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.
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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
- Caverage
- average concentration
- Cmax
- maximum concentration
- Cmin
- minimum concentration
- CV
- coefficient of variability
- FDA
- Food and Drug Administration
- FIH
- first in human
- HED
- human equivalent dose
- IgG2
- immunoglobulin isotype G2
- ka
- absorption rate constant
- Kd
- equilibrium dissociation constant
- kel
- elimination rate constant
- kon
- association rate constant
- koff
- 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
- tlast
- 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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