Format

Send to

Choose Destination
Cancer Chemother Pharmacol. 2016 Aug;78(2):341-51. doi: 10.1007/s00280-016-3079-6. Epub 2016 Jun 21.

Population pharmacokinetics of bevacizumab in cancer patients with external validation.

Author information

1
Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. kelong.x.han@gsk.com.
2
GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA, 19406, USA. kelong.x.han@gsk.com.
3
Pharsight Consulting Services, Montreal, QC, Canada.
4
Pharsight Consulting Services, Marseille, France.
5
Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
6
Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. jin.jin@gene.com.

Abstract

BACKGROUND:

Bevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics.

METHODS:

Rich and sparse bevacizumab serum concentrations were collected from Phase I through IV studies in early and metastatic cancers. Bevacizumab was given intravenously as single agent or in combination with chemotherapy for single- and multiple-dose schedules.

RESULTS:

Model-building used 8943 bevacizumab concentrations from 1792 patients with colon/colorectal, non-small cell lung, kidney, pancreatic, breast, prostate and brain cancer. Bevacizumab doses ranged from 1 to 20 mg/kg given once every 1, 2 or 3 weeks. A two-compartment model best described the data. The population estimates of clearance (CL), central volume of distribution (V1) and half-life for a typical 70-kg patient were 9.01 mL/h, 2.88 L and 19.6 days. CL and V1 increased with body weight and were higher in males than females by 14 and 18 %, respectively. CL decreased with increasing albumin and decreasing alkaline phosphatase. The final model was externally validated using 1670 concentrations from 146 Japanese patients that were not used for model-building. Mean prediction errors were -2.1, 3.1 and 1.0 % for concentrations, CL and V1, respectively, confirming adequate predictive performance.

CONCLUSIONS:

A robust bevacizumab pharmacokinetic model was developed and externally validated, which may be used to simulate bevacizumab exposure to optimize dosing strategies. Asian and non-Asian patients exhibited similar bevacizumab pharmacokinetics. Given the similarity in pharmacokinetics among monoclonal antibodies, this may inform pharmacokinetic studies in different ethnic groups for other therapeutic antibodies.

KEYWORDS:

Adult; Asian; Bevacizumab; Cancer; External validation; Japan; Population pharmacokinetics

PMID:
27329360
PMCID:
PMC4965493
DOI:
10.1007/s00280-016-3079-6
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center