Abstract
Intravenous enzyme replacement therapy with iduronate-2-sulfatase is an approved treatment for Hunter syndrome, however, conventional intravenous delivery cannot treat the neurologic manifestations of the disease due to its limited central nervous system penetration. Intrathecal administration of iduronate-2-sulfatase for delivery to the central nervous system is currently under investigation. The objective of this study was to evaluate the pharmacokinetics of idursulfase in the central nervous system of cynomolgus monkeys (Macaca fasicularis) after intravenous and intrathecal administration. Twenty-seven monkeys, treatment-naïve to enzyme replacement therapy, were placed into 4 groups according to body weight: Group 1 was administered 0.5 mg/kg idursulfase intravenously, Groups 2–4 were administered an intrathecal formulation (1-, 10-, and 30-mg doses). Blood samples and cerebrospinal fluid (sampled at the cisterna magna or lumbar level) were collected at the same time points for 72 hours post dosing. Following intravenous administration, a high maximum serum concentration and rapid distribution of iduronate-2-sulfatase out of the central compartment were observed (elimination half-life: 4.3 hours). Iduronate-2-sulfatase exposure in the cerebrospinal fluid was limited, suggesting intravenous administration provided minimal penetration of the blood–brain barrier. Following intrathecal administration, a high maximum observed concentration was immediately noted and elimination half-life ranged between 7.8–10 hours and 5.9–6.7 hours (cisterna magna and lumbar sampling, respectively). Cerebrospinal fluid pharmacokinetic profiles at different doses of iduronate-2-sulfatase were similar and the dose/exposure relationship was proportional. After intrathecal administration, movement of iduronate-2-sulfatase from cerebrospinal fluid to serum was observed (systemic bioavailability was 40–83%). The clear penetration of iduronate-2-sulfatase into the cerebrospinal fluid and the dose response suggest that intrathecal delivery of iduronate-2-sulfatase may be suitable for treating the central nervous system manifestations associated with Hunter syndrome.
Highlights
Hunter syndrome is a rare, X-linked disease caused by a deficiency or absence of the enzyme iduronate-2-sulfatase (I2S), a lysosomal storage enzyme required for the degradation of glycosaminoglycans [2]
Conventional enzyme replacement therapy with idursulfase administered intravenously is unlikely to enter the brain in sufficient amounts to treat the often very serious central nervous system (CNS) manifestations of Hunter syndrome [5]
The objectives of this study were to investigate the pharmacokinetic behaviours of idursulfase after intravenous and IT-L administration, the dynamics of idursulfase transfer in the cerebrospinal fluid (CSF), and the dynamics of idursulfase movement from the CSF to the systemic circulation in cynomolgus monkeys
Summary
Hunter syndrome is a rare (prevalence 1 in 162,000 male live births [1]), X-linked disease caused by a deficiency or absence of the enzyme iduronate-2-sulfatase (I2S), a lysosomal storage enzyme required for the degradation of glycosaminoglycans [2]. When the enzyme is deficient, the glycosaminoglycans heparan sulfate and dermatan sulfate accumulate in the lysosomes, causing the cells to enlarge, leading to organ failure, tissue dysfunction, and reduced life expectancy. Conventional enzyme replacement therapy with idursulfase administered intravenously is unlikely to enter the brain in sufficient amounts to treat the often very serious central nervous system (CNS) manifestations of Hunter syndrome [5]. This is a major challenge for the treatment of patients with Hunter syndrome who have CNS manifestations and is a problem common to many life-threatening CNS diseases, where an effective method of administering drug therapy to the brain is unavailable
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