A pharmacokinetic analysis of a novel enzyme replacement therapy with Gene-Activated human glucocerebrosidase (GA-GCB) in patients with type 1 Gaucher disease.
OBJECTIVE
To evaluate pharmacokinetics of Gene-Activated human glucocerebrosidase (GA-GCB), a novel enzyme replacement therapy, in patients with type 1 Gaucher disease.


METHODS
Open-label study of GA-GCB, administered as a 1-h intravenous (IV) infusion every other week was evaluated. The first three patients sequentially received one infusion each at 15 U/kg, 30 U/kg, and 60 U/kg at 2-week intervals and then continued with 60 U/kg/infusion every other week; subsequently nine more patients received GA-GCB at 60 U/kg/infusion every other week. Each patient received 20 infusions (40 weeks). Pharmacokinetic (PK) parameters reported are from blood samples collected at Weeks 1, 3, and 5 for dose-escalated patients and at Week 1 from the other nine patients.


RESULTS
GA-GCB was rapidly cleared from the circulation and followed first-order elimination kinetics in the 12 patients who received IV infusions. Maximum serum concentration (C(max)) coincided with the end of the 1-h infusion. Both C(max) and area under the curve (AUC) were linearly proportional to dose from 15 U/kg to 60 U/kg. Elimination half-life was independent of dose; mean elimination half-life at 60 U/kg was approximately 10 min (range: 4-15 min). Mean serum clearance was 13 ml/min/kg (range: 9-20 ml/min/kg) and V(ss) (apparent volume of distribution) was approximately 18% body weight (range: 11-27% body weight).


CONCLUSIONS
GA-GCB demonstrated linear PK parameters over clinically relevant doses (15 U/kg-60 U/kg) indicating that the dose of IV-administered GA-GCB to target tissues should also be linearly proportional to dose.
Zimran
Ari
A
Gaucher Clinic, Shaare Zedek Medical Center, POB 3235, Jerusalem 91031, Israel.
Loveday
Kenneth
K
Fratazzi
Candida
C
Elstein
Deborah
D
D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005776:Gaucher Disease / Q000097:blood* / Q000188:drug therapy*; D005962:Glucosylceramidase / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D013997:Time Factors
D005962:Glucosylceramidase