Predicting Free Sclerostin from Free AMG 785 and Total Sclerostin
Thuy Vu, Edward Lee, Naren Narayanan, Graham Jang, and Peiming Ma
Amgen Inc.
Objectives: Therapeutic mAbs often exhibit complex nonlinear pharmacokinetics as a result of the targets' facilitating their elimination or inactivation. Our objective is to characterize the disposition of AMG 785, an anti-sclerostin IgG2 compound, using a mechanistic model, the target mediated drug disposition (TMDD) model.
Methods: Nonlinear mixed-effects modeling with FOCE-interaction estimation in NONMEM was used to fit various TMDD models to log-transformed unbound AMG 785 and total sclerostin concentrations from two Phase 1 studies in healthy men and PMO women. Single doses studied were 1 and 5 mg/kg IV; 0.1, 0.3, 1, 3, 5, and 10 mg/kg SC; multiple ascending SC doses studied were 1 and 2 mg/kg Q2W; 2 and 3 mg/kg Q4W. The analysis data set included 1521 AMG 785 and 962 sclerostin concentrations from 118 subjects, which was simultaneously modeled with between-subject and within-subject variability estimated.
Results: The final PK model is a quasi-steady state TMDD that assumes a balance between synthesis and elimination of sclerostin. Age and sex did not affect PK. Absorption is best described by two parallel first-order processes in which approximately 44% of available dose absorbed at a faster rate.
Conclusions: Quasi-steady state TMDD described the mechanism of nonlinear clearance and PK in AMG 785 over a wide dose range studied. Patient factors did not affect the disposition of AMG 785 in the current population. The model is useful in predicting the time course of unbound and complex sclerostin concentration that could be related to AMG 785 efficacy on bone mineral density.
References:
[1] Gibiansky, L., et al.,J Pharmacokinet Pharmacodyn, 2008. 35(5): p. 573-91