Population Pharmacokinetic Modeling of LY2189102 after Multiple Intravenous and Subcutaneous Administrations
- 333 Downloads
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.
KEY WORDSinterleukin-1 beta (IL-1β) LY2189102 population pharmacokinetics
- 2.Kineret (anakinra) [package insert]. Stockholm, Sweden: Swedish Orphan Biovitrum AB; 2012. http://www.kineretrx.com/fileadmin/user_upload/kineretus/documents/Kineret_Full_Prescribing_Information.pdf. Published Dec 2012. Accessed 20 Feb 2014.
- 3.Kineret (anakinra). Summary of product characteristics. 2002. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000363/WC500042310.pdf. Accessed 20 Feb 2014.
- 4.Donath MY, Weder C, Whitmore J, Bauer RJ, Der K, Scannon PJ, et al. XOMA 052, an anti–IL–1β antibody, in a double-blind, placebo-controlled, dose escalation study of the safety and pharmacokinetics in patients with type 2 diabetes mellitus—a new approach to therapy. Diabetologia. 2008;51 Suppl 1:S7.Google Scholar
- 9.Maedler K, Storling J, Sturis J, Zuellig RA, Spinas GA, Arkhammar PO, et al. Glucose–and interleukin–1beta induced beta–cell apoptosis requires Ca2+ influx and extracellular signal–regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets. Diabetes. 2004;53(7):1706–13.PubMedCrossRefGoogle Scholar
- 11.Sloan-Lancaster J, Abu-Raddad E, Polzer J, Miller JW, Scherer JC, De Gaetano A, et al. Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1β antibody, in patients with type 2 diabetes. Diabetes Care. 2013;36(8):2239–46.PubMedCentralPubMedCrossRefGoogle Scholar
- 12.Abu-Raddad E, DeGaetano A, Bihorel S, Fiedler-Kelly J, Sloan-Lancaster J. Pharmacokinetic (PK) and pharmacodynamic (PD) modeling of subcutaneous (SC) LY2189102, a neutralizing IL–1β antibody, in patients with type 2 diabetes mellitus. Diabetologia. 2011;54 Suppl 1:S366.Google Scholar
- 14.NONMEM [computer program]. Version VI. Ellicott City, MD: ICON Development Solutions; 2006.Google Scholar
- 16.Peck CC, Conner DP, Murphy MG. Bedside clinical pharmacokinetics: Simple techniques for individualized drug therapy. Vancouver: Applied Therapeutics, Inc; 1989.Google Scholar
- 18.R Development Core Team (2010). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org.
- 28.Deng R, Loyet KM, Lien S, Iyer S, DeForge LE, Theil FP, et al. Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-α antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys. Drug Metab Dispos. 2010;38(4):600–5. doi: 10.1124/dmd.109.031310.PubMedCrossRefGoogle Scholar
- 33.Food and Drug Administration. Guidance for industry: immunogenicity assessment for therapeutic protein products (draft guidance). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM338856.pdf. Published Feb 2013. Accessed 22 May 2013.
- 34.Goldsby RA, Kindt TJ, Osborne BA, Kuby J. Antigens. In: Goldsby RA, Kindt TJ, Kuby J, Osborne BA, editors. Immunology. 5th ed. New York: WH Freeman & Co Publishers; 2002. p. 57–75.Google Scholar