A pharmacokinetic analysis of a novel enzyme replacement therapy with Gene-Activated® human glucocerebrosidase (GA-GCB) in patients with type 1 Gaucher disease

Abstract Objectives To evaluate pharmacokinetics of Gene-Activated® human glucocerebrosidase (GA-GCB), a novel enzyme replacement therapy, in patients with type 1 Gaucher disease. Study design 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 ∼ 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.