EXTH-64. COMPARISON OF PANOBINOSTAT CSF PENETRATION WITH CNS PENETRATION FOLLOWING SYSTEMIC ADMINISTRATION IN A PRE-CLINICAL NON-HUMAN PRIMATE MODEL

Abstract Targeted therapies developed for diffuse midline gliomas (DMG) expressing H3K27M have focused on histone deacetylase inhibitors (HDACi). High-throughput drug screening with patient derived DMG cell lines identified the HDACi panobinostat as a prominent clinical agent as well as pre-clinical studies with orthotopic mouse tumors models proving efficacious. Diametrically there is a pronounced lack of measurable panobinostat CSF concentrations in a non-human primate (NHP) non-tumor bearing pre-clinical model and in pediatric brain tumor patients. Notwithstanding, adult and pediatric glioma clinical trials and clinical observation with panobinostat alone or in combination have demonstrated minor responses. Pharmacokinetic models utilize the premise that CSF drug penetration is a surrogate of CNS drug penetration. However, the direct correlation between CSF and CNS drug levels is undefined especially in lieu of geographic CNS extracellular fluid drug variability previously demonstrated in the same NHP pre-clinical model. Utilizing the same NHP model, this study sought to compare panobinostat CSF penetration to CNS penetration via analysis of homogenized normal cerebrum, cerebellum, and brainstem tissue utilizing LC-MS/MS. METHODS: Panobinostat was administered orally as a single dose to three non-human primates. Pre panobinostat plasma and CSF were collected. Following panobinostat administration (1-hr Tmax) CSF, cerebrum, cerebellum, and brain stem tissue were collected as well as plasma to confirm the presence of panobinostat. Tissue slices were individually homogenized and panobinostat extracted via protein precipitation. Plasma, CSF, and tissue panobinostat concentrations were quantified using a LC-MS/MS assay. The lower limit of quantitation (LLOQ) for plasma-0.1 ng/ml, CSF-0.5 ng/ml, and tissue-10.0 pg/mg. RESULTS: Panobinostat was quantifiable in plasma (n=2) at the 1 hour (20.033 ng/mL and 0.153 ng/mL). CSF and CNS tissue samples were below the LLOQ for panobinostat in all samples. CONCLUSIONS: Panobinostat was not measurable from CSF and homogenized brain tissue in a non-tumor bearing NHP model at 1-hour post-administration using LC-MS/MS.

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Comparative Pathogenesis of Asian and African-Lineage Zika Virus in Indian Rhesus Macaque’s and Development of a Non-Human Primate Model Suitable for the Evaluation of New Drugs and Vaccines

10.20944/preprints201804.0096.v1 ◽

2018 ◽

Author(s):

Jonathan O. Rayner ◽

Raj Kalkeri ◽

Scott Goebel ◽

Zhaohui Cai ◽

Brian Green ◽

...

Keyword(s):

Immune Response ◽

Zika Virus ◽

Rhesus Macaques ◽

New Drugs ◽

Primate Model ◽

Robust Immune Response ◽

African Lineage ◽

Limit Of Quantitation ◽

Asian Lineage ◽

Human Primate

The establishment of a well characterized non-human primate model of Zika virus (ZIKV) infection is critical for the development of medical interventions. In this study, challenging Indian rhesus macaques (IRMs) with ZIKV strains of the Asian lineage resulted in dose dependent peak viral loads between days 2 and 5 post infection; and a robust immune response which protected the animals from homologous and heterologous re-challenge. In contrast, viremia in IRMs challenged with an African lineage strain was below the assays lower limit of quantitation and the immune response was insufficient to protect from re-challenge. These results corroborate previous observations but are contrary to reports using other African strains obviating the need for additional studies to elucidate the variables contributing to the disparities. Nonetheless, the utility of an Asian lineage ZIKV IRM model for countermeasures development was verified by vaccinating animals with a formalin inactivated reference vaccine and demonstrating sterilizing immunity against a subsequent subcutaneous challenge.

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EPCT-09. CNS LEVELS OF PANOBINOSTAT IN A NON-HUMAN PRIMATE MODEL: COMPARISON OF BLOOD AND CEREBROSPINAL FLUID PHARMACOKINETIC METHODS AND MALDI MSI

Neuro-Oncology ◽

10.1093/neuonc/noab090.195 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i48-i48

Author(s):

Katherine Warren ◽

Cynthia Lester McCully ◽

Rafael Cruz Garcia ◽

Sylwia Stopka ◽

Michael Regan ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Model Comparison ◽

Ex Vivo ◽

Clinical Activity ◽

Ionization Mass ◽

Primate Model ◽

Drug Levels ◽

Drug Concentrations ◽

Limit Of Quantitation ◽

Human Primate

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-25. THE CSF PENETRATION OF THE PROCASPASE-ACTIVATING COMPOUND (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE (TMZ) IN A NONHUMAN PRIMATE CSF ACCESS MODEL

Neuro-Oncology ◽

10.1093/neuonc/noaa215.379 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii92-ii92

Author(s):

Cynthia Lester McCully ◽

Priya Shankarappa ◽

Rafael Cruz Garcia ◽

Cody Peer ◽

Alexander Zakharov ◽

...

Keyword(s):

Nonhuman Primate ◽

Rhesus Macaques ◽

Single Agent ◽

Pharmacokinetic Parameters ◽

Synergistic Activity ◽

Concurrent Administration ◽

Primate Model ◽

Csf Penetration ◽

Tumor Bearing ◽

Access Model

Abstract BACKGROUND The synergistic activity of temozolomide (TMZ) administered in combination with procaspase-activating compound (PAC-1) has been reported in pre-clinical mouse models and canine patients, leading to clinical trials in adults with glioblastoma. To optimize pediatric clinical trial design, a translational pharmacokinetic CSF penetration study was conducted using a pre-clinical nonhuman primate non-tumor bearing CSF access model with TMZ and PAC-1 administered alone and in combination. METHODS Four male rhesus macaques with CSF lateral ventricular reservoirs received PAC-1, 15 mg/kg orally [Human Equivalent Dose (HED) 558 mg/m2/day] or TMZ, 1-hr IV infusion, 7.5 mg/kg (HED 150 mg/m2) as single and combination agent administration. Paired plasma and CSF samples were collected for 0–96 hours. PAC-1 and TMZ were quantified by LC-MS/MS. Pharmacokinetic parameters were calculated using noncompartmental methods. Statistics were determined via Mann-Whitney test. RESULTS (Mean ± Standard Deviation): For TMZ: Plasma AUC0-24 (hr*ng/ml) single agent (n=4): 28590 ± 4888 and in combination (n=4): 32736 ± 10147. CSF AUC0-24 (hr*ng/ml) single agent (n=4):14406 ± 1279 and in combination (n=4):15614 ± 1767. CSF penetration (% AUCCSF: AUCPLASMA) single agent: 50.9% ± 2.2 and in combination:49.6% ± 8.4. For PAC-1: Plasma PAC-1 AUC0-24 (hr*ng/ml) single agent (n=4): 2556 ± 2157 and in combination (n=4): 1947 ± 1311. CSF PAC-1 AUC0-24 (hr*ng/ml) single agent (n=2): 8.7 ± 1.1 and in combination (n=3):12.9 ± 10.2. CSF penetration single agent: 0.2% ± 0.03 and in combination: 0.4% ± 0.38. CSF PAC-1 tlag and Tmax pharmacokinetic parameters decreased with concurrent TMZ administration. CONCLUSIONS In this non-tumor bearing pre-clinical nonhuman primate model the CSF penetration of PAC-1 was low and not notably affected by the concurrent administration of TMZ. TMZ CSF penetration for single administration was within previously reported ranges and also appeared unaffected when administered in combination with PAC-1.

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CNS Penetration of Cyclophosphamide and Metabolites in Mice Bearing Group 3 Medulloblastoma and Non-Tumor Bearing Mice

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/jpps30608 ◽

2019 ◽

Vol 22 ◽

pp. 612-629

Author(s):

Clinton Stewart ◽

Olivia Campagne ◽

Abigail Davis ◽

Bo Zhong ◽

Sreenath Nair ◽

...

Keyword(s):

Extracellular Fluid ◽

Population Based ◽

Cerebral Microdialysis ◽

Post Dose ◽

Brain Penetration ◽

Tumor Bearing ◽

Exposure Response ◽

Group 3 ◽

Cns Penetration ◽

The Brain

PURPOSE: Cyclophosphamide is widely used to treat children with medulloblastoma; however, little is known about its brain penetration. We performed cerebral microdialysis to characterize the brain penetration of cyclophosphamide (130 mg/kg, IP) and its metabolites [4-hydroxy-cyclophosphamide (4OH-CTX) and carboxyethylphosphoramide mustard (CEPM)] in non-tumor bearing mice and mice bearing orthotopic Group 3 medulloblastoma. METHODS: A plasma pharmacokinetic study was performed in non-tumor-bearing CD1-nude mice, and four cerebral microdialysis studies were performed in non-tumor-bearing (M1 and M3) and tumor-bearing mice (M2 and M4). Plasma samples were collected up to 6-hours post-dose, and extracellular fluid (ECF) samples were collected over 60-minute intervals for 24-hours post-dose. To stabilize and quantify 4OH-CTX, a derivatizing solution was added in blood after collection, and either directly in the microdialysis perfusate (M1 and M2) or in ECF collection tubes (M3 and M4). Plasma/ECF cyclophosphamide and CEPM, and 4OH-CTX concentrations were separately measured using different LC-MS/MS methods. RESULTS: All plasma/ECF concentrations were described using a population-based pharmacokinetic model. Plasma exposures of cyclophosphamide, 4OH-CTX, and CEPM were similar across studies (mean AUC=112.6, 45.6, and 80.8 µmol∙hr/L). Hemorrhage was observed in brain tissue when the derivatizing solution was in perfusate compared with none when in collection tubes, which suggested potential sample contamination in studies M1 and M2. Model-derived unbound ECF to plasma partition coefficients (Kp,uu) were calculated to reflect CNS penetration of the compounds. Lower cyclophosphamide Kp,uu was obtained in tumor-bearing mice versus non-tumor bearing mice (mean 0.15 versus 0.22, p=0.019). No differences in Kp,uu were observed between these groups for 4OH-CTX and CEPM (overall mean 0.10 and 0.07). CONCLUSIONS: Future studies will explore potential mechanisms at the brain-tumor barrier to explain lower cyclophosphamide brain penetration in tumor-bearing mice. These results will be used to further investigate exposure-response relationships in medulloblastoma xenograft models.

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Characterization of baboon fetal membranes: Evaluation as a non-human primate model of fetal membrane rupture

Journal of the Society for Gynecologic Investigation ◽

10.1016/s1071-5576(97)86699-3 ◽

1998 ◽

Vol 5 (1) ◽

pp. 192A-192A

Author(s):

J MCLAREN ◽

S BELL ◽

A FAALEABAS

Keyword(s):

Fetal Membrane ◽

Fetal Membranes ◽

Primate Model ◽

Membrane Rupture ◽

Fetal Membrane Rupture ◽

Human Primate

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Cardiac Pacing in a Chronically Instrumented Non-Human Primate Model During Centrifuge,

10.21236/ada316940 ◽

1996 ◽

Author(s):

S. C. Koenig ◽

Craig Reister ◽

J. Schtaub ◽

Gary Muniz ◽

Tim Fergusan

Keyword(s):

Cardiac Pacing ◽

Primate Model ◽

Human Primate

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Combined therapy of mesenchymal stem cells with a GLP-1 receptor agonist, liraglutide, on an inflammatory-mediated diabetic non-human primate model

Life Sciences ◽

10.1016/j.lfs.2021.119374 ◽

2021 ◽

Vol 276 ◽

pp. 119374

Author(s):

Roghayeh Navabi ◽

Babak Negahdari ◽

Ensiyeh Hajizadeh-Saffar ◽

Mostafa Hajinasrollah ◽

Yaser Jenab ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Receptor Agonist ◽

Combined Therapy ◽

Primate Model ◽

Human Primate

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Neonatal Immune System Ontogeny: The Role of Maternal Microbiota and Associated Factors. How Might the Non-Human Primate Model Enlighten the Path?

Vaccines ◽

10.3390/vaccines9060584 ◽

2021 ◽

Vol 9 (6) ◽

pp. 584

Author(s):

Natalia Nunez ◽

Louis Réot ◽

Elisabeth Menu

Keyword(s):

Immune System ◽

Mode Of Delivery ◽

Microbial Colonization ◽

Therapeutic Interventions ◽

Primate Model ◽

Neonatal Immune System ◽

Gastrointestinal Colonization ◽

The Impact ◽

Human Primate

Interactions between the immune system and the microbiome play a crucial role on the human health. These interactions start in the prenatal period and are critical for the maturation of the immune system in newborns and infants. Several factors influence the composition of the infant’s microbiota and subsequently the development of the immune system. They include maternal infection, antibiotic treatment, environmental exposure, mode of delivery, breastfeeding, and food introduction. In this review, we focus on the ontogeny of the immune system and its association to microbial colonization from conception to food diversification. In this context, we give an overview of the mother–fetus interactions during pregnancy, the impact of the time of birth and the mode of delivery, the neonate gastrointestinal colonization and the role of breastfeeding, weaning, and food diversification. We further review the impact of the vaccination on the infant’s microbiota and the reciprocal case. Finally, we discuss several potential therapeutic interventions that might help to improve the newborn and infant’s health and their responses to vaccination. Throughout the review, we underline the main scientific questions that are left to be answered and how the non-human primate model could help enlighten the path.

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Combination therapy protects macaques against advanced Marburg virus disease

Nature Communications ◽

10.1038/s41467-021-22132-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Robert W. Cross ◽

Zachary A. Bornholdt ◽

Abhishek N. Prasad ◽

Viktoriya Borisevich ◽

Krystle N. Agans ◽

...

Keyword(s):

Combination Therapy ◽

Rhesus Monkeys ◽

Viral Infections ◽

Virus Disease ◽

Marburg Virus ◽

Therapeutic Window ◽

Post Inoculation ◽

Primate Model ◽

Lethal Infection ◽

Human Primate

AbstractMonoclonal antibodies (mAbs) and remdesivir, a small-molecule antiviral, are promising monotherapies for many viruses, including members of the genera Marburgvirus and Ebolavirus (family Filoviridae), and more recently, SARS-CoV-2. One of the major challenges of acute viral infections is the treatment of advanced disease. Thus, extending the window of therapeutic intervention is critical. Here, we explore the benefit of combination therapy with a mAb and remdesivir in a non-human primate model of Marburg virus (MARV) disease. While rhesus monkeys are protected against lethal infection when treatment with either a human mAb (MR186-YTE; 100%), or remdesivir (80%), is initiated 5 days post-inoculation (dpi) with MARV, no animals survive when either treatment is initiated alone beginning 6 dpi. However, by combining MR186-YTE with remdesivir beginning 6 dpi, significant protection (80%) is achieved, thereby extending the therapeutic window. These results suggest value in exploring combination therapy in patients presenting with advanced filovirus disease.

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