Dose escalation and pharmacokinetic study of a humanized anti-HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer

Abstract

SummaryWe conducted a phase I pharmacokinetic dose escalation study of a recombinant humanized anti-p185 HER2 monoclonal antibody (MKC-454) in 18 patients with metastatic breast cancer refractory to chemotherapy. Three or six patients at each dose level received 1, 2, 4 and 8 mg kg -1 of MKC-454 as 90-min intravenous infusions. The first dose was followed in 3 weeks by nine weekly doses. Target trough serum concentration has been set at 10 µg ml -1 based on in vitro observations. The mean value of minimum trough serum concentrations at each dose level were 3.58 ± 0.63, 6.53 ± 5.26, 40.2 ± 7.12 and 87.9 ± 23.5 µg ml -1 respectively. At 2 mg kg -1 , although minimum trough serum concentrations were lower than the target trough concentration with a wide range of variation, trough concentrations increased and exceeded the target concentration, as administrations were repeated weekly. Finally 2 mg kg -1 was considered to be sufficient to achieve the target trough concentration by the weekly dosing regimen. One patient receiving 1 mg kg -1 had grade 3 fever, one at the 1 mg kg -1 level had severe fatigue defined as grade 3, and one at 8 mg kg -1 had severe bone pain of grade 3. No antibodies against MKC-454 were detected in any patients. Objective tumour responses were observed in two patients; one receiving 4 mg kg -1 had a partial response in lung metastases and the other receiving 8 mg kg -1 had a complete response in soft tissue metastases. These results indicate that MKC-454 is well tolerated and effective in patients with refractory metastatic breast cancers overexpressing the HER2 proto-oncogene. Further evaluation of this agent with 2-4 mg kg -1 weekly intravenous infusion is warranted.

Population Pharmacokinetics of Therapeutic Monoclonal Antibodies: Examples and Estimation Method Performance Differences

“…A compartmental model with linear elimination may adequately describe the data at these high concentrations, as the nonsaturable Fc-mediated elimination pathway becomes the major determinant of mAb clearance. Nonlinear clearance has been observed for efalizumab and trastuzumab, and this was attributed to saturation of targetmediated clearance pathways via their respective targets, CD11a and HER-2 (33,35,79,82). Contrary to these observations, two separate population PK analyses of efalizumab and trastuzumab found that their PK was adequately described using a compartmental model with linear elimination (33,46).…”

“…Contrary to these observations, two separate population PK analyses of efalizumab and trastuzumab found that their PK was adequately described using a compartmental model with linear elimination (33,46). Based on PK data from dose escalation studies of efalizumab (35) and trastuzumab (82), the doses of these mAbs investigated in the aforementioned population PK analyses may have resulted in steady-state concentrations where target-mediated clearance was saturated and thus the use of a PK model with linear elimination was warranted. In a population PK analysis of bevacizumab in patients with solid tumors, concentration data was pooled from a number of different clinical trials where the dosing regimen for bevacizumab varied (28).…”

“…As discussed in Chapter 1, these clinical study design limitations are often due to the doses (concentrations) studied, because the doses (which may be clinically relevant) result in concentrations that are high enough to saturate the nonlinear target-mediated elimination of the therapeutic mAb. For example, nonlinear elimination has been observed for efalizumab and trastuzumab and attributed to saturable target-mediated elimination (33,35,79,82), but population PK analyses of the two mAbs were able to adequately describe their PK using a compartmental model with linear elimination (33,46). Based on PK data from dose escalation studies of efalizumab (35) and trastuzumab (82), the doses of these mAbs investigated in the aforementioned population PK analyses may have resulted in steady-state concentrations where targetmediated clearance was saturated, and thus the use of a PK model with linear elimination was warranted.…”

“…For example, nonlinear elimination has been observed for efalizumab and trastuzumab and attributed to saturable target-mediated elimination (33,35,79,82), but population PK analyses of the two mAbs were able to adequately describe their PK using a compartmental model with linear elimination (33,46). Based on PK data from dose escalation studies of efalizumab (35) and trastuzumab (82), the doses of these mAbs investigated in the aforementioned population PK analyses may have resulted in steady-state concentrations where targetmediated clearance was saturated, and thus the use of a PK model with linear elimination was warranted. In this study, the estimation methods were evaluated under similar conditions with the uninformative study designs where concentration data was only available from a single dose level, and the dose levels selected resulted in concentrations that were generally above the K m .…”

“…At high concentrations, the total clearance approaches that of the first-order process (CL L ), while the contribution from the nonlinear pathway becomes negligible. A biphasic clearance versus dose profile has been observed for several therapeutic mAbs including cetuximab, trastuzuamb, and efalizumab (35,(79)(80)(81)(82). Another characteristic of this model is an S-shaped curve in the concentration-time profile (Figure 1-2C).…”