Exposure-Response Model of Subcutaneous C1-Inhibitor Concentrate to Estimate the Risk of Attacks in Patients With Hereditary Angioedema
Open Access
- 9 January 2018
- journal article
- research article
- Published by Wiley in CPT: Pharmacometrics & Systems Pharmacology
- Vol. 7 (3), 158-165
- https://doi.org/10.1002/psp4.12271
Abstract
Subcutaneous C1‐inhibitor (HAEGARDA, CSL Behring), is a US Food and Drug Administration (FDA)‐approved, highly concentrated formulation of a plasma‐derived C1‐esterase inhibitor (C1‐INH), which, in the phase III Clinical Studies for Optimal Management in Preventing Angioedema with Low‐Volume Subcutaneous C1‐inhibitor Replacement Therapy (COMPACT) trial, reduced the incidence of hereditary angioedema (HAE) attacks when given prophylactically. Data from the COMPACT trial were used to develop a repeated time‐to‐event model to characterize the timing and frequency of HAE attacks as a function of C1‐INH activity, and then develop an exposure–response model to assess the relationship between C1‐INH functional activity levels (C1‐INH(f)) and the risk of an attack. The C1‐INH(f) values of 33.1%, 40.3%, and 63.1% were predicted to correspond with 50%, 70%, and 90% reductions in the HAE attack risk, respectively, relative to no therapy. Based on trough C1‐INH(f) values for the 40 IU/kg (40.2%) and 60 IU/kg (48.0%) C1‐INH (SC) doses, the model predicted that 50% and 67% of the population, respectively, would see at least a 70% decrease in the risk of an attack.Keywords
This publication has 11 references indexed in Scilit:
- Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 InhibitorNew England Journal of Medicine, 2017
- Repeated Time-to-event Analysis of Consecutive Analgesic Events in Postoperative PainAnesthesiology, 2015
- Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1‐inhibitor concentrateAllergy, 2015
- US Hereditary Angioedema Association Medical Advisory Board 2013 Recommendations for the Management of Hereditary Angioedema Due to C1 Inhibitor DeficiencyThe Journal of Allergy and Clinical Immunology: In Practice, 2013
- A Time to Event Tutorial for PharmacometriciansCPT: Pharmacometrics & Systems Pharmacology, 2013
- WAO Guideline for the Management of Hereditary AngioedemaWorld Allergy Organization Journal, 2012
- Performance of Three Estimation Methods in Repeated Time-to-Event ModelingThe AAPS Journal, 2011
- Hereditary AngioedemaNew England Journal of Medicine, 2008
- Efficient screening of covariates in population models using Wald's approximation to the likelihood ratio test.Journal of Pharmacokinetics and Pharmacodynamics, 2001
- Quantification of Cl-Inhibitor Functional Activities by Immunodiffusion Assay in Plasma of Patients with Hereditary Angioedema - Evidence of a Functionally Critical Level of Cl-Inhibitor ConcentrationComplement (Basel, Switzerland), 1984