@article{2a0683fe7c7a430c960c54d6a37aaf9d,
title = "Population pharmacokinetics of subcutaneous C1-inhibitor for prevention of attacks in patients with hereditary angioedema",
abstract = "Background: Long-term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma-derived C1-esterase inhibitor (C1-INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention. Objective: To characterize the population pharmacokinetics of C1-INH (SC) (HAEGARDA{\textregistered}; CSL Behring) in healthy volunteers and HAE patients, and assess the variability and influence of covariates on pharmacokinetics. Methods: C1-INH functional activity data obtained after administration of various C1-INH (intravenous; IV) and C1-INH (SC) doses from 1 study in healthy volunteers (n = 16) and 2 studies in subjects with HAE (n = 108) were pooled to develop a population pharmacokinetic model (NONMEM v7.2). Pharmacokinetic parameters derived from steady-state simulations based on the final model were also evaluated. Results: C1-INH functional activity following C1-INH (SC) administration was described by a linear one-compartment model with first-order absorption and elimination, with inter-individual variability in all parameters tested. The mean population bioavailability of C1-INH (SC), and pharmacokinetic parameters for clearance (CL), volume of distribution, and absorption rate were estimated to be ~43%, 1.03 mL/hour/kg, 0.05 L/kg and 0.0146 hour−1, respectively. The effect of bodyweight on CL of C1-INH functional activity was included in the final model, estimated to be 0.74. Steady-state simulations of C1-INH functional activity vs time profiles in 1000 virtual HAE patients revealed higher minimum functional activity (Ctrough) levels after twice-weekly dosing with 40 IU/kg (~40%) and 60 IU/kg (~48%) compared with 1000 IU IV (~30%). Based on the population pharmacokinetic model, the median time to peak concentration was ~59 hours and the median apparent plasma half-life was ~69 hours. Conclusions and Clinical Relevance: Twice-weekly bodyweight-adjusted dosing of C1-INH (SC) exhibits linear pharmacokinetics and dose-dependent increases in Ctrough levels at each dosing interval. In this analysis, SC dosing led to maintenance of higher Ctrough levels than IV dosing.",
keywords = "angioedema, clinical immunology, prevention",
author = "Dipti Pawaskar and Tortorici, {Michael A.} and Bruce Zuraw and Timothy Craig and Marco Cicardi and Hilary Longhurst and Li, {H. Henry} and Lumry, {William R.} and Inmaculada Martinez-Saguer and Joshua Jacobs and Bernstein, {Jonathan A.} and Riedl, {Marc A.} and Katelaris, {Constance H.} and Keith, {Paul K.} and Annette Feussner and Jagdev Sidhu",
note = "Funding Information: DP, MT, AF and JS are employees of CSL Behring. BZ has acted as a paid consultant to Adverum, Alnylam, BioCryst, CSL Behring, Novar-tis, Sanofi and Shire, and has received or may receive funding from Shire and Ionis, unrelated to this work. TC has received fees from CSL Behring for speaking and consulting. MC has received consulting and speaker fees, and for attending symposia from Shire, CSL Behring and Pharming. He has also received funds for research from Shire and Pharming, and consulting fees from BioCryst and Adverum. HL received funding to attend conferences and educational events, has acted as a medical advisor or speaker, has received departmental funding, has received financial and other assistance with patient care projects and has participated in clinical trials with the following companies: Adverum, BioCryst, CSL Behring, Kalvista, and Pharming and Shire (Dyax). HHL has acted as a paid consultant and speaker to CSL Behring and has received funding for research carried out in this work. WL reports consultant fees from Adverum, BioCryst, CSL Behring and Shire, as well as speakers{\textquoteright} fees from CSL Behring and Shire. He also reports grants and research support from Hereditary Angioedema Association and BioCryst, CSL Behring, Circassia and Shire. IMS has no conflicts of interest to declare. JJ has acted as a paid consultant, speaker and researcher for Shire PLC and CSL Behring. He has also acted as a paid consultant and speaker for Pharming and a researcher for BioCryst. JB has received consultancy fees from Shire, CSL Behring and Biocryst; has received research support from Shire; has received lecture fees from Shire, Pharming and CSL Behring; and is a HAEA organization Medical Advisory Board member. MAR reports funding for research related to this work. Unrelated to this work he reports research funding from BioCryst, Pharming, Shire, as well as consultant fees from Adverum, Alnylam, BioCryst, CSL Behring, Kalvista, Pharming, Shire and speaker honorarium from CSL Behring, Pharming and Shire. CHK has received honoraria for presentations and for Advisory Board work. She has also received institutional funding for clinical trials. PKK has received fees for speaking and consulting, as well as research grants from CSL Behring and Shire. Funding Information: This study was sponsored by CSL Behring. Editorial assistance was provided by Succinct Medical Communications, with financial support from CSL Behring. Publisher Copyright: {\textcopyright} 2018 CSL Behring. Clinical & Experimental Allergy Published by John Wiley & Sons Ltd",
year = "2018",
month = oct,
doi = "10.1111/cea.13220",
language = "English (US)",
volume = "48",
pages = "1325--1332",
journal = "Clinical Allergy",
issn = "0954-7894",
publisher = "Wiley-Blackwell",
number = "10",
}