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- Title
The pharmacokinetics of the bispecific antibody MDX-H210 when combined with interferon gamma-1b in a multiple-dose phase I study in patients with advanced cancer.
- Authors
Lewis, Lionel D.; Beelen, Andrew P.; Cole, Bernard F.; Wallace, Paul K.; Fisher, Jan L.; Waugh, Mary G.; Kaufman, Peter A.; Ernstoff, Marc S.
- Abstract
Introduction: MDX-H210 is a Fab′×Fab′ bispecific antibody (BsAb) constructed chemically by crosslinking Fab′ mAb 520C9 (anti-HER-2/neu) and humanized Fab′ mAbH22 (anti-CD64). Study design and objectives: This was a phase I dose-escalation study of intravenous MDX-H210 (1–70 mg/m2) combined with subcutaneous IFN-γ, 50 µg/m2 given 24 h before the BsAb, both drugs being given three times a week for 3 weeks. The major objectives of the study were to define the safety, tolerability and pharmacokinetics of MDX-H210 when given with IFN-γ on this schedule. Results: The study group comprised 23 patients (19 female, 4 male; median age 51.5 years, range 25–72 years) with advanced HER-2/neu-positive cancers (19 breast, 3 prostate and 1 lung). Inspection of the log plasma MDX-H210 concentrations-time data for both days 1 and 17 of treatment revealed monoexponential decay in the majority of patients with adequate concentration-time data points. The MDX-H210 T1/2 ranged from 2.9 to 21.9 h. The MDX-H210 Cmax on day 1 (means±SD) increased from 0.30±0.22 µg/ml at the 1-mg/m2 dose tier to 86.91±6.46 µg/ml at 70 mg/m2. Equivalent day-17 values were 0.27±0.30 µg/ml increasing to 147.85±40.23 µg/ml. The MDX-H210 Tmax occurred at or after the end of the infusion for all treatments. The mean MDX-H210 total body clearance (Cl) was in the range 0.01–0.34 ml/min per kg and the mean MDX-H210 apparent volume of distribution at steady-state (Vdss) in the range 20–170 ml/kg, compatible with distribution primarily limited to the intravascular space. MDX-H210 T1/2 increased with dose (ANOVA P=0.001) and Cl decreased with dose (ANOVA P=0.006). There were no significant changes in MDX-H210 Cmax, AUC, Cl or Vdss between day 1 and day 17. Conclusions: MDX-H210 pharmacokinetics appeared saturable over the dose range 1–70 mg/m2, and there was no significant change in MDXH210 pharmacokinetics over the course of the study, or evidence of excessive accumulation of MDX-H210 on this multiple dosing schedule. When MDX-H210 was combined with IFN-γ, the estimated MDX-H210 pharmacokinetic parameters were similar to the published data for single-agent MDX-H210.
- Subjects
PHARMACOKINETICS; IMMUNOGLOBULINS; INTERFERONS; CANCER patients; BLOOD plasma; CHEMICAL kinetics
- Publication
Cancer Chemotherapy & Pharmacology, 2002, Vol 49, Issue 5, p375
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-002-0424-8