Case Report: Variable Pharmacokinetic Profile of Eculizumab in an aHUS Patient

Abstract

BackgroundWith the introduction of eculizumab, a C5-inhibitor, morbidity and mortality improved significantly for patients with atypical hemolytic uremic syndrome (aHUS). In view of the high costs, actual needs of the drug, and increasing evidence in literature, aHUS patients can be treated according to a restrictive eculizumab regimen. We retrospectively analyzed the pharmacokinetic and dynamic parameters of eculizumab in one patient in time, emphasizing various factors which could be taken into account during tapering of treatment.Case PresentationA nowadays 18-year-old male with a severe, frequently relapsing form of atypical HUS due to a hybrid CFH/CFHR1 gene in combination with the homozygous factor H haplotype, required chronic plasma therapy (PT), including periods with plasma infusion, from the age of onset at 5 months until initiation of eculizumab at the age of 11 years. A mild but stable chronic kidney disease (CKD) and 9 years of disease remission enabled prolongation of eculizumab interval. At the age of 15 years, a sudden yet multifactorial progression of chronic kidney disease (CKD) was observed, without any signs of disease recurrence. However, an acquired glomerulocystic disease, a reduced left kidney function, and abnormal abdominal venous system of unknown etiology were found. In addition, after an aHUS relapse, an unexpected increase in intra-patient variability of eculizumab concentrations was seen. Retrospective pharmacokinetic analysis revealed a change in eculizumab clearance, associated with a simultaneous increase in proteinuria.ConclusionHigh intra-patient variability of eculizumab pharmacokinetics were observed over time, emphasizing the necessity for adequate and continuous therapeutic drug monitoring in aHUS patients. Eculizumab serum trough levels together with complement activation markers (CH50) should be frequently assessed, especially during tapering of drug therapy and/or changing clinical conditions in the patient. In addition, an increase in proteinuria could result in urinary eculizumab loss, indicating that urinary monitoring of eculizumab may be important in aHUS patients with an unexplained decline in serum concentrations.

Proteinuria and Exposure to Eculizumab in Atypical Hemolytic Uremic Syndrome

“…We showed a pronounced effect of proteinuria on the pharmacokinetics of eculizumab in patients with aHUS. It has been demonstrated that severe proteinuria at (or shortly after) aHUS onset is very common, 17,18 underlining the relevance of our findings. In our aHUS population, severe proteinuria was mainly seen at diagnosis but can also occur during treatment over time.…”

“…10 Previous studies showed that several monoclonal antibodies, including eculizumab, can be detected in urine of patients with severe proteinuria. [11][12][13][14] In addition, proteinuria was associated with increased clearance of various monoclonal antibodies, 13,[15][16][17] but the effect of different degrees of proteinuria on the exposure to eculizumab has not been studied.…”

Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective

“…[ 27 ] reported faster eculizumab clearance when patients had higher sC5b-9 concentrations. We recently showed a case of increased eculizumab clearance that was probably due to increased proteinuria, a condition that is not uncommon in aHUS patients [ 33 ]. Due to the high variability in PK of eculizumab, TDM is recommended to optimize therapy.…”

Case Report: Atypical HUS Presenting With Acute Rhabdomyolysis Highlights the Need for Individualized Eculizumab Dosing

“…This may also be due in part to the dose of intravenous immunoglobulin he received prior to eculizumab therapy, as it has been shown that patients receiving intravenous immunoglobulin have increased clearance of monoclonal antibodies via the neonatal Fc receptor, which results in significantly lower mean serum levels of eculizumab ( 18 ). Other factors, such as gastrointestinal bleeding and severe proteinuria, have also been suggest to affect eculizumab clearance ( 8 , 11 , 19 ). Unfortunately, one limitation of our report is that eculizumab levels, sC5b-9, and CH50 were not monitored initially in the patient's hospitalization in correlation with his worsening thrombocytopenia, though his clinical course supports that he subsequently responded to increased doses of eculizumab.…”

“…Thus, the annual cost of maintenance therapy in a patient ≥40 kg is $576,000 for drug alone, not including intravenous access and infusion costs, patient time, and quality of life. Recently, there have been a number of reports in the literature describing various factors that affect eculizumab pharmacokinetics, including varying disease severity as well as other medical co-morbidities, further highlighting the need to individualize treatment approaches (6)(7)(8)(9). However, there remains only limited, and somewhat variable, reports in the literature to guide such approaches for patients with aHUS, For example, one published strategy for cost reduction that simply reported holding eculizumab and monitoring for relapse.…”