Population Pharmacokinetic Modeling of LY2189102 after Multiple Intravenous and Subcutaneous Administrations
| Autor: | Joanne Sloan-Lancaster, Eyas Raddad, Sebastien Bihorel, Elizabeth Ludwig, Jill Fiedler-Kelly |
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| Rok vydání: | 2014 |
| Předmět: |
Metabolic Clearance Rate
Injections Subcutaneous Population Anti-Inflammatory Agents Biological Availability Pharmaceutical Science Arthritis Renal function Pharmacology Antibodies Monoclonal Humanized Models Biological Drug Administration Schedule Arthritis Rheumatoid Humans Hypoglycemic Agents Medicine Distribution (pharmacology) Drug Dosage Calculations Dosing education Randomized Controlled Trials as Topic education.field_of_study business.industry medicine.disease Bioavailability Treatment Outcome Diabetes Mellitus Type 2 Rheumatoid arthritis Injections Intravenous Monoclonal Linear Models business Half-Life Research Article |
| Zdroj: | The AAPS Journal. 16:1009-1017 |
| ISSN: | 1550-7416 |
| Popis: | Interleukin-1 beta (IL-1β) is an inflammatory mediator which may contribute to the pathophysiology of rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). Population pharmacokinetics (PK) of LY2189102, a high affinity anti-IL-1β humanized monoclonal immunoglobulin G4 evaluated for efficacy in RA and T2DM, were characterized using data from 79 T2DM subjects (Study H9C-MC-BBDK) who received 13 weekly subcutaneous (SC) doses of LY2189102 (0.6, 18, and 180 mg) and 96 RA subjects (Study H9C-MC-BBDE) who received five weekly intravenous (IV) doses (0.02–2.5 mg/kg). Frequency of anti-drug antibody (ADA) development appears dose-dependent and is different between studies (36.7% in Study H9C-MC-BBDK vs. 2.1% in Study H9C-MC-BBDE), likely due to several factors, including differences in patient population and background medications, administration routes, and assays. A two-compartment model with dose-dependent bioavailability best characterizes LY2189102 PK following IV and SC administration. Typical elimination and distribution clearances, central and peripheral volumes of distribution are 0.222 L/day, 0.518 L/day, 3.08 L, and 1.94 L, resulting in a terminal half-life of 16.8 days. Elimination clearance increased linearly, yet modestly, with baseline creatinine clearance and appears 37.6% higher in subjects who developed ADA. Bioavailability (0.432–0.721) and absorption half-life (94.3–157 h) after SC administration are smaller with larger doses. Overall, LY2189102 PK is consistent with other therapeutic humanized monoclonal antibodies and is likely to support convenient SC dosing. |
| Databáze: | OpenAIRE |
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