Clinical Pharmacokinetics and Pharmacodynamics of Biologic Therapeutics for Treatment of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with potentially severe clinical manifestation that mainly affects women of child-bearing age. Patients who do not respond to standard-of-care therapies, such as corticosteroids and immunosuppressants, require biologic therapeutics that specifically target a single or multiple SLE pathogenesis pathways. This review summarizes the clinical pharmacokinetic and pharmacodynamic characteristics of biologic agents that are approved, used off-label, or in the active pipeline of drug development for SLE patients. Depending on the type of target, the interacting biologics may exhibit linear (non-specific) or non-linear (target-mediated) disposition profiles, with terminal half-lives varying from approximately 1 week to 1 month. Biologics given by subcutaneous administration, which offers dosing flexibility over intravenous administration, demonstrated a relatively slow absorption with a time to maximum concentration of approximately 1 day to 2 weeks and a variable bioavailability of 30-82 %. The population pharmacokinetics of monoclonal antibodies were best described by a two-compartment model with central clearance and steady-state volume of distribution ranging from 0.176 to 0.215 L/day and 3.60-5.29 L, respectively. The between-subject variability in pharmacokinetic parameters were moderate (20-79 %) and could be partially explained by body size. The development of linked pharmacokinetic-pharmacodynamic models incorporating SLE disease biomarkers are an attractive strategy for use in dosing regimen simulation and optimization. The relationship between efficacy/adverse events and biologic concentration should be evaluated to improve clinical trial outcomes, especially for biologics in the advanced phase of drug development. New strategies, such as model-based precision dosing dashboards, could be utilized to incorporate information collected from therapeutic drug monitoring into pharmacokinetic/pharmacodynamic models to enable individualized dosing in real time.

Fig. 1

Schematic presentation of SLE pathogenesis and targeting pathways of potential or approved SLE biologic therapies. SLE patients develop defective clearance of apoptotic cells, resulting in increased levels of dsDNA, ssDNA, or other apoptotic cell material circulating in the bloodstream [4]. Antigen presenting cells, mainly dendritic cells and B cells, are activated by these self-antigens and produce increased levels of inflammatory cytokines, including type I IFN [4]. Inflammatory cytokines induce maturation of antigen presenting cells, leading to self-antigen presentation to T cells. Primed autoreactive T cells crosstalk to B cells, which in turn produce autoantibodies against self-antigens [4]. Other cytokines predominantly produced by myeloid cells, such as BLyS and APRIL, stimulate B cell proliferation and eventually autoantibody production [4]. Autoantibodies bind to self-antigens and form the immune complexes, which get deposited to various tissues and cause organ damage [4]. SLE pathogenesis is summarized into 3 major pathways: the IFN pathway (blue line), B cell pathway (orange lines), and T cell pathway (green line), with biologic therapeutics (yellow rectangles) targeting the receptors (short lines) or cytokines (green rectangles) involved in each pathway. Detailed mechanisms of action are discussed in Sect. 4 of this article. APRIL a proliferation-inducing ligand, BAFF B cell-activating factor belonging to the tumor necrosis factor family, BAFF-R BAFF receptor, BCMA B cell maturation antigen, BCR B cell receptor, BLyS B lymphocyte stimulator (also known as BAFF), CD cluster of differentiation, CD40L CD40 ligand, dsDNA double-stranded DNA, ICOS inducible T-cell co-stimulator, ICOSL inducible T-cell co-stimulator ligand, IFN interferon, IFN-αR interferon-α receptor, IL interleukin, IL-6R interleukin-6 receptor, MHCII major histocompatibility complex class II molecules, SLE systemic lupus erythematosus, ssDNA single-stranded DNA, TACI transmembrane activator and calcium modulator and cyclophilin-ligand interactor

Fig. 2

Schematic representation of the pharmacokinetic/pharmacodynamic structural model of AMG 811, IFN-γ, and CXCL10. The pharmacokinetics of AMG 811 were best described by a two-compartment model with sequential zero-order (D₁), first-order absorption (K_a), and first-order elimination. Absolute bioavailability (F₁) was estimated by simultaneously analyzing SC and IV pharmacokinetic data. R and RC represent free IFN-γ and AMG 811–IFN-γ complex compartments, respectively. The production and degradation of IFN-γ was assumed to follow the zero-order synthesis kinetics (K_syn) and the first-order elimination (K_deg), respectively. The AMG 811–IFN-γ binding affinity was estimated by quasi-steady-state approximation with the constant (K_ss) calculated as (K_off⁺-K_met)/K_on, where K_on, K_off, and K_met were the drug–target association rate constant, dissociation rate constant, and drug–target complex elimination rate constant, respectively. CXCL10 expression was induced by free IFN-γ in a linear relationship for their log-transformed values (reprinted and adapted with permission from Chen et al. [22]. Copyright 2015 Springer). CL clearance, CXCL10 IFN-γ-induced protein 10, CXCL10 ~ f(R) CXCL10 concentration change was a function of free IFN-γ, IFN interferon, IV intravenous, Q inter-compartment clearance, R₀ baseline IFN-γ concentration, SC subcutaneous, V_c central volume of distribution, V_p peripheral volume of distribution