Low-dose Preventive Therapy Yields Variable FVIII Levels, Study Reports
Preventive treatment with a low dose of factor replacement therapy in children with hemophilia A led to sufficient levels of the clotting factor in most patients, but the time in which it did so varied, a recent study reported.
Researchers noted that while findings support the use of this treatment regimen to prevent bleeds in hemophilia A patients, they also highlighted the importance of monitoring the therapy’s pharmacokinetics, or movement through each individual’s body, in order to better tailor treatment to each patient.
The study, “Pharmacokinetic profile of children with haemophilia A receiving low-dose FVIII prophylaxis in Indonesia: A single centre experience,” was published in the journal Haemophilia.
Hemophilia is a rare genetic bleeding disorder caused by the lack of proteins involved in blood clotting. In hemophilia A, the deficient blood clotting protein is called factor VIII (FVIII).
Replacement therapy to restore levels of the missing FVIII is a standard treatment approach for the condition. For many patients, it is given on an on-demand basis whenever bleeding occurs.
In countries with limited resources, the World Federation of Hemophilia instead recommends that a low dose of FVIII be administered two to three times weekly to maintain adequate blood levels of FVIII, thereby preventing bleeds from occurring. This type of preventive treatment is known as prophylaxis.
While a standard dose of 10–20 international units per kilogram of body weight (IU/kg) is recommended for this purpose, the treatment’s pharmacokinetics — its movement into, through, and out of the body — likely differs from patient to patient.
A better understanding of individual pharmacokinetic profiles could help clinicians better tailor FVIII treatment to each person in order to maximize its benefits while also being cost-efficient.
A team of researchers examined the pharmacokinetic profiles of 25 children with severe hemophilia A (FVIII levels of less than 1%). Children received low-dose FVIII therapy twice weekly at the Dr. Cipto Mangunkusumo Hospital in Indonesia.
Patients had a mean age of 12.4 years, and all had hemophilia-associated joint disease.
Blood samples were taken from each patient at four different times following FVIII replacement infusion: at a mean of 2.3 hours, 24 hours (one day), 48.1 hours (two days), and 70.9 hours (about three days) post-infusion.
Results overall showed that the pharmacokinetics of FVIII replacement therapy differed across participants. Specifically, its half-life, or the time it takes for 50% of the substance to be cleared from the blood, varied among the children.
The expected concentrations of of FVIII in the blood in the days following treatment also varied. Overall, 19 of the 25 patients achieved a FVIII level of over 1% — its target concentration — that was maintained for at least two days. FVIII levels declined below 1% after three days.
In patients for whom the half-life of FVIII was shorter, indicating a faster degradation, the decline of FVIII levels to under 1% was also faster.
These findings highlight that pharmacokinetics can and should be used to help tailor each individual’s treatment to maintain sufficient FVIII levels at all times, the researchers noted, which is especially important for those who bleed frequently.
“To tailor prophylaxis, data from individual [pharmacokinetic] profiles in our study should be combined with other factors, such as [annual joint bleeding rates], joint disease, physical activity, and adherence to prophylaxis,” the team wrote.
Adherence to the therapy schedule is critical, the researchers noted, pointing out that for every hour a patient’s FVIII level is less than 1%, the bleeding rate increases.
“Delaying infusion for a few hours can influence the time needed to reach a critical level, thus increasing the risk of a breakthrough bleed,” the researchers wrote, adding that patients in this study “were compliant but had to be encouraged to administer the FVIII concentrate according to schedule.”
This study was funded by Grifols, a company that markets FVIII replacement therapy.