Chemical formula: C₂₅₈₀H₃₉₁₈N₆₈₀O₇₂₇S₁₇
Gaucher disease is an autosomal recessive disorder caused by mutations in the human glucocerebrosidase gene, which results in a reduced activity of the lysosomal enzyme glucocerebrosidase. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency results in accumulation of substrate glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam cells or “Gaucher cells”, which accumulate in the liver, spleen and bone marrow.
Taliglucerase alfa, a long term enzyme replacement therapy, is a recombinant analog of human lysosomal glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, reducing the amount of accumulated glucocerebroside. Taliglucerase alfa uptake into cellular lysosomes is mediated by binding of taliglucerase alfa mannose oligosaccharide chains to specific mannose receptors on the cell surface leading to internalization and subsequent transport to the lysosomes.
Pharmacokinetics of taliglucerase alfa were evaluated in 38 patients (29 adult and 9 pediatric patients) who received intravenous infusions of taliglucerase alfa 30 units/kg or 60 units/kg every other week. Taliglucerase alfa 30 units/kg is not a recommended dose in treatment-naïve Gaucher disease patients. The pharmacokinetic parameters in adult and pediatric patients are summarized in the table below.
In adult Type 1 Gaucher disease patients treated with taliglucerase alfa 30 units/kg or 60 units/kg (N=29) every other week as initial therapy, pharmacokinetics were determined with the first dose and at Week 38 of treatment. The pharmacokinetics of taliglucerase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure at the doses studied.
No significant accumulation or change in taliglucerase alfa pharmacokinetics over time from Weeks 1 to 38 was observed with repeated dosages of 30 units/kg or 60 units/kg every other week. Based on the limited data, there were no significant pharmacokinetic differences between male and female patients in this study.
The pharmacokinetics of taliglucerase alfa were evaluated in 9 pediatric patients 4 to 17 years of age with Type 1 Gaucher disease who were treated with taliglucerase alfa for 10 to 27 months. Six of the 9 patients were treatment-naïve, and 3 patients were switched from imiglucerase. In both the 30 units/kg and 60 units/kg dose groups, clearance values in pediatric patients were similar to those in adult patients. AUC values in pediatric patients were lower than AUC values in adult patients, due to weight-based dosing of taliglucerase alfa and lower body weights in pediatric patients.
Taliglucerase Alfa Pharmacokinetic Parameters after Repeated Dosing in Adult and Pediatric Patients with Type 1 Gaucher Disease:
| Pediatric Patients (N=9) Median (Range) | Adult Patients at Week 38 (N=29) Median (Range) | |||
|---|---|---|---|---|
| 30 units/kg n=5 | 60 units/kg n=4 | 30 units/kg n=14 | 60 units/kg n=15 | |
| Age (years) | 15 (10, 17) | 11 (4, 16) | 35 (19, 74) | 33 (19, 58) |
| Weight (kg) | 44.3 (22.8, 71.0) | 28.6 (16.5, 50.4) | 72.5 (51.5, 99.5) | 73.5 (58.5, 87.0)* |
| AUC0–∞ (ng*h/mL)† | 1416 (535, 1969) | 2984 (1606, 4273) | 2007 (1007, 10092) | 6459 (2548, 21020)* |
| T1/2 (min) | 37.1 (22.5, 56.8) | 32.5 (18.0, 42.9) | 18.9 (9.20, 57.9) | 28.7 (11.3, 104)* |
| CL (L/h) | 30.5 (17.4, 37.8) | 15.8 (11.7, 24.9) | 30.5 (6.79, 68.0) | 18.5 (6.20, 37.9)* |
| Vss (L) | 14.9 (10.1, 35.6) | 8.80 (3.75, 21.4) | 11.7 (2.3, 22.7) | 10.7 (1.4, 18.5)* |
* n=14
† Values were derived from concentration data expressed in ng/mL
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