Investigational New Drugs

, Volume 22, Issue 1, pp 39-52

First online:

Population Pharmacokinetics of Sibrotuzumab, A Novel Therapeutic Monoclonal Antibody, in Cancer Patients

  • C. KloftAffiliated withFreie Universitaet Berlin
  • , E-U. GraefeAffiliated withBoehringer Ingelheim Pharma KG
  • , P. TanswellAffiliated withBoehringer Ingelheim Pharma KG
  • , A. M. ScottAffiliated withLudwig Institute for Cancer Research
  • , R. HofheinzAffiliated withUniversitaetsklinikum Mannheim
  • , A. AmelsbergAffiliated withBoehringer Ingelheim Pharmaceuticals, Inc.
  • , M. O. KarlssonAffiliated withUppsala University

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Population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein, were determined after multiple intravenous infusions of dosages ranging from 5mg/m2 to an absolute dose of 100mg, in patients with advanced or metastatic carcinoma. In total, 1844 serum concentrations from 60 patients in three Phase I and II clinical studies were analyzed. The structural model incorporated two disposition compartments and two parallel elimination pathways from the central compartment, one linear and one nonlinear. Finally estimated pharmacokinetic parameters (%RSE) were: linear clearance CLL 22.1ml/h (9.6), central distribution volume V1 4.13l (3.7), peripheral volume V2 3.19l (8.8), inter-compartmental clearance Q 37.6ml/h (9.6); for the nonlinear clearance Vmax was 0.0338mg/h (25) and Km 0.219μg/ml (57). At serum concentrations between approximately 20ng/ml and 7μg/ml, the effect of the nonlinear clearance on pharmacokinetics was marked. Only at >7μg/ml did CLL dominate overall clearance. Interindividual variability was 57% for CLL, 20% for V1 and V2, and 29% for Vmax and was larger than the inter-occasional variability of 13%. Of the many investigated patient covariates, only body weight was found to contribute to the population model. It significantly affected CLL, V1, V2 and Vmax resulting in marked differences in the model-predicted concentration–time profiles after multiple dosing in patients with low and high body weights. In conclusion, a robust population pharmacokinetic model was developed and evaluated for sibrotuzumab, which identified a possible need to consider body weight when designing dosage regimen for future clinical cancer trials.

sibrotuzumab humanized monoclonal antibody immunotherapy fibroblast activation protein population pharmacokinetics nonlinear kinetics