Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors
- Amit GargAffiliated withClinical Pharmacology, MS 463a, Genentech, Inc.
- , Angelica QuartinoAffiliated withClinical Pharmacology, MS 463a, Genentech, Inc. Email author
- , Jing LiAffiliated withClinical Pharmacology, MS 463a, Genentech, Inc.MedImmune
- , Jin JinAffiliated withClinical Pharmacology, MS 463a, Genentech, Inc.
- , D. Russell WadaAffiliated withQuantitative Solutions Inc.
- , Hanbin LiAffiliated withQuantitative Solutions Inc.
- , Javier CortésAffiliated withDepartment of Oncology, Vall d’Hebron University Hospital
- , Virginia McNallyAffiliated withF. Hoffmann-La Roche Ltd
- , Graham RossAffiliated withF. Hoffmann-La Roche Ltd
- and 2 more
- , Jennifer VisichAffiliated withClinical Pharmacology, MS 463a, Genentech, Inc.
- , Bert LumAffiliated withClinical Pharmacology, MS 463a, Genentech, Inc.
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To characterize the population pharmacokinetics (PK) of pertuzumab across clinical trials in a variety of solid tumors, evaluate the potential impact of patient characteristics on PK, and confirm the appropriateness of the fixed (non-weight-based) dose.
Pertuzumab concentration data collected following intravenous administration during eleven phase I/II studies and the pivotal phase III trial CLEOPATRA were analyzed using nonlinear mixed-effects modeling. The potential impact of patient and laboratory characteristics and HER2 target-related variables on pertuzumab PK were investigated in a covariate analysis. The final model was used to confirm selection of fixed, non-weight-based dosing of pertuzumab, and to compare pertuzumab PK in CLEOPATRA with the other studies.
The analysis included 4,525 serum concentration measurements from 481 patients with solid tumors. Pertuzumab PK in the 2–25 mg/kg dose range was described by a two-compartment linear model with first-order elimination. The elimination clearance and central compartment volume were 0.235 L/day, and 3.11 L, respectively, and the terminal elimination half-life was 18.0 days. Baseline serum albumin and lean body weight had statistically significant effects on pertuzumab clearance; however, simulations showed that the magnitude of their effects on pertuzumab exposure was minimal compared with overall variability and was not clinically relevant. Thus, variations in these factors do not require dose adjustments.
The fixed, non-weight-based dosing of pertuzumab, 840 mg loading dose followed by a 420 mg maintenance dose every 3 weeks, in patients with the solid tumors in this analysis is well supported by the population pharmacokinetic modeling and simulation results.
KeywordsFixed dose HER2 Pertuzumab Population pharmacokinetics modeling Metastatic breast cancer NONMEM
- Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors
Cancer Chemotherapy and Pharmacology
Volume 74, Issue 4 , pp 819-829
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- Print ISSN
- Online ISSN
- Springer Berlin Heidelberg
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- Fixed dose
- Population pharmacokinetics modeling
- Metastatic breast cancer
- Industry Sectors
- Author Affiliations
- 1. Clinical Pharmacology, MS 463a, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
- 5. MedImmune, 24500 Clawiter Road, Hayward, CA, 94545, USA
- 2. Quantitative Solutions Inc., Menlo Park, CA, 94025, USA
- 3. Department of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain
- 4. F. Hoffmann-La Roche Ltd, 6 Falcon Way, Shire Park, Hexagon Place, Welwyn Garden City, AL7 1TW, Hertfordshire, UK