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Rationale for fixed dosing of pertuzumab by population pharmacokinetic (POP PK) modeling
Author(s) -
Ng C.,
Lum B. L.,
Kelsey S.,
HersbergerGimenez V.,
Allison D.E.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.019
Subject(s) - dosing , pertuzumab , nonmem , trough concentration , pharmacokinetics , medicine , population , pharmacology , body weight , breast cancer , metastatic breast cancer , environmental health , cancer
Background Pertuzumab (rhuMAb 2C4), a humanized IgG1 monoclonal antibody, is a novel HER2 dimerization inhibitor (HDI) being evaluated in the clinic for a variety of solid tumors. Objective To develop a POP PK model for pertuzumab, evaluate predictive covariates, and examine the variability of steady‐state trough concentrations after fixed (FBD), or body weight‐based dosing (WBD). Methods Pertuzumab was administered by IV infusion (q3 week) either as a weight‐based dose (0.5–15 mg/kg) or a fixed dose (420 mg or 1050 mg). PK data from one Phase Ia and two Phase II trials (Ovarian and Breast), comprising of 153 patients and 1458 concentration‐time points, were pooled for this analysis using NONMEM with the FOCE interaction method. Patient weights ranged from 45.0–150.6 kg. Results A linear 2‐compartment model best described the data. Body weight, serum albumin, and alkaline phosphatase were significant covariates affecting clearance (CL). Weight only explained 8.3% of inter‐patient variability for CL. Evaluation of the final POP PK model using a posterior predictive check showed good performance. Simulations showed that the percentages of predicted steady‐state trough concentrations below 20 mcg/mL were similar between FBD and WBD, with WBD reducing the population variability by only 6.2%. Conclusion Although humanized antibodies are typically dosed by weight, our analyses demonstrate the feasibility of administrating pertuzumab using a fixed dose in patients with ovarian and breast cancers. Clinical Pharmacology & Therapeutics (2005) 77 , P33–P33; doi: 10.1016/j.clpt.2004.12.019