancer; Fixed dose; HER2; NONMEM; Population pharmacokinetics modeling; Trastuzumab