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Kai Liao, Pamela Garzone, Sangeetha Bollini, Philip Fanning, Gilbert Wong, Xu Meng; A Mechanism-Based Binding Model for the Pharmacokinetics and Pharmacodynamics (PK-PD) of RN6G (PF-04382923), a Humanized Monoclonal Antibody against Amyloid β Peptides, in Subjects with Dry, Age-Related Macular Degeneration Including Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3287.
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RN6G (PF-04382923) is a humanized IgG2Δa monoclonal antibody that binds with high affinity to amyloid β (Aβ) peptides Aβ1-40 and Aβ1-42 at the free C-terminal region. It is under development as treatment for patients with geographic atrophy (GA) related to dry age-related macular degeneration (ARMD). Data from a single ascending dose (SAD) and emerging data from a multiple ascending dose (MAD) study in subjects with dry ARMD showed distinctive RN6G PK profiles characterized by a dose-dependent distribution phase, which cannot be fully explained by the observed PD (Aβ) concentration profiles in plasma. The objective of this analysis was to develop and evaluate a mechanism-based predictive population PK-PD model that describes the data from these Phase I studies in subjects with early and with advanced dry ARMD.
The database included 714 RN6G and 1178 Aβ1-x (n=864 from Gyros assay, n=314 from liquid chromatography-tandem mass spectrometry) samples from the Phase I studies (B1181001 and B1181002). These data were simultaneously analyzed via nonlinear mixed-effects modeling with NONMEM, v 7.1.2.
The time course of RN6G and its interplay with Aβ1-x were delineated in the mechanism-based PK-PD model. By incorporating an Aβ1-x-rich compartment, the model was able to adequately describe the dose-dependent distribution phase of RN6G, as well as the Aβ1-x profiles observed in plasma. The initial model from the SAD study was used to select the dosage regimen for the MAD study. The preliminary PK/PD data from the MAD study provided verification of the predictions by the model, which was then used for the dose regimen selection for the proof-of-concept study. Simulation results suggest that the level of sequestration for free Aβ in plasma might not be indicative of that in tissues with higher Aβ1-x concentration such as choroid or vitreous humour.
A mechanism-based binding model was developed to adequately describe the distinctive disposition profiles of RN6G and the observed Aβ1-x concentration profiles in plasma. This modeling work provided the rationale for dosage regimens for RN6G early clinical trials.
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