The Application of Target Information and Preclinical Pharmacokinetic/Pharmacodynamic Modeling in Predicting Clinical Doses of a Dickkopf-1 Antibody for Osteoporosis (original) (raw)

Research ArticleENDOCRINE AND DIABETES

, Tracey H. Clark, Jianxin Yang, Judith L. Treadway, Mei Li, Michael A. Giovanelli, Yasmina Abdiche, Donna M. Stone and Vishwas M. Paralkar

Journal of Pharmacology and Experimental Therapeutics April 2010, 333 (1) 2-13; DOI: https://doi.org/10.1124/jpet.109.164129

Abstract

PF-04840082 is a humanized prototype anti-Dickkopf-1 (Dkk-1) immunoglobulin isotype G2 (IgG2) antibody for the treatment of osteoporosis. In vitro, PF-04840082 binds to human, monkey, rat, and mouse Dkk-1 with high affinity. After administration of PF-04840082 to rat and monkey, free Dkk-1 concentrations decreased rapidly and returned to baseline in a dose-dependent manner. In rat and monkey, PF-04840082 exhibited nonlinear pharmacokinetics (PK) and a target-mediated drug disposition (TMDD) model was used to characterize PF-04840082 versus Dkk-1 concentration response relationship. PK/pharmacodynamic (PK/PD) modeling enabled estimation of antibody non-target-mediated elimination, Dkk-1 turnover, complex formation, and complex elimination. The TMDD model was translated to human to predict efficacious dose and minimum anticipated biological effect level (MABEL) by incorporating information on typical IgG2 human PK, antibody-target association/dissociation rates, Dkk-1 expression, and turnover rates. The PK/PD approach to MABEL was compared with the standard “no adverse effect level” (NOAEL) approach to calculating clinical starting doses and a pharmacological equilibrium method. The NOAEL method gave estimates of dose that were too high to ensure safety of clinical trials. The pharmacological equilibrium approach calculated receptor occupancy (RO) based on equilibrium dissociation constant alone and did not take into account rate of turnover of the target or antibody–target complex kinetics and, as a result, it likely produced a substantial overprediction of RO at a given dose. It was concluded that the calculation of MABEL according to the TMDD model was the most appropriate means for ensuring safety and efficacy in clinical studies.

Footnotes

• Received November 25, 2009.

• Accepted January 19, 2010.

• Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
  doi:10.1124/jpet.109.164129.

• ABBREVIATIONS:
  Dkk-1
  Dickkopf-1
  AUC0-tlast
  area under the concentration time curve to time of last observation
  AUC0-inf
  area under the concentration time curve extrapolated to infinity
  _C_average
  average concentration
  _C_max
  maximum concentration
  _C_min
  minimum concentration
  CV
  coefficient of variability
  FDA
  Food and Drug Administration
  FIH
  first in human
  HED
  human equivalent dose
  IgG2
  immunoglobulin isotype G2
  _k_a
  absorption rate constant
  _K_d
  equilibrium dissociation constant
  _k_el
  elimination rate constant
  _k_on
  association rate constant
  _k_off
  dissociation rate constant
  λz
  slope of terminal phase
  LLOQ
  lower limit of quantification
  LRP5
  low-density lipoprotein receptor-related protein
  MABEL
  minimum anticipated biological effect level
  MRD
  minimum required dilution
  MRSD
  maximum recommended starting dose
  NOAEL
  no adverse effect level
  PK/PD
  pharmacokinetic/pharmacodynamic
  RO
  receptor occupancy
  _t_last
  time of last observation
  TMDD
  target-mediated drug disposition
  MSD
  Meso Scale Discovery
  PBS
  phosphate-buffered saline
  BSA
  bovine serum albumin
  QC
  quality control
  ADA
  antidrug antibodies.

• Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics

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