Pharmacokinetics and distribution of 2‐hydroxypropyl‐β‐cyclodextrin following a single intrathecal dose to cats

Abstract

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) is an experimental therapy for Niemann-Pick disease type C (NPC) that reduced neuronal cholesterol and ganglioside storage, reduced Purkinje cell death, and increased lifespan in npc1−/− mice and NPC1 cats. In this study, tissue distribution was investigated in normal cats that received a single 120-mg dose of [ 14 C]-HP-β-CD (approximately 200 μCi/cat) via the cerebellomedullary cistern (CBMC) and lumbar cistern. One cat was euthanized at each of various time points up to 24 hours postdose for subsequent processing and quantitative whole-body autoradiographic analysis. HP-β-CD-derived radioactivity absorbed from the CBMC was widely distributed to cat tissues; most tissues were observed to have reached their highest concentration at 1 hour postdose. HP-β-CD-derived radioactivity penetrated into the deeper parts of the central nervous system with the highest concentration at 4 hours (403 μg Eq/g or 0.28 mM) and remained high (49.7 μg Eq/g or 0.03 mM) at 24 hours. The relatively long halflife (11-30 hours) in cerebral ventricles and the subarachnoid space surrounding the brain and spinal cord might contribute to the efficacy of HP-β-CD in NPC1 cats. Other tissues with high concentrations of radioactivity were nasal turbinates, pituitary gland, and urinary bladder, while relatively low concentrations were observed in blood and bile. K E Y W O R D S animal model, brain, cholesterol, drug therapy, inborn errors of metabolism, Niemann Pick type C, storage diseases Abbreviations: AUC, area under the tissue concentration-time curve; AUC inf , AUC from time 0 to infinity with extrapolation of the terminal phase; AUC last , AUC from time 0 to the time correspondent to the last quantifiable

A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice

“…The translatability and effectiveness of the intrathecal administration route have been demonstrated in larger animals (82,83) and in human trials (NCT03381729, NCT02362438), which showed effects in nerves distal to the injection site, including transduction of SCs in the tibial nerve of dogs after intrathecal injection of AAV9 (83). Another route of administration that could be easily translated to the clinic is intravenous injections.…”

Understanding and Treating Niemann–Pick Type C Disease: Models Matter

“…A first study using intra-peritoneal or intra-thecal injection in NPC1-deficient mice failed to show a positive effect [362]. However, subsequent reports revealed that CD prolongs the life span, slows down neurologic disease progression, and halts the degeneration of Purkinje cells in the mouse and cat model [177][178][179][180][181]363,364]. Intra-thecal injections were required, as CD cannot pass the blood-brain barrier [365].…”

Development of an LC‐MS/MS method for simultaneous quantitative analysis of macromolecular pharmaceutical adjuvant 2‐hydroxypropyl‐β‐cyclodextrin and active pharmaceutical ingredients butylphthalide in rat plasma

“…Research showed that the hydrophobic inner cavity of HP-β-CD could form an inclusion compound with intracellular accumulated lipids, which could promote lipid efflux, and regulated intracellular lipid homeostasis [12]. Studies in various animal models had demonstrated that HP-β-CD could reduce neuron cholesterol and ganglioside storage and had the potential to treat Niemann-Pick Type C disease (NPC) [13][14][15][16]. HP-β-CD could reduce the levels of membrane cholesterol and Aβ42 in N2a cells by reducing the enzymatic hydrolysis of amyloid precursor protein (APP), becoming a new strategy for treating Alzheimer's disease (AD) [17][18][19][20].…”