Clinical pharmacokinetics of bevacizumab in patients with solid tumors.
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.


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 approximately 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.


CONCLUSIONS
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.
Lu
Jian-Feng
JF
Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., 1 DNA Way, MS70, South San Francisco, CA 94080, USA.
Bruno
Rene
R
Eppler
Steve
S
Novotny
William
W
Lum
Bert
B
Gaudreault
Jacques
J
D000465:Algorithms; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D002986:Clinical Trials as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D011153:Population
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab