Extending the dosing interval of Soliris (eculizumab) maintenance treatment from standard two weeks to three weeks may equally achieve therapeutic blood levels in most adults with atypical hemolytic uremic syndrome (aHUS), a study suggests.
The findings are based on a Soliris pharmacokinetic model, which considers its movement into, through, and out of the body, and on monitoring of therapy levels in the blood. They support a personalized Soliris dosing schedule in this patient population, which can reduce treatment burden and costs.
The study, “Feasibility and safety of tailored dosing schedule for eculizumab based on therapeutic drug monitoring: lessons from a prospective multicentric study,” was published in the British Journal of Clinical Pharmacology.
Developed and marketed by Alexion, Soliris is an approved treatment for aHUS that specifically targets a component (the C5 protein) of the complement system — a part of the immune system chronically and uncontrollably activated in aHUS patients.
By blocking C5’s activity, Soliris prevents small blood vessel destruction, formation of blood clots, and consequent organ damage — all hallmark features of this rare disease.
The therapy is administered intravenously (directly into the bloodstream) and comprises an induction phase of once-weekly treatments, followed by a maintenance phase in which Soliris is given every other week.
However, increasing evidence points to Soliris overexposure in a large proportion of aHUS patients when considering the target trough level of 50–100 mg/L and some case studies reported the benefits of an every-three-weeks maintenance regimen. (Trough levels are the lowest therapy levels before the next dose is administered.)
Soliris dosing optimization is particularly relevant due to its high cost (more than $500,000 per year) and need for biweekly doses — potentially for a lifetime — representing a high economic and physical burden to aHUS patients.
Now, researchers in France evaluated the feasibility of personalizing Soliris dosing schedules in 36 adults with aHUS and four adults with C3 glomerulopathy (another complement system-related disease) who were followed at six French hospitals.
Patients’ mean age was 43 years (range, 20–75 years), most were women (70%) and had received a previous kidney transplant (80%); 80% were receiving the standard Soliris dosing schedule of 1,200 mg every other week.
To identify patients who could benefit from an interval extension between Soliris doses, the team developed a pharmacokinetic population model based on Soliris trough levels.
Results showed that all participants had mean Soliris trough levels higher than the target value of 100 mg/L (range, 124–1,065 mg/L), of whom 35 (87.5%) had more than 200 mg/L and 26 (65%) more than 400 mg/L.
Further analyses highlighted that body weight was the most important factor influencing Soliris clearance from the body, followed by sex, with men showing higher clearance than women.
At the recommended maintenance dosing schedule, Soliris trough levels were very likely to be more than 100 mg/L in women weighing up to 90 kg (about 198.4 pounds), but less than target levels in men weighing 90 kg or more.
These findings suggested that monitoring Soliris trough levels “may be useful even without an interval extension,” the researchers wrote.
Additional simulations predicted that 90% of participants would still have Soliris trough levels higher than 100 mg/L with a one‐week longer interval between doses.
Such interval extension was performed in 15 of these patients and in an additional eligible patient who did not participate in the first part of the study. The interval was extended to every three weeks in 12 patients (80%) and to every four weeks in three (20%) of them.
Results showed that 10 (67%) of the 15 patients had Soliris trough levels greater than 100 mg/L after interval lengthening; nine were receiving Soliris every three weeks and one every four weeks.
No biological or clinical disease relapse was observed, even in the five patients with trough levels less than 100 mg/L, in whom the initial dosing regimen was resumed.
The team noted that the model resulted in a slight overestimation for Soliris trough levels below 200 mg/L and that additional trough level data may help in the development of a better predictive model.
“Our prospective multicenter study establishes, for the first time, that therapeutic [dose] monitoring of [Soliris] in patients with aHUS is feasible and allows for safe personalization of the infusion interval during maintenance phase, with expected important cost savings and improved quality-of-life,” the researchers wrote.
They also noted that in France, extending the dosing interval from two to three weeks would save €128,835 (almost $153,000) per patient per year.
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