Gaucher Disease
Conditions
Keywords
Gaucher disease, Imiglucerase, Pharmacokinetics
Brief summary
Rational: Imiglucerase has been used to treat Gaucher disease since 1997 but data about its pharmacokinetics have been partial; investigators know that imiglucerase undergoes a quick clearance from plasma compartment following the infusion (1/2 life: 1-6 min, from tissue: \<24h), an observation apparently contradictory with usual infusion rhythm (one infusion every two weeks). Furthermore, by going by GD response, the rhythm of Infusion is sometimes diminished (for example, every 3 or 4 wks) without pharmacological rational ; In parallel, investigators demonstrated that monocytes represent a satisfactory surrogate of GD target cells and that enzyme activity into monocytes varies between individuals. Our hypothesis is that enzyme activity into monocyte compartment could be different and could be related to GD response. Primary purpose: to evaluate the pharmacokinetics of Imiglucerase activity into target cellular compartment depending on dose and frequency of infusions. Secondary purposes : 1) to establish a possible relationship between the intra-monocytic activity of glucocerebrosidase and the clinical and biological activity of Gaucher disease and to define a possible threshold value of enzyme activity; 2) to establish a better correlation with known biomarkers of disease (routine markers and markers recently identified), which would better predict and / or monitor response to treatment ; 3) to compare the residual and natural rate of activity enzyme intra-monocytic for untreated patients (low severity disease).
Detailed description
Rational: Imiglucerase has been used to treat Gaucher disease since 1997 but data about its pharmacokinetics have been partial; investigators know that imiglucerase undergoes a quick clearance from plasma compartment following the infusion (1/2 life: 1-6 min, from tissue: \<24h), an observation apparently contradictory with usual infusion rhythm (one infusion every two weeks). Furthermore, by going by GD response, the rhythm of Infusion is sometimes diminished (for example, every 3 or 4 wks) without pharmacological rational ; In parallel, investigators demonstrated that monocytes represent a satisfactory surrogate of GD target cells and that enzyme activity into monocytes varies between individuals. Our hypothesis is that enzyme activity into monocyte compartment could be different and could be related to GD response. Primary purpose: to evaluate the pharmacokinetics of Imiglucerase activity into target cellular compartment depending on dose and frequency of infusions. Secondary purposes : 1) to establish a possible relationship between the intra-monocytic activity of glucocerebrosidase and the clinical and biological activity of Gaucher disease and to define a possible threshold value of enzyme activity; 2) to establish a better correlation with known biomarkers of disease (routine markers and markers recently identified), which would better predict and / or monitor response to treatment ; 3) to compare the residual and natural rate of activity enzyme intra-monocytic for untreated patients (low severity disease).
Interventions
DRUGImiglucérase (drug) pharmacokinetics
Sponsors
University Hospital, Clermont-Ferrand
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient older than 12 years old with Gaucher disease type 1 or type 3 and having signed an informed consent * Treated with imiglucerase (Cerezyme ®) with a stable therapeutic strategy for at least 3 months. OR * Untreated patient, with no therapeutic indication at the time of inclusion and having a diagnosis older than 2 years (non progressive disease) * Patients must have a social security system
Exclusion criteria
* Age \<12 years old * Gaucher disease unproven * Gaucher disease treated with therapeutic changes in the previous 3 months, or current treatment different from imiglucerase * Gaucher disease untreated whose diagnosis was established for under 2 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Enzyme intra-monocyte activity (sum of endogenous enzyme activities and therapeutic enzyme)in patients treated with imiglucerase | at day 1 | Enzyme intra-monocyte activity (sum of endogenous enzyme activities and therapeutic enzyme) in patients treated with imiglucerase will be assessed at different times between infusions (8 to 10 time points), and just before an infusion (residual rate). The population pharmacokinetics method allows to perform this analysis in measurement windows that are not necessarily included in the period between two consecutive infusions of imiglucerase but may be spread over several cycles. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Residual rate | every 6 months during 2 years. | Pharmacokinetics descriptive criteria are the area under curve at balance, the terminal half-life and the residual rate. |
| Endogeneous intra-monocyte glucocérébrosidase activity from untreated patients | every 6 months during 2 years | — |
| Biomarker dosages will provide serum concentration values | at D0, M3, M6 and every 6 months during 2 years: | 1\) routine biomarkers (ACE, TRAP, chitotriosidase, ferritin) and 2) potentially interesting biomarkers but not routinely evaluated in France (CCL18, MIP1a, MIP1b, MCP1, IL-8, glycated ferritin). \- Gaucher disease status will be assessed by clinical and biological criteria defined by the HAS (Haute Autorité de Santé = High Health Authority). We will consider the two-year periods before and after treatment to identify progressive diseases (clinical or biological significant events associated with Gaucher disease in the two years before and 2 years after the enrolment time |
Countries
France
Contacts
Primary ContactPatrick LACARIN
Outcome results
None listed