Target-Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model-Informed Dose Selection for the First-in-Human Study of AVB-S6-500

Clin Transl Sci. 2020 Jan;13(1):204-211. doi: 10.1111/cts.12706. Epub 2019 Oct 25.


AVB-S6-500 neutralized growth arrest-specific 6 (GAS6) protein and effectively inhibited AXL signaling in preclinical cancer models. A target-mediated drug disposition (TMDD) pharmacokinetic/pharmacodynamic (PK/PD) model was used to select first-in-human (FIH) doses for AVB-S6-500 based on predicted target (GAS6) suppression in the clinic. The effect of TMDD on AVB-S6-500 clearance was incorporated into a standard two-compartment model, providing parallel linear and nonlinear clearance. Observed AVB-S6-500 and GAS6 concentration data in cynomolgus monkeys and relevant interspecies differences were used to predict the PK (serum concentration)/PD (GAS6 suppression) relationship in humans. Human exposure and GAS6 suppression were simulated for the proposed FIH doses of 1, 2.5, 5, and 10 mg/kg. A dose of 1 mg/kg was selected to target GAS6 suppression for 2 weeks in the initial healthy volunteer study. The cynomolgus monkey:human ratios for the highest proposed FIH dose were anticipated to yield more than a 10-fold margin to the nonclinical no observed adverse event level while maintaining > 90% GAS6 suppression. In human subjects, the first dose (1 mg/kg) model-projected and clinically observed maximal concentration (Cmax ) was within 10% of predicted; repeat dosing at 5 mg/kg was within 1% (Cmax ) and 45% (area under the serum concentration-time curve from time 0 to end of dosing interval) of predicted. Predicted GAS6 suppression duration of 14 days was accurate for the 1 mg/kg dose. A PK/PD model expedited clinical development of AVB-S6-500, minimized exposure of patients with cancer to subtherapeutic doses, and rationally guided the optimal dosing in patients.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / adverse effects*
  • Antineoplastic Agents, Immunological / pharmacokinetics
  • Area Under Curve
  • Axl Receptor Tyrosine Kinase
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Evaluation, Preclinical
  • Female
  • Healthy Volunteers
  • Humans
  • Immunoconjugates / administration & dosage
  • Immunoconjugates / adverse effects*
  • Immunoconjugates / pharmacokinetics
  • Infusions, Intravenous
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Macaca fascicularis
  • Male
  • Middle Aged
  • Models, Biological*
  • Neoplasms / drug therapy
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / adverse effects*
  • Recombinant Fusion Proteins / pharmacokinetics
  • Young Adult


  • Antineoplastic Agents, Immunological
  • Immunoconjugates
  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • growth arrest-specific protein 6
  • Receptor Protein-Tyrosine Kinases
  • Axl Receptor Tyrosine Kinase