Skip to main content
Top
Published in: Rheumatology and Therapy 3/2024

Open Access 25-04-2024 | Hemophagocytic Lymphohistiocytosis | Brief Report

Population Pharmacokinetics of the Anti-Interferon-Gamma Monoclonal Antibody Emapalumab: An Updated Analysis

Authors: Patrick Brossard, Christian Laveille

Published in: Rheumatology and Therapy | Issue 3/2024

Login to get access

Abstract

Introduction

Emapalumab is a fully human monoclonal antibody that targets free and receptor-bound interferon-gamma (IFNγ), neutralizing its biological activity. IFNγ levels differ by orders of magnitude between patients with primary hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS; a form of secondary HLH) in systemic juvenile idiopathic arthritis (sJIA). Therefore, this study aimed to develop a population pharmacokinetic model for emapalumab across a patient population with a wide range of total (free and emapalumab-bound) IFNγ levels using observations from patients with primary HLH or MAS in sJIA in clinical trials.

Methods

Pharmacokinetic data were pooled (n = 58; 2709 observations) from studies enrolling patients administered emapalumab for primary HLH or MAS in sJIA. Patients with primary HLH were administered emapalumab 1 mg/kg (potentially increasing to 3, 6, and up to 10 mg/kg based on clinical response) every 3 days. Patients with MAS in sJIA were administered emapalumab 6 mg/kg, followed by 3 mg/kg every 3 days until day 15 and twice weekly until day 28. An earlier population PK model was re-parameterized using this data.

Results

The final model for emapalumab comprised a 2-compartment model with first-order elimination. Emapalumab clearance remains constant when the total IFNγ concentration (free and emapalumab-bound) is < ~ 10,000 pg/ml but increases proportionally to total IFNγ concentration above this threshold. Emapalumab clearance was estimated to be 0.00218, 0.00308, 0.00623 and 0.01718 l/h at total serum IFNγ concentrations of 103, 104, 105 and 106 pg/ml, respectively, with corresponding terminal half-lives of 19.2, 13.8, 7.18 and 3.12 days for a 1-year-old patient weighing 10 kg with primary HLH. The median terminal half-life for emapalumab in patients with MAS in sJIA was estimated to be 24.0 (range, 6.13–32.4) days, which is similar to observations in healthy volunteers.

Conclusions

Emapalumab pharmacokinetics in patients with primary HLH and MAS in sJIA were described by a two-compartment model with fixed allometric exponents and an age-related effect. Differences in total IFNγ levels between patients with primary HLH and MAS may affect emapalumab pharmacokinetics, suggesting that each indication may require different dosing to rapidly control hyperinflammation.

Trial registration

Clinicaltrials.gov identifiers: NCT01818492, NCT03311854 and NCT02069899.
Appendix
Available only for authorised users
Literature
1.
go back to reference Allen CE, McClain KL. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematol Am Soc Hematol Educ Prog. 2015;2015:177–82.CrossRef Allen CE, McClain KL. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematol Am Soc Hematol Educ Prog. 2015;2015:177–82.CrossRef
2.
go back to reference Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: Pathogenesis and treatment. Hematol Am Soc Hematol Educ Prog. 2013;2013:605–11.CrossRef Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: Pathogenesis and treatment. Hematol Am Soc Hematol Educ Prog. 2013;2013:605–11.CrossRef
4.
go back to reference La Rosee P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133:2465–77.CrossRefPubMed La Rosee P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133:2465–77.CrossRefPubMed
5.
go back to reference Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood. 2015;125:2908–14.CrossRefPubMed Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood. 2015;125:2908–14.CrossRefPubMed
6.
go back to reference Hines MR, von Bahr GT, Beutel G, et al. Consensus-based guidelines for the recognition, diagnosis, and management of hemophagocytic lymphohistiocytosis in critically ill children and adults. Crit Care Med. 2022;50:860–72.CrossRefPubMed Hines MR, von Bahr GT, Beutel G, et al. Consensus-based guidelines for the recognition, diagnosis, and management of hemophagocytic lymphohistiocytosis in critically ill children and adults. Crit Care Med. 2022;50:860–72.CrossRefPubMed
7.
go back to reference Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383:1503–16.CrossRefPubMed Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383:1503–16.CrossRefPubMed
8.
go back to reference Jordan MB. Hemophagocytic lymphohistiocytosis: A disorder of T cell activation, immune regulation, and distinctive immunopathology. Immunol Rev. 2024;322:339–50.CrossRefPubMed Jordan MB. Hemophagocytic lymphohistiocytosis: A disorder of T cell activation, immune regulation, and distinctive immunopathology. Immunol Rev. 2024;322:339–50.CrossRefPubMed
11.
12.
go back to reference Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol. 2007;96:41–101.PubMed Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol. 2007;96:41–101.PubMed
13.
go back to reference Jacqmin P, Laveille C, Snoeck E, et al. Emapalumab in primary haemophagocytic lymphohistiocytosis and the pathogenic role of interferon gamma: a pharmacometric model-based approach. Br J Clin Pharmacol. 2022;88:2128–39.CrossRefPubMed Jacqmin P, Laveille C, Snoeck E, et al. Emapalumab in primary haemophagocytic lymphohistiocytosis and the pathogenic role of interferon gamma: a pharmacometric model-based approach. Br J Clin Pharmacol. 2022;88:2128–39.CrossRefPubMed
14.
go back to reference Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382:1811–22.CrossRefPubMed Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382:1811–22.CrossRefPubMed
15.
go back to reference De Benedetti F, Grom AA, Brogan PA, et al. Efficacy and safety of emapalumab in macrophage activation syndrome. Ann Rheum Dis. 2023;82:857–65.CrossRefPubMed De Benedetti F, Grom AA, Brogan PA, et al. Efficacy and safety of emapalumab in macrophage activation syndrome. Ann Rheum Dis. 2023;82:857–65.CrossRefPubMed
17.
go back to reference Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976;58:259–63.CrossRefPubMed Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976;58:259–63.CrossRefPubMed
18.
go back to reference Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.CrossRefPubMed Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.CrossRefPubMed
19.
20.
go back to reference Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13:143–51.CrossRefPubMedPubMedCentral Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13:143–51.CrossRefPubMedPubMedCentral
21.
go back to reference Jordan MB, Locatelli F. Exposure–safety relationship for patients with primary hemophagocytic lymphohistiocytosis treated with emapalumab. Pediatr Blood Cancer. 2023:e30778. Jordan MB, Locatelli F. Exposure–safety relationship for patients with primary hemophagocytic lymphohistiocytosis treated with emapalumab. Pediatr Blood Cancer. 2023:e30778.
Metadata
Title
Population Pharmacokinetics of the Anti-Interferon-Gamma Monoclonal Antibody Emapalumab: An Updated Analysis
Authors
Patrick Brossard
Christian Laveille
Publication date
25-04-2024
Publisher
Springer Healthcare
Published in
Rheumatology and Therapy / Issue 3/2024
Print ISSN: 2198-6576
Electronic ISSN: 2198-6584
DOI
https://doi.org/10.1007/s40744-024-00669-y

Other articles of this Issue 3/2024

Rheumatology and Therapy 3/2024 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Webinar | 06-02-2024 | 20:00 (CET)

Mastering chronic pancreatitis pain: A multidisciplinary approach and practical solutions

Severe pain is the most common symptom of chronic pancreatitis. In this webinar, experts share the latest insights in pain management for chronic pancreatitis patients. Experts from a range of disciplines discuss pertinent cases and provide practical suggestions for use within clinical practice.

Sponsored by: Viatris

Developed by: Springer Healthcare