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Pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration.

Xie H, Chung JK, Mascelli MA, McCauley TG - PLoS ONE (2015)

Bottom Line: 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%).

View Article: PubMed Central - PubMed

Affiliation: Shire, Lexington, Massachusetts, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Mean serum and CSF I2S concentration-time profiles with 0.5 mg/kg idursulfase intravenous dose.Error bars represent standard deviation.CM, cisterna magna; CSF, cerebrospinal fluid; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar.
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pone.0122453.g001: Mean serum and CSF I2S concentration-time profiles with 0.5 mg/kg idursulfase intravenous dose.Error bars represent standard deviation.CM, cisterna magna; CSF, cerebrospinal fluid; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar.

Mentions: The mean serum and CSF I2S concentration-time profiles of an intravenous injection of 0.5 mg/kg idursulfase are shown in Fig 1. Serum I2S concentrations declined rapidly from a peak of 10,029 ± 3,127 ng/ml and the last time point with a measurable concentration (122 ± 26 ng/ml) was 8 h after dosing. The serum I2S pharmacokinetic parameters are listed in Table 2. Serum total clearance for intravenously administered idursulfase was 57.5 ± 22.4 ml/h/kg with a elimination half-life (t1/2) 4.3 ± 4.4 h, and the mean residual time derived from time 0 to infinity (MRTinf) was 4.8 ± 7.4 h. The volume of distribution at steady state (Vss) was 198 ± 191 ml/kg.


Pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration.

Xie H, Chung JK, Mascelli MA, McCauley TG - PLoS ONE (2015)

Mean serum and CSF I2S concentration-time profiles with 0.5 mg/kg idursulfase intravenous dose.Error bars represent standard deviation.CM, cisterna magna; CSF, cerebrospinal fluid; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383552&req=5

pone.0122453.g001: Mean serum and CSF I2S concentration-time profiles with 0.5 mg/kg idursulfase intravenous dose.Error bars represent standard deviation.CM, cisterna magna; CSF, cerebrospinal fluid; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar.
Mentions: The mean serum and CSF I2S concentration-time profiles of an intravenous injection of 0.5 mg/kg idursulfase are shown in Fig 1. Serum I2S concentrations declined rapidly from a peak of 10,029 ± 3,127 ng/ml and the last time point with a measurable concentration (122 ± 26 ng/ml) was 8 h after dosing. The serum I2S pharmacokinetic parameters are listed in Table 2. Serum total clearance for intravenously administered idursulfase was 57.5 ± 22.4 ml/h/kg with a elimination half-life (t1/2) 4.3 ± 4.4 h, and the mean residual time derived from time 0 to infinity (MRTinf) was 4.8 ± 7.4 h. The volume of distribution at steady state (Vss) was 198 ± 191 ml/kg.

Bottom Line: 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%).

View Article: PubMed Central - PubMed

Affiliation: Shire, Lexington, Massachusetts, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus