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.
abstract: BACKGROUND
  MDX-H210 is a Fab'xFab' bispecific antibody (BsAb) constructed chemically by crosslinking Fab' mAb 520C9 (anti-HER-2/neu) and humanized Fab' mAbH22 (anti-CD64).
  
  
  OBJECTIVE
  This was a phase I dose-escalation study of intravenous MDX-H210 (1-70 mg/m(2)) combined with subcutaneous IFN-gamma, 50 microg/m(2) 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-gamma 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 T(1/2) ranged from 2.9 to 21.9 h. The MDX-H210 C(max) on day 1 (means+/-SD) increased from 0.30+/-0.22 microg/ml at the 1-mg/m(2) dose tier to 86.91+/-6.46 microg/ml at 70 mg/m(2). Equivalent day-17 values were 0.27+/-0.30 microg/ml increasing to 147.85+/-40.23 microg/ml. The MDX-H210 T(max) 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 (Vd(ss)) in the range 20-170 ml/kg, compatible with distribution primarily limited to the intravascular space. MDX-H210 T(1/2) increased with dose (ANOVA P=0.001) and Cl decreased with dose (ANOVA P=0.006). There were no significant changes in MDX-H210 C(max), AUC, Cl or Vd(ss) between day 1 and day 17.
  
  
  CONCLUSIONS
  MDX-H210 pharmacokinetics appeared saturable over the dose range 1-70 mg/m(2), 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-gamma, the estimated MDX-H210 pharmacokinetic parameters were similar to the published data for single-agent MDX-H210.
authors.affiliation: Department of Medicine, Dartmouth Medical School and The Norris Cotton Cancer Center, Lebanon, NH 03756, USA. Lionel.D.Lewis@Dartmouth.edu
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Beelen
authors.forename: Bernard F
authors.initials: BF
authors.lastname: Cole
authors.forename: Paul K
authors.initials: PK
authors.lastname: Wallace
authors.forename: Jan L
authors.initials: JL
authors.lastname: Fisher
authors.forename: Mary G
authors.initials: MG
authors.lastname: Waugh
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kaufman
authors.forename: Marc S
authors.initials: MS
authors.lastname: Ernstoff
mesh_terms: D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D011994:Recombinant Proteins
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C121360:MDX-H210 antibody; D011994:Recombinant Proteins; D007371:Interferon-gamma