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

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

Whole Body and CNS Biodistribution of rhHNS in Cynomolgus Monkeys after Intrathecal Lumbar Administration: Treatment Implications for Patients with MPS IIIA

Mucopolysaccharidosis III type A (MPS IIIA; Sanfilippo syndrome), a genetic lysosomal disorder causing a deficiency of heparan N-sulfatase (HNS), leads to progressive cognitive decline from an early age. An effective enzyme replacement therapy (ERT) for MPS IIIA requires central nervous system (CNS) biodistribution. Recombinant human heparan N-sulfatase (rhHNS), an investigatory ERT for MPS IIIA, has been formulated for intrathecal (IT) administration since intravenous (IV) administration cannot cross the blood brain barrier (BBB) in sufficient amounts to have a therapeutic effect. In this study, systemic and CNS distribution of rhHNS in cynomolgus monkeys following IV and IT administration was evaluated by quantitation of rhHNS in serum, cerebral spinal fluid (CSF) and various tissues, and positron emission tomography (PET) imaging of live animals. Following IV administration, rhHNS levels were low to non-detectable in the CSF, and systemic clearance was rapid (≤2 h). With IT administration, rhHNS was observable in CNS tissues in ≤1 h, with varying Tmax (1–24 h). Appreciable systemic distribution was observed up to 7 days. This provides evidence that in this animal model, intrathecal administration of rhHNS delivers the replacement enzyme to therapeutically relevant tissues for the treatment of Sanfilippo Syndrome type A. Penetration into grey matter and cortex was 3–4 times greater than concentrations in white matter and deeper parenchymal regions, suggesting some limitations of this ERT strategy

Comparisons of serum I2S pharmacokinetic parameters after 4 different idursulfase treatments.

<p><i>AUC</i>_inf, area under the concentration-time curve extrapolated to infinity; <i>AUC</i>_0-t, area under the concentration-time curve from time 0 to the last sampling time; CL, total clearance; <i>C</i>_max, maximum observed concentration; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar; IV, intravenous; <i>MRT</i>_inf, mean residual time derived from time 0 to infinity; na, not available; SD, standard deviation; <i>t</i>_½, terminal half-life; <i>T</i>_max, time of occurrence of <i>C</i>_max; <i>V</i>_ss, volume of distribution at steady state; <i>V</i>_z, volume of distribution during terminal phase; λ_Z, apparent terminal rate constant.</p><p>^aUnits were ml/kg for IV dosing and ml for IT-L</p><p>^bn = 6</p><p>^cn = 7</p><p>^dUnits were ml/h/kg for IV dosing and ml/h for IT-L.</p><p>Comparisons of serum I2S pharmacokinetic parameters after 4 different idursulfase treatments.</p

CSF pharmacokinetic parameters of idursulfase IV and IT at CM level.

<p><i>AUC</i>_inf, area under the concentration-time curve extrapolated to infinity; <i>AUC</i>_0-t, area under the concentration-time curve from time 0 to the last sampling time; CL, total clearance; CM, cisterna magna; <i>C</i>_max, maximum observed concentration; CSF, cerebrospinal fluid; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar; IV, intravenous; <i>MRT</i>_inf, mean residual time derived from time 0 to infinity; na, not available; SD, standard deviation; <i>t</i>_½, terminal half-life; <i>T</i>_max, time of occurrence of <i>C</i>_max; <i>V</i>_ss, volume of distribution at steady state; <i>V</i>_z, volume of distribution during terminal phase; λ_Z, apparent terminal rate constant.</p><p>^aUnits were ml/kg for IV and ml for IT-L dosing</p><p>^bn = 3</p><p>^cUnits were ml/h/kg for IV dosing and ml/h for IT-L.</p><p>CSF pharmacokinetic parameters of idursulfase IV and IT at CM level.</p

CSF pharmacokinetic parameters of idursulfase IV and IT at lumbar level.

<p><i>AUC</i>_inf, area under the concentration-time curve extrapolated to infinity; <i>AUC</i>_0-t, area under the concentration-time curve from time 0 to the last sampling time; CL, total clearance; <i>C</i>_max, maximum observed concentration; CSF, cerebrospinal fluid; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar; IV, intravenous; <i>MRT</i>_inf, mean residual time derived from time 0 to infinity; na, not available; <i>t</i>_½, terminal half-life; <i>T</i>_max, time of occurrence of <i>C</i>_max; <i>V</i>_ss, volume of distribution at steady state; <i>V</i>_z, volume of distribution during terminal phase; λ_Z, apparent terminal rate constant.</p><p>^aUnits were ml/kg for IV and ml for IT-L dosing</p><p>^bUnits were ml/h/kg for IV dosing and ml/h for IT-L.</p><p>CSF pharmacokinetic parameters of idursulfase IV and IT at lumbar level.</p

Mean intravenous and IT-L serum I2S concentration-time profiles.

<p>Error bars represent standard deviation.I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar; IV, intravenous.</p

Bioavailability and exposure fraction (<i>AUC</i>_inf) of I2S in the serum and CSF after IT-L dosing.

<p><i>AUC</i>_inf, area under the concentration-time curve extrapolated to infinity; CM, cisterna magna; CSF, cerebrospinal fluid; EF, exposure fraction; F, bioavailability; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar; IV, intravenous.</p><p>^aMean body weights were calculated from the animals whose CSF samples were collected at the CM level.</p><p>^bSampled at CM level.</p><p>Bioavailability and exposure fraction (<i>AUC</i>_inf) of I2S in the serum and CSF after IT-L dosing.</p

Cynomolgus dosing and administration route groups.

<p>IT-L, intrathecal lumbar; IV, intravenous, SD, standard deviation.</p><p>Cynomolgus dosing and administration route groups.</p

Mean serum and CSF I2S concentration-time profiles with 0.5 mg/kg idursulfase intravenous dose.

<p>Error bars represent standard deviation.CM, cisterna magna; CSF, cerebrospinal fluid; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar.</p