Newly discovered data on the activity of glucocerebrosidase after treatment with Sanofi Genzyme’s Cerezyme (imiglucerase) — an enzyme replacement therapy for Gaucher disease — supports current guidelines for its administration every two weeks, according to researchers.
Their study, “Intra‑monocyte Pharmacokinetics of Imiglucerase Supports a Possible Personalized Management of Gaucher Disease Type 1,” was published in the journal Clinical Pharmacokinetics.
The development of enzyme replacement therapy (ERT) to compensate for low levels of the glucocerebrosidase enzyme in the early 1990s has revolutionized the management of Gaucher disease type 1 (GD1).
ERT regimens currently available include Cerezyme, Vpriv (velaglucerase-alfa, by Shire), and Elelyso (taliglucerase-alfa, by Pfizer).
All of these ERTs are administered by infusion every two weeks. These guidelines are based on clinical studies conducted with a similar compound. But there is no pharmacological evidence to explain the clinical effectiveness of this regimen, as the half-life of Cerezyme is estimated to be shorter than 10 minutes.
Also, studies have indicated that the recommended dosage guidelines should be individually tailored. The evidence for this comes from the fact that GD1 patients who receive the same dose will display variable outcomes.
Clinicians are also puzzled about why some patients seem to do well after they stop taking the treatment or they’re put on a lower dose. Indeed, after all parameters improve, physicians often adjust and lower the dose, which has been shown to stably control the disease.
And, after a Cerezyme shortage in 2009, only those with the most severe disease were given the drug. A follow-up study indicated that in some of those who stopped taking Cerezyme, there were no consequences for more than a year.
More knowledge of the pharmacokinetics of Cerezyme can help the community advance toward ERT personalization and cost effectiveness. Pharmacokinetics is the study of how a drug is processed in the body, including its distribution, metabolism, and excretion.
Researchers have previously shown that Cerezyme uptake by blood monocytes (a type of blood cell involved in Gaucher disease) is an appropriate method for assessing Cerezyme’s function.
Therefore, researchers measured the pharmacokinetics of Cerezyme in blood monocytes taken from 31 patients with GD1 who either started or were receiving long-term treatment with Cerezyme.
Researchers discovered that Cerezyme had a high peak followed by a decay in two phases.
Essentially, the drug has two half-lives, a fast one and a slow one. The first phase half-life is 0.36 days, and the second one is 9.7 days.
Administering Cerezyme in this manner led to a median increase in glucocerebrosidase activity in blood monocytes by 1.4-fold.
The second phase half-life of Cerezyme, which was unexpected, may explain “the observed clinical efficacy of enzyme replacement therapy, as usually administered (every 2-4 weeks).”
In patients who received long-term treatment, and for whom the Cerezyme dose guidelines per infusion were chosen on the basis of disease aggressiveness and response, the clearance of Cerezyme correlated with the dose given. So, the higher the dose, the longer it takes to be cleared from the body.
Additionally, the pre-infusion glucocerebrosidase activity in blood monocytes is largely independent of the ERT dose administered, which explains clinical studies that show that some individuals respond well at low ERT doses.
Finally, contrary to prior evidence that monocytes cannot accurately predict Gaucher disease severity, researchers found that “glucocerebrosidase intra-monocyte activity does relate to disease severity scores and can guide the decision to initiate Gaucher disease-specific treatment.”
“This study provides novel pharmacokinetic data that support current imiglucerase administration [guidelines] and suggests the existence of a glucocerebrosidase activity threshold related to Gaucher disease type 1 aggressiveness,” researchers concluded.
