Efficacy of 2-Hydroxypropyl-β-cyclodextrin in Niemann-Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease

Efficacy of 2-Hydroxypropyl-β-cyclodextrin in Niemann-Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease

Niemann-Pick type C disease (NPC), an autosomal recessive lysosomal storage disorder, is an inherited disease characterized by the accumulation of intracellular unesterified cholesterol. A solubilizing agent of lipophilic compounds, 2-hydroxypropyl-β-cyclodextrin (HPBCD), is an attractive drug candi...

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Bibliographic Details
Published in:Biological and Pharmaceutical Bulletin Vol. 38; no. 6; pp. 844 - 851
Main Authors: Yuta Tanakaa, Yusei Yamadaa, Yoichi Ishitsukaa, Muneaki Matsuob, Koki Shiraishia, Koki Wadac, Yushiro Uchioa, Yuki Kondoa, Toru Takeod, Naomi Nakagatad, Taishi Higashie, Keiichi Motoyamae, Hidetoshi Arimae, Sakiko Mochinagaf, Katsumi Higakig, Kousaku Ohnoh, Tetsumi Iriea
Format: Journal Article
Language:Japanese
Published: Pharmaceutical Society of Japan 01-06-2015
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Summary:Niemann-Pick type C disease (NPC), an autosomal recessive lysosomal storage disorder, is an inherited disease characterized by the accumulation of intracellular unesterified cholesterol. A solubilizing agent of lipophilic compounds, 2-hydroxypropyl-β-cyclodextrin (HPBCD), is an attractive drug candidate against NPC disease. However, establishment of the optimum dosage of HPBCD remains to be determined. In this study, we evaluated the effective dosage of HPBCD in NPC model (Npc1-/-) mice, and determined serum HPBCD concentrations. Subcutaneous injection of 1000-4000mg/kg HPBCD improved the lifespan of Npc1-/- mice. In addition, liver injury and cholesterol sequestration were significantly prevented by 4000mg/kg HPBCD in Npc1-/- mice. Serum HPBCD concentrations, when treated at the effective dosages (1000-4000mg/kg), were approximately 1200-2500μg/mL at 0.5h after subcutaneous injection, and blood HPBCD concentrations were immediately eliminated in Npc1-/- mice. Furthermore, we examined serum HPBCD concentrations when treated at 40000mg (approximately 2500mg/kg) in a patient with NPC. We observed that the effective concentration in the in vivo study using Npc1-/- mice was similar to that in the patient. In the patient, systemic clearance and the volume of distribution of HPBCD were in accordance with the glomerular filtration rate and extracellular fluid volume, respectively. These results could provide useful information for developing the optimal dosage regimen for HPBCD therapy when administered intravenously to NPC patients.
ISSN:0918-6158