title: The application of target information and preclinical pharmacokinetic/pharmacodynamic modeling in predicting clinical doses of a Dickkopf-1 antibody for osteoporosis.
abstract: PF-04840082 is a humanized prototype anti-Dickkopf-1 (Dkk-1) immunoglobulin isotype G(2) (IgG(2)) 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 IgG(2) 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.
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA. alison.betts@pfizer.com
authors.forename: Alison M
authors.initials: AM
authors.lastname: Betts
authors.forename: Tracey H
authors.initials: TH
authors.lastname: Clark
authors.forename: Jianxin
authors.initials: J
authors.lastname: Yang
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Michael A
authors.initials: MA
authors.lastname: Giovanelli
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Abdiche
authors.forename: Donna M
authors.initials: DM
authors.lastname: Stone
authors.forename: Vishwas M
authors.initials: VM
authors.lastname: Paralkar
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001851:Bone Diseases, Metabolic / Q000097:blood; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D010024:Osteoporosis / Q000097:blood* / Q000188:drug therapy; D015663:Osteoporosis, Postmenopausal / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000911:Antibodies, Monoclonal; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins