title: 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.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, SLC, Utah 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Yu
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, SLC, Utah 295 Chipeta Way, Salt Lake City, UT, 84108, USA.|Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Enioutina
authors.affiliation: Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Hermine I
authors.initials: HI
authors.lastname: Brunner
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, SLC, Utah 295 Chipeta Way, Salt Lake City, UT, 84108, USA. Catherine.sherwin@hsc.utah.edu.|Department of Pediatrics, Clinical Trials Office, Salt Lake City, UT, USA. Catherine.sherwin@hsc.utah.edu.|Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA. Catherine.sherwin@hsc.utah.edu.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Sherwin
mesh_terms: D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001688:Biological Products / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D001688:Biological Products