PMID- 26645407
OWN - NLM
STAT- MEDLINE
DCOM- 20160517
LR  - 20181113
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 77
IP  - 1
DP  - 2016 Jan
TI  - 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.
PG  - 77-88
LID - 10.1007/s00280-015-2922-5 [doi]
AB  - PURPOSE: 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 microg/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. CONCLUSION: A fixed 600 mg SC dose of trastuzumab 
      provides the desired exposure, with steady-state trough concentrations (35-123 
      mug/mL for the 5th-95th percentiles) above the historical target concentration of 
      20 mug/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.
FAU - Quartino, Angelica L
AU  - Quartino AL
AD  - Genentech, Inc., California, CA, USA.
FAU - Hillenbach, Carina
AU  - Hillenbach C
AD  - Roche, Basel, Switzerland.
FAU - Li, Jing
AU  - Li J
AD  - Genentech, Inc., California, CA, USA.
FAU - Li, Hanbin
AU  - Li H
AD  - Quantitative Solutions, Inc., Menlo Park, CA, USA.
FAU - Wada, Russell D
AU  - Wada RD
AD  - Quantitative Solutions, Inc., Menlo Park, CA, USA.
FAU - Visich, Jennifer
AU  - Visich J
AD  - Genentech, Inc., California, CA, USA.
FAU - Li, Chunze
AU  - Li C
AD  - Genentech, Inc., California, CA, USA.
FAU - Heinzmann, Dominik
AU  - Heinzmann D
AD  - Roche, Basel, Switzerland.
FAU - Jin, Jin Y
AU  - Jin JY
AD  - Genentech, Inc., California, CA, USA.
FAU - Lum, Bert L
AU  - Lum BL
AD  - Genentech, Inc., California, CA, USA. blum@gene.com.
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20151208
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antineoplastic Agents)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Antineoplastic Agents/*administration & dosage/pharmacokinetics/therapeutic use
MH  - Biological Availability
MH  - Breast Neoplasms/*drug therapy
MH  - Female
MH  - Humans
MH  - Infusions, Intravenous
MH  - Injections, Subcutaneous
MH  - Logistic Models
MH  - Nonlinear Dynamics
MH  - Receptor, ErbB-2
MH  - Syringes
MH  - Tissue Distribution
MH  - Trastuzumab/*administration & dosage/metabolism/therapeutic use
PMC - PMC4706584
OTO - NOTNLM
OT  - Early breast cancer
OT  - Fixed dose
OT  - HER2
OT  - NONMEM
OT  - Population pharmacokinetics modeling
OT  - Trastuzumab
EDAT- 2015/12/10 06:00
MHDA- 2016/05/18 06:00
PMCR- 2015/12/08
CRDT- 2015/12/10 06:00
PHST- 2015/05/14 00:00 [received]
PHST- 2015/11/14 00:00 [accepted]
PHST- 2015/12/10 06:00 [entrez]
PHST- 2015/12/10 06:00 [pubmed]
PHST- 2016/05/18 06:00 [medline]
PHST- 2015/12/08 00:00 [pmc-release]
AID - 10.1007/s00280-015-2922-5 [pii]
AID - 2922 [pii]
AID - 10.1007/s00280-015-2922-5 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2016 Jan;77(1):77-88. doi: 10.1007/s00280-015-2922-5. 
      Epub 2015 Dec 8.