Herbert Struemper (1), Mark Sale (2), Bela R. Patel (1), Roxanne C. Jewell (1)
(1) Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, RTP, NC & King of Prussia, PA, USA; (2) Next Level Solutions, LLC, Raleigh, NC, USA
Objectives: Ofatumumab is a CD20-targeted monoclonal antibody indicated for the treatment of patients with refractory chronic lymphocytic leukemia (CLL) and under investigation in other hematological malignancies and autoimmune conditions. The objective of this analysis was to revise a previous population pharmacokinetic (popPK) model for ofatumumab [1] based on additional data in refractory CLL (Study Hx-CD20-406) and to analyze the differential impact of the disease state on target-mediated clearance (TMC).
Methods: PopPK analysis was performed on data from 4 Phase I and II studies (rheumatoid arthritis (RA), 2 doses, 300-1000 mg, N=187; follicular lymphoma (FL), 4 doses, 300-1000 mg, N=38; relapsed CLL, 4 doses, 100-2000 mg, N=33; refractory CLL, 12 doses, 300+11×2000 mg, N=219) using NONMEM. The starting point of this analysis was a linear two-compartment model representing nonspecific clearance (NSC) of ofatumumab, augmented by a TMC component representing the specific clearance of ofatumumab by CD20 expressed on B cells and the interconnected kinetics of drug and target levels. Various parameterizations of the TMC component were explored to obtain a concise and flexible representation of B-cell kinetics in the different populations. Post hoc parameters and predicted drug and target profiles were used to examine the relative contributions of NSC and TMC and their changes over time.
Results: The nonspecific linear model component had a systemic clearance of 0.31 L/d (7.5 mL/h), inter-compartmental clearance of 0.93 L/d, central volume of 3.3 L and peripheral volume of 2.1 L. The terminal half-life of 21.8 days for the linear model component is consistent with other IgG antibodies. The predicted target kinetics reproduced the features of B-cell depletion observed in refractory CLL (initial rapid decline and eventual rebound of B-cell counts). Accordingly, TMC was initially large compared to NSC but was reduced (absolutely and relative to NSC) when target levels decreased. The magnitude of TMC relative to NSC was largest for refractory CLL (initial dominance of TMC over NSC) followed by relapsed CLL, FL, and RA (TMC was initially small, negligible after second dose).
Conclusions: This analysis demonstrates that the relative and temporal impact of TMC can vary considerably between disease states. The resulting model allows the simulation of ofatumumab PK in untested disease populations if data or hypotheses for disease-specific B-cell turnover are available.
References:
[1] Sale M, Jewell RC, Patel BR. Ofatumumab population pharmacokinetic analysis in patients with chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and rheumatoid arthritis (RA). ACoP 2011.
Reference: PAGE 21 (2012) Abstr 2471 [www.page-meeting.org/?abstract=2471]
Poster: Other Drug/Disease Modelling