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.

• Authors: Tian Yu, Elena Y Enioutina, Hermine I Brunner, Alexander A Vinks, Catherine M Sherwin
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 56 Issue 2 Pg. 107-125 (02 2017) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 27384528 (Publication Type: Journal Article, Review)

Chemical References

• Antibodies, Monoclonal
• Biological Products

Topics

• Antibodies, Monoclonal (pharmacokinetics, pharmacology, therapeutic use)
• B-Lymphocytes (drug effects, metabolism)
• Biological Products (pharmacokinetics, pharmacology, therapeutic use)
• Female
• Humans
• Lupus Erythematosus, Systemic (drug therapy, metabolism)
• Male
• T-Lymphocytes (drug effects, metabolism)
• Treatment Outcome