The Pharmacokinetics and Pharmacodynamics of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria (PREPARE)

Because of the inter and intra individual variability in pharmacokinetics and pharmacodynamics of eculizumab in PNH patients, a tailored treatment approach for the individual is probably preferable. The starting point of a robust tailored dosing approach for eculizumab is the development of a population pharmacokinetic-pharmacodynamic model. In this cross-sectional observational pharmacokinetic and pharmacodynamic study, trough and peak concentrations of eculizumab are measured to describe the pharmacokinetics and complement activation markers to describe the pharmacodynamics.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria; Eculizumab; PK-PD
• Intervention / Treatment: Other: Blood collection for measurement of eculizumab peak concentrations

Detailed Description

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder which is characterized by hemolytic anemia, cytopenias and thrombosis. PNH is caused by clonal expansion of hematopoietic stem cells with an acquired somatic mutation in the X-linked phosphatidylinositol glycan class A gene (4). This gene encodes a protein required for synthesis of glycosylphosphatidylinositol (GPI) anchors. As a result of the mutation, affected stem cells are deficient in GPI anchored proteins. Clonal expansion leads to the production of hematological cells lacking the expression of GPI anchored complement regulatory proteins CD55 and CD59.

This leads to chronic complement-mediated hemolysis of the GPI-deficient erythrocytes. Eculizumab is a humanized chimeric monoclonal anti-C5 inhibitor which is approved for the treatment of PNH and was the first licensed drug targeting the complement system. By binding to C5, eculizumab prevents the activation of C5 into C5a and C5b and subsequent the formation of the terminal complement complex C5b-9. Eculizumab is currently administered in a flat fixed dose for every patient. However, because of the inter and intra individual variability in pharmacokinetics and pharmacodynamics of eculizumab in PNH patients, a tailored treatment approach for the individual is probably preferable. We have recently shown, by means of pharmacokinetic modelling and simulation, based on the drug approval data, that eculizumab dosing in PNH patients can be successfully tailored by means of Therapeutic Drug Monitoring.

This approach when implemented in practice will result in overall less pharmacokinetic variability, less under-treatment and an average dose reduction of 11%. It should be noted that the yearly eculizumab drug costs are about 400.000 euro per patient. Considering the fact that in the Netherlands alone approximately 60 patients with PNH are yearly treated with this drug, this indicates that development of a model-informed precision dosing tool based on the actual pharmacokinetics and pharmacodynamics of eculizumab has the potential to decrease treatment costs with 2.640.000 euro on a yearly basis. The starting point of a robust tailored dosing approach for eculizumab is the development of a population pharmacokinetic-pharmacodynamic model. The majority of the pharmacokinetic and pharmacodynamic data in PNH patients are derived from controlled clinical studies and may not be representative for general PNH patient population. Therefore, it is pivotal to collect more pharmacokinetic and pharmacodynamic data in PNH patients in the actual clinical setting.

This study is a cross-sectional observational pharmacokinetic study in which we collect trough and peak concentrations of eculizumab to describe the pharmacokinetics and complement activation markers to describe the pharmacodynamics. With this data, a pharmacokinetic-pharmacodynamic model will be developed.

• Study Type: Observational
• Enrollment (Actual): 27

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands
    • Radboudumc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

PNH patients treated with eculizumab

Description

Inclusion Criteria:

• Diagnosis of PNH
• Treated with eculizumab
• Willing to give informed consent

Exclusion Criteria:

• Not applicable

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with paroxysmal nocturnal hemoglobinuria; Patients are already treated with eculizumab. The only intervention is the collection of extra blood samples to measure peak concentrations of eculizumab	Other: Blood collection for measurement of eculizumab peak concentrations; collection of blood; Other Names: blood collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clearance	Peak and trough concentrations will be measured in order to determine clearance	9 months
Volume of distribution	Peak and trough concentrations will be measured in order to determine volume of distribution	9 months

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2021
• Primary Completion (Actual): July 1, 2022
• Study Completion (Actual): July 1, 2022

Study Registration Dates

• First Submitted: July 11, 2019
• First Submitted That Met QC Criteria: September 4, 2019
• First Posted (Actual): September 6, 2019

Study Record Updates

• Last Update Posted (Actual): August 24, 2022
• Last Update Submitted That Met QC Criteria: August 23, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: PREPARE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No