EXTH-57. PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF THE PROCASPASE-ACTIVATING COMPOUND, PAC-1, FOLLOWING ORAL ADMINISTRATION IN A NON-HUMAN PRIMATE MODEL

Abstract Adequate exposure (effective concentration over time) of a therapeutic agent at its site of action is essential for antitumor efficacy. Given constraints of repeat tissue sampling, non-human primate models predictive of pharmacokinetics in pediatric patients have been utilized to assess central nervous system (CNS) exposure. Assessment of cerebrospinal fluid (CSF) drug levels have been used to extrapolate CNS penetration but the relationship of CSF drug levels with tissue distribution is unclear. Utilizing microdialysis, we previously demonstrated geographic variability of drug permeability across the blood:brain barrier (BBB), but this technique is complex and has a high standard deviation. We, therefore, explored a novel technique, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI), to compare plasma, CSF, and tissue drug levels in a terminal non-human primate model. Panobinostat, an HDAC inhibitor in clinical trials for DIPG/DMG, was selected for study as it has previously demonstrated poor CNS tissue penetration but suggested modest clinical activity. Methods Panobinostat (p.o., dose 1.6 mg/kg) was administered to non-tumor bearing primates (n=2). One hour following administration (Tmax), blood and CSF were collected, the animal euthanized, brain and spinal cord extracted, and immediately frozen at -80. Panobinostat distribution was mapped on ex vivo sagittal tissue sections using MALDI MSI. To provide specificity and degree of permeability, anatomical structures were segmented for analysis to determine drug concentrations. Blood, CSF and tissue levels of panobinostat were measured via LC-MS/MS. Results Segmentation analysis revealed quantifiable panobinostat, particularly in the lateral ventricles and choroid plexus, and also in the subventricular zone and brainstem, although the overall panobinostat concentration was below the limit of quantitation in these areas. Conclusions Although not reflected in CSF PK, panobinostat is widely distributed in brain tissue. MALDI MSI allows regional assessment of panobinostat penetration and complements CSF pharmacokinetics.

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EXTH-02. PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF 5-AZACYTIDINE ALONE AND IN COMBINATION WITH INULIN IN A NON-HUMAN PRIMATE MODEL

Neuro-Oncology ◽

10.1093/neuonc/nox168.298 ◽

2017 ◽

Vol 19 (suppl_6) ◽

pp. vi73-vi73

Author(s):

Cynthia Lester McCully ◽

Louis Rodgers ◽

Rafael Cruz ◽

Marvin Thomas ◽

Cody Peer ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Primate Model ◽

Human Primate

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Oral administration of an anti-CfaE secretory IgA antibody protects against Enterotoxigenic Escherichia coli diarrheal disease in a non-human primate model

10.1101/748442 ◽

2019 ◽

Author(s):

Matteo Stoppato ◽

Carlos Gaspar ◽

James Regeimbal ◽

Gladys Nunez ◽

Serena Giuntini ◽

...

Keyword(s):

Escherichia Coli ◽

Oral Administration ◽

Attack Rate ◽

Protective Efficacy ◽

Enterotoxigenic Escherichia Coli ◽

Secretory Iga ◽

Primate Model ◽

Group 3 ◽

Group 2 ◽

Human Primate

ABSTACTEnterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea-associated illness in developing countries. There is currently no vaccine licensed to prevent ETEC and the development of an efficacious prophylaxis would provide an intervention with significant impact. Recent studies suggested that effective protection could be achieved by inducing immunity to block colonization of ETEC. Here, we evaluated the efficacy of secretory (s) IgA2 and dimeric (d) IgA2 of an anti-colonization factor antigen antibody, 68-61, in the Aotus nancymaae non-human primate (NHP) ETEC challenge model via oral and parental delivery. Thirty-nine animals were distributed across 3 groups of 13, and challenged with 5.0×1011 cfu of H10407 on Day 0. Group 1 received a dIgA2 68-61 subcutaneously on day 0. Group 2 received a SIgA2 68-61 orally on days −1, 0, and +1, and Group 3 received an irrelevant SIgA2 antibody orally on days −1, 0, and +1. All animals were observed for symptoms of diarrhea, and stools were collected for ETEC colony counts. SIgA2 treatment significantly lowered the attack rate, resulting in a protective efficacy of 71.4% (p=0.025) in Group 2 as compared to Group 3. Anti-CfaE dIgA2 treatment group reduced the diarrheal attack rate, although the reduction did not reach significance (57.1%; P=0.072) as compared to the irrelevant SIgA2 Group 3. Our results demonstrated the feasibility of oral administration of SIgA as a potential immunoprophylaxis against enteric infections. To our knowledge, this is the first study to demonstrate the efficacy of administrated SIgA in a non-human primate model.

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