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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.

Objective: To evaluate safety, pharmacokinetics, pharmacodynamics, and clinical response of single subcutaneous (SC) administrations of a human monoclonal antibody against the p40 subunit of IL-12/23 (IL-12/23 mAb) in subjects with moderate-to-severe psoriasis.Methods: Twenty-one subjects were enrolled sequentially into 4 dose cohorts (0.27, 0.675, 1.35, and 2.7 mg/kg) and randomized to IL-12/23 mAb or placebo in a 4:1 ratio. Laboratory/clinical parameters and pharmacokinetics were evaluated through Week 24; mRNA cytokine expression was measured in psoriatic plaques at Week 1.Results: Mostly mild adverse events and no serious adverse events were reported. The pharmacokinetics (Cmax and AUC) of IL-12/23 mAb increased in an approximately dose-proportional manner. Of the 17 subjects who received IL-12/23 mAb, 13 achieved PASI 75 (compared with no placebo subjects). mRNA expression of IL-8, IL-18, and IFN-γ in psoriatic plaques decreased in subjects with sustained Psoriasis Area and Severity Index (PASI) improvement.Limitations: Interpretation of results is limited due to the small sample size in each dose cohort.Conclusion: A single SC administration of IL-12/23 mAb was well tolerated and showed clinical response in subjects with moderate-to-severe psoriasis. [ABSTRACT FROM AUTHOR]