Continuous infusion of enzyme replacement therapy is inferior to weekly infusions in MPS I dogs

Abstract

Intravenous enzyme replacement therapy with recombinant human α-L-iduronidase (rhIDU) is used weekly to treat mucopolysaccharidosis (MPS) I. We tested continuous administration of rhIDU at two dosing levels (0.58 mg/kg per week and 2 mg/kg per week) in MPS I dogs, and compared the efficacy of continuous infusion with the clinically used 0.58 mg/kg weekly three-hour infusion. Peak plasma concentrations of rhIDU were much higher in weekly-treated dogs (mean 256 units/ml) than steady-state concentrations in dogs treated with continuous infusion (mean 1.97 units/ml at 0.58 mg/kg per week; 8.44 units/ml at 2 mg/kg per week). Dogs receiving continuous IV rhIDU, even at a higher (2 mg/kg per week) dose, had consistently lower iduronidase levels in tissues than dogs receiving a weekly (0.58 mg/kg per week) dose. GAG storage was also less improved by continuous intravenous infusion. Adverse events were similar in all dosing groups. We found that continuous administration of 2 mg/kg per week rhIDU to MPS I dogs was insufficient to achieve GAG storage reduction comparable to 0.58 mg/kg weekly dosing.

Fig. 1

a) Plasma iduronidase levels during and following a weekly rhIDU infusion. Plasma iduronidase levels were taken at hourly intervals during the infusion of enzyme, and then 2, 5, 10, 15, 30, 45, 60, 90, 120, and 240 minutes after the end of the infusion. Weeks 24 (ET) and 26 (XB, XY) are shown. Iduronidase levels tested once per week in continuous dogs (CH, DA, EM, IR, LA) are shown for comparison. Weeks 24-26 are shown. b) Iduronidase levels at all treatment weeks in continuous dogs.

Fig. 1

a) Plasma iduronidase levels during and following a weekly rhIDU infusion. Plasma iduronidase levels were taken at hourly intervals during the infusion of enzyme, and then 2, 5, 10, 15, 30, 45, 60, 90, 120, and 240 minutes after the end of the infusion. Weeks 24 (ET) and 26 (XB, XY) are shown. Iduronidase levels tested once per week in continuous dogs (CH, DA, EM, IR, LA) are shown for comparison. Weeks 24-26 are shown. b) Iduronidase levels at all treatment weeks in continuous dogs.

Fig. 2

Tissue iduronidase levels in dogs treated weekly and continuously with IV rhIDU. Means of the means are shown. Error bars represent standard deviation.