title: Pharmacokinetics, immunogenicity and safety of bivatuzumab mertansine, a novel CD44v6-targeting immunoconjugate, in patients with squamous cell carcinoma of the head and neck.
abstract: The prodrug bivatuzumab mertansine (BIWI 1) is a novel CD44v6-targeting humanized monoclonal antibody coupled to the toxin mertansine. In a phase I dose escalation trial 31 patients with squamous cell carcinomas of the head and neck were treated with doses of 25-325 mg/m2 as a 30-min infusion. Thirteen patients received a second infusion after 3 weeks. Serial serum samples were collected to determine the pharmacokinetic parameters of the prodrug BIWI 1 and of deconjugated BIWI 1 as well as the occurrence of anti-BIWI 1 antibodies. The maximum tolerated dose was reached at 300 mg/m2 attributable to skin toxicity. No immune response was observed in any patient. For BIWI 1 and deconjugated BIWI 1, clearance values were low and distribution was limited resulting in half-lives of approximately 3-3.5 days and approximately 6-7 days, respectively, for single and repeated dosing after three weeks. Overall, interindividual variability of the pharmacokinetic parameters was low. In general, the pharmacokinetics of both compounds after single and repeated dosing was comparable across the entire dose range and no significant accumulation took place. Over the dose range investigated, a dose proportional increase in the exposure of BIWI 1 and deconjugated BIWI 1 was observed. Dose individualization according to body size (weight or body surface area) was found to be appropriate and is recommended for the novel immunoconjugate.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sauter
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kloft
authors.forename: Silke
authors.initials: S
authors.lastname: Gronau
authors.forename: Felix
authors.initials: F
authors.lastname: Bogeschdorfer
authors.forename: Thomas
authors.initials: T
authors.lastname: Erhardt
authors.forename: Wolfram
authors.initials: W
authors.lastname: Golze
authors.forename: Carsten
authors.initials: C
authors.lastname: Schroen
authors.forename: Alexander
authors.initials: A
authors.lastname: Staab
authors.forename: Herbert
authors.initials: H
authors.lastname: Riechelmann
authors.forename: Karl
authors.initials: K
authors.lastname: Hoermann
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D008297:Male; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000031:analogs & derivatives* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012449:Safety
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C112697:CD44v6 antigen; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D011355:Prodrugs; C519271:bivatuzumab mertansine; D008453:Maytansine