Population pharmacokinetics and exposure-response relationship of trastuzumab and bevacizumab in early-stage breast cancer

Aims To describe the sources of interindividual variability of bevacizumab and trastuzumab pharmacokinetics in early-stage breast cancer, and to study the relationship between exposure and both early clinical response and specific adverse events. Patients and methods Patients (n = 86) received 6 cycles of docetaxel + trastuzumab. Early tumour response was assessed by determination of the maximum standard uptake value (SUVmax) variation (Delta SUVmax) after 1 cycle using [F-18]-fluorodeoxyglucose (FDG) PET. Early poor responders (Delta SUVmax <70%) also received bevacizumab from cycle 3 to cycle 6. Sources of interindividual variability in pharmacokinetics of both antibodies were studied by population compartment modelling. Exposure as assessed by area under the concentration-versus-time curve (AUC) was compared between responders and non-responders and between patients experiencing specific adverse events or not. Results A two-compartment model described the pharmacokinetics of both antibodies satisfactorily. Their central volume of distributions (Vc) increased with body surface area and their elimination half-lives were shorter (similar to 14 days) than previously reported (similar to 26-28 days). There was a time-dependent increase in trastuzumab Vc, positively correlated to baseline SUVmax. Bevacizumab elimination rate (k(10)) was positively correlated with Delta SUVmax measured at the end of the first cycle. Bevacizumab had no significantly influence on trastuzumab pharmacokinetics. No relationship between exposure and clinical response or occurrence of adverse events was found. Conclusion Tumour uptake as assessed by SUVmax influences the pharmacokinetics of bevacizumab and trastuzumab. In early-stage breast cancer, elimination half-lives of these therapeutic monoclonal antibodies may be shorter than those previously reported in more advanced disease.

Automated summary

The study aimed to describe the sources of interindividual variability of bevacizumab and trastuzumab pharmacokinetics and to study the relationship between exposure and early clinical response and specific adverse events in early-stage breast cancer patients. The results showed that tumor uptake influenced the pharmacokinetics of these antibodies, and in this population, elimination half-lives of these therapeutic monoclonal antibodies may be shorter than previously reported in more advanced disease.