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

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• 作者：Tian Yu ; Elena Y. Enioutina ; Hermine I. Brunner…
• 刊名：Clinical Pharmacokinetics
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：56
• 期：2
• 页码：107-125
• 全文大小：
• 刊物主题：Pharmacotherapy; Pharmacology/Toxicology; Internal Medicine;
• 出版者：Springer International Publishing
• ISSN：1179-1926
• 卷排序：56

文摘

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.