Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 5, pp 779–786

Clinical pharmacokinetics of bevacizumab in patients with solid tumors

  • Jian-Feng Lu
  • Rene Bruno
  • Steve Eppler
  • William Novotny
  • Bert Lum
  • Jacques Gaudreault
Original Article

Abstract

Objective

To characterize the population pharmacokinetics of bevacizumab and the influence of demographic factors, disease severity, and concomitantly used chemotherapy agents on it’s pharmacokinetic behavior.

Patients and methods

Data from eight clinical trials with bevacizumab administered by intravenous infusion were included. A total of 4,629 bevacizumab concentrations from 491 patients with solid tumors, who received bevacizumab doses ranging from 1 to 20 mg/kg at a dosing frequency ranging from weekly to every 3 weeks, were analyzed using a nonlinear mixed-effects modeling approach (NONMEM).

Results

The best structural model was a two-compartment model with first-order elimination. In the final model, estimated clearance (CL) and central compartment volume of distribution (Vc) were 0.207 L/day and 2.39 L for a typical female. The terminal half-life estimate was ∼20 days for both men and women. Body weight and gender were the most significant covariates to explain interpatient variability for CL and Vc. Clearance was 26% faster in men than in women. Patients with low serum albumin and high serum alkaline phosphatase had 19 and 23% faster CL, respectively, than a typical patient. Consistent with the long elimination half life, simulations showed that similar steady-state exposures can be maintained when the weekly mg/kg dose rate is maintained, therefore allowing administration of bevacizumab to coincide with the frequency of administration of the cytotoxic agents.

Conclusion

The PK parameters were consistent with those of other IgG molecules. The results support dosing bevacizumab on a once every 2 weeks or once every 3 weeks dosing schedule on a mg/kg basis.

Keywords

Population pharmacokinetics Bevacizumab Monoclonal antibody Covariate effect Dosing schedule 

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Jian-Feng Lu
    • 1
  • Rene Bruno
    • 1
    • 4
  • Steve Eppler
    • 1
  • William Novotny
    • 2
  • Bert Lum
    • 1
  • Jacques Gaudreault
    • 1
    • 3
  1. 1.Department of Pharmacokinetic and Pharmacodynamic SciencesGenentech, Inc.South San FranciscoUSA
  2. 2.Department of Clinical SciencesGenentech, Inc.South San FranciscoUSA
  3. 3.F Hoffmann-La Roche, LtdBaselSwitzerland
  4. 4.Pharsight CorporationMountain ViewUSA

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