A Nonclinical Safety Assessment of MnTE-2-PyP, a Manganese Porphyrin

Manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP or BMX-010; CASRN 219818-60-7) is a manganese porphyrin compound developed as a potential drug substance for use as a radioprotective and for the ex vivo treatment of cells, tissues, and organs intended for transplantation. In preparation for an investigational new drug filing, a full good laboratory practice nonclinical safety assessment was conducted in order to evaluate the safety of MnTE-2-PyP and included the performance of in vitro genotoxicity studies, local tissue tolerance evaluation, safety pharmacology core battery studies, and single- and repeat-dose intravenous (iv) toxicity studies in mice and monkeys. The MnTE-2-PyP was determined not to be genotoxic or hemolytic, did not demonstrate flocculation or elicit adverse pharmacologic effects on respiration, the central nervous system (CNS), and had limited transitory effects on the cardiovascular system only at levels well above the therapeutic target dose. The intended iv clinical solution did not cause venous irritation in rabbits. The no observed adverse effect level (NOAEL) in mice was determined to be 10 mg/kg/day after 18 consecutive days of bolus iv dosing once daily in the morning. The NOAEL in monkeys after 14 days of bolus iv dosing in the morning was determined to be 5 mg/kg/day. At doses relevant to clinical use in humans, neither study revealed any indication of any specific target organ toxicity, including the classic heme porphyrin kidney, liver, CNS, or cardiac toxicities, or manganese toxicity. Mortality seen shortly after dosing in individual animals at higher doses was not accompanied by any organ or clinical pathology indications, suggesting a functional pharmacological-mediated effect. Based on the results of these studies, a conservative safe initial starting clinical dose of 5.0 mg (0.083 mg/kg in a 60 kg adult) was proposed for the initiation of human trials. Because of patent life issues, use of MnTE-2-PyP as a transplantation aid or radioprotective agent is not currently being pursued past the preclinical stages. It serves as a model for the clinical development of this class of drugs.

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Nonclinical Development of ANX005: A Humanized Anti-C1q Antibody for Treatment of Autoimmune and Neurodegenerative Diseases

International Journal of Toxicology ◽

10.1177/1091581817740873 ◽

2017 ◽

Vol 36 (6) ◽

pp. 449-462 ◽

Cited By ~ 15

Author(s):

Janice A. Lansita ◽

Kirsten M. Mease ◽

Haiyan Qiu ◽

Ted Yednock ◽

Sethu Sankaranarayanan ◽

...

Keyword(s):

Healthy Volunteers ◽

Recombinant Antibody ◽

Serum Levels ◽

Repeat Dose ◽

Complement Cascade ◽

Immunoglobulin G4 ◽

Adverse Effect Level ◽

Classical Complement

ANX005 is a humanized immunoglobulin G4 recombinant antibody against C1q that inhibits its function as the initiating molecule of the classical complement cascade. The safety and tolerability of ANX005 are currently being evaluated in a phase I trial in healthy volunteers ( www.clinicaltrials.gov Identifier: NCT03010046). Inhibition of C1q can be applied therapeutically in a broad spectrum of diseases, including acute antibody-mediated autoimmune disease, such as Guillain-Barré syndrome (GBS), and in chronic diseases of the central nervous system involving complement-mediated neurodegeneration, such as Alzheimer's disease (AD). To support the clinical development of ANX005, several studies were conducted to assess the pharmacology, pharmacokinetics, and potential toxicity of ANX005. ANX-M1, the murine precursor of ANX005, functionally inhibits the classical complement cascade both in vitro and in vivo, to protect against disease pathology in mouse models of GBS and AD. Toxicology studies with ANX005, itself, showed that intravenous administration once weekly for 4 weeks was well tolerated in rats and monkeys, with no treatment-related adverse findings. Serum levels of ANX005 in monkeys correlate with a reduction in free C1q levels both in the serum and in the cerebrospinal fluid. In summary, ANX005 has shown proof of concept in in vitro and in vivo nonclinical pharmacology models, with no toxicity in the 4-week repeat-dose studies in rats and monkeys. The no observed adverse effect level was 200 mg/kg/dose, which is 200-fold higher than the first-in-human starting dose of 1 mg/kg in healthy volunteers.

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A contribution to safety assessment of veterinary drug residues: in vitro / ex vivo studies on the intestinal toxicity and transport of covalently bound residues

Xenobiotica ◽

10.1080/004982599238452 ◽

1999 ◽

Vol 29 (6) ◽

pp. 641-654 ◽

Cited By ~ 8

Author(s):

S. KLEE ◽

I. BAUMUNG ◽

K. KLUGE ◽

F. R. UNGEMACH ◽

E. HORNE ◽

...

Keyword(s):

Safety Assessment ◽

Ex Vivo ◽

Veterinary Drug ◽

Veterinary Drug Residues ◽

Drug Residues ◽

Intestinal Toxicity ◽

Bound Residues ◽

Covalently Bound

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Final Amended Report on the Safety Assessment of Ammonium Thioglycolate, Butyl Thioglycolate, Calcium Thioglycolate, Ethanolamine Thioglycolate, Ethyl Thioglycolate, Glyceryl Thioglycolate, Isooctyl Thioglycolate, Isopropyl Thioglycolate, Magnesium Thioglycolate, Methyl Thioglycolate, Potassium Thioglycolate, Sodium Thioglycolate, and Thioglycolic Acid

International Journal of Toxicology ◽

10.1177/1091581809339890 ◽

2009 ◽

Vol 28 (4_suppl) ◽

pp. 68-133 ◽

Cited By ~ 7

Author(s):

Christina L. Burnett ◽

Wilma F. Bergfeld ◽

Donald V. Belsito ◽

Curtis D. Klaassen ◽

James G. Marks ◽

...

Keyword(s):

Safety Assessment ◽

Thioglycolic Acid ◽

Developmental Toxicity ◽

In Vitro Tests ◽

Oral Toxicity ◽

Adverse Effect Level ◽

Effect Level ◽

Clinically Significant ◽

Skin Irritants

This safety assessment includes Ammonium and Glyceryl Thioglycolate and Thioglycolic Acid Butyl, Calcium, Ethanolamine, Ethyl, Isooctyl, Isopropyl, Magnesium, Methyl, Potassium, and Sodium Thioglycolate, as used in cosmetics. Thioglycolates penetrate skin and distribute to the kidneys, lungs, small intestine, and spleen; excretion is primarily in urine. Thioglycolates were slightly toxic in rat acute oral toxicity studies. Thioglycolates are minimal to severe ocular irritants. Thioglycolates can be skin irritants in animal and in vitro tests, and can be sensitizers. A no-observable-adverse-effect level for reproductive and developmental toxicity of 100 mg/kg per day was determined using rats. Thioglycolates were not mutagenic, and there was no evidence of carcinogenicity. Thioglycolates were skin irritants in some clinical tests. Clinically significant adverse reactions to these ingredients used in depilatories are not commonly seen, suggesting current products are formulated to be practically nonirritating under conditions of recommended use. Formulators should take steps necessary to assure that current practices are followed.

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Pharmacokinetics and Disposition of Contezolid in Humans—Resolution of a Disproportionate Human Metabolite for Clinical Development

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00409-21 ◽

2021 ◽

Author(s):

Xiaojie Wu ◽

Jian Meng ◽

Hong Yuan ◽

Dafang Zhong ◽

Jicheng Yu ◽

...

Keyword(s):

Total Radioactivity ◽

Repeat Dose ◽

Plasma Exposure ◽

Primary Metabolite ◽

Balance Study ◽

Adverse Effect Level ◽

Effect Level ◽

Mass Balance Study ◽

Cross Species Comparison

Contezolid (MRX-I), a novel oxazolidinone antibiotic, was recently approved for the treatment of serious Gram-positive infections. The pharmacokinetics and disposition of [ 14 C]contezolid were investigated in a single-dose human mass balance study. Cross-species comparison of plasma exposure for contezolid and metabolites was performed, and the safety of the disproportionate metabolite in human was evaluated with additional nonclinical studies. After an oral administration of 99.1 μCi/602 mg dose of [ 14 C]contezolid, approximately 91.5% of the radioactivity was recovered in 0–168 h postdose, mainly in urine and followed by feces. The principal metabolic pathway of contezolid in human comprised an oxidative ring opening of 2,3-dihydropyridin-4-one fragment into polar metabolites MRX445-1 and MRX459, with recovery of approximately 48% and 15% of the dose, respectively, in urine and feces. Contezolid, MRX445-1, and MRX459 accounted for 68.0%, 19.5%, and 4.84% of the plasma exposure of the total radioactivity, respectively. Metabolites MRX445-1 and MRX459 were observed in disproportionately higher amounts in human plasma as compared to that rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies, wherein the primary metabolite, MRX445-1, was further characterized. The no observed adverse effect level (NOAEL) of MRX445-1 was determined as 360 mg/kg/day in 14-day repeat-dose test in pregnant and non-pregnant SD rats. Furthermore, MRX445-1 exhibited no antibacterial activity in vitro. Thus, MRX445-1 is not expected to exert clinically relevant pharmacology and toxicity.

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In vitro-ex vivo model systems for nanosafety assessment

European Journal of Nanomedicine ◽

10.1515/ejnm-2014-0049 ◽

2015 ◽

Vol 7 (3) ◽

Cited By ~ 7

Author(s):

Peter Wick ◽

Savvina Chortarea ◽

Olivier T. Guenat ◽

Matthias Roesslein ◽

Janick D. Stucki ◽

...

Keyword(s):

Safety Assessment ◽

Ex Vivo ◽

Current Method ◽

Model Systems ◽

Animal Testing ◽

Ex Vivo Model ◽

Testing Strategies ◽

Nano Material ◽

New Applications

AbstractEngineered nanomaterials have unique and novel properties enabling wide-ranging new applications in nearly all fields of research. As these new properties have raised concerns about potential adverse effects for the environment and human health, extensive efforts are underway to define reliable, cost- and time-effective, as well as mechanistic-based testing strategies to replace the current method of animal testing, which is still the most prevalent model used for the risk assessment of chemicals. Current approaches for nanomaterials follow this line. The aim of this review is to explore and qualify the relevance of new in vitro and ex vivo models in (nano)material safety assessment, a crucial prerequisite for translation into applications.

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Fabrication of novel ultradeformable bilosomes for enhanced ocular delivery of terconazole: In vitro characterization, ex vivo permeation and in vivo safety assessment

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2016.10.006 ◽

2016 ◽

Vol 513 (1-2) ◽

pp. 688-696 ◽

Cited By ~ 32

Author(s):

Aly A. Abdelbary ◽

Wessam H. Abd-Elsalam ◽

Abdulaziz M. Al-mahallawi

Keyword(s):

Safety Assessment ◽

Ex Vivo ◽

Ocular Delivery ◽

In Vitro Characterization ◽

Ex Vivo Permeation

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Effects of the Tibetan herbal preparation PADMA 28 on blood lipids and lipid oxidisability in subjects with mild hypercholesterolaemia

VASA ◽

10.1024/0301-1526.34.1.11 ◽

2005 ◽

Vol 34 (1) ◽

pp. 11-17 ◽

Cited By ~ 12

Author(s):

Brunner-La Rocca ◽

Schindler ◽

Schlumpf ◽

Saller ◽

Suter

Keyword(s):

Endothelial Dysfunction ◽

Blood Lipids ◽

Ex Vivo ◽

Hdl Cholesterol ◽

Blood Lipid ◽

Tibetan Medicine ◽

Double Blind ◽

Intraarterial Infusion ◽

Padma 28

Background: Previous studies showed an anti-atherosclerotic effect of PADMA 28, an herbal formula based on Tibetan medicine. As the mechanisms of action are not fully understood, we investigated whether PADMA 28 may lower blood lipids and lipid oxidisability, and affect early endothelial dysfunction. Patients and methods: Sixty otherwise healthy subjects with total cholesterol ≥5.2 mmol/l and < 8.0 mmol/l were randomly assigned to placebo or PADMA 28, 3 x 2 capsules daily, for 4 weeks (double-blind). Blood lipids (total, LDL-, and HDL-cholesterol, triglycerides, Apo-lipoprotein A1 and B) and ex vivo lipid oxidisability were measured before and after treatment. In a subset of 24 subjects, endothelial function was assessed using venous occlusion plethysmography with intraarterial infusion of acetylcholine. Isolated LDL and plasma both untreated and pre-treated with PADMA 28 extract were oxidised by the radical generator AAPH. Conjugated diene formation was measured at 245 nm. Results: Blood lipids did not change during the study in both groups. In contrast to previous reports in mild hypercholesterolaemia, no endothelial dysfunction was seen and, consequently, was not influenced by therapy. Ex vivo blood lipid oxidisability was significantly reduced with PADMA 28 (area under curve: 5.29 ± 1.62 to 4.99 ± 1.46, p = 0.01), and remained unchanged in the placebo group (5.33 ± 1.88 to 5.18 ± 1.78, p > 0.1). This effect persisted one week after cessation of medication. In vitro experiments confirmed the prevention of lipid peroxidation in the presence of PADMA 28 extracts. Persistent protection was also seen for LDL isolated from PADMA 28-pretreated blood after being subjected to rigorous purification. Conclusions: This study suggests that the inhibition of blood lipid oxidisability by PADMA 28 may play a role in its anti-atherosclerotic effect.

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The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000116 ◽

2012 ◽

Vol 82 (3) ◽

pp. 228-232 ◽

Cited By ~ 7

Author(s):

Mauro Serafini ◽

Giuseppa Morabito

Keyword(s):

Antioxidant Capacity ◽

Dietary Intervention ◽

Ex Vivo ◽

The Body ◽

Dietary Polyphenols ◽

Enzymatic Antioxidant ◽

Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

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