Sky One Toxicology LLC

Sky One Toxicology LLC and international regulations.

SOM provides services in developing CMC, non-clinical, clinical, and regulatory compliance programs in support of product development and commercialization of biopharmaceutical, medical device, biologics, and chemical products. SOM takes the weight-of-evidence approach to delineate the toxicology profile, prepare scientific position papers, information dossiers, drug and chemical safety assessments, and toxicological support in compliance with U.S.

12/11/2023

A Weight of Evidence Approach to Inform Design of Repeated Dose Animal Studies.

Dosage regimen in repeated-dose animal toxicity studies can be selected based on various approaches, such as, using of a maximum tolerated dose (MTD), the limit dose (LD), toxicokinetic (TK) data, and/or clinical indication and usages. The study protocols for repeated dose animal studies are developed typically based on data obtained from shorter-term or dose range finding (DRF) studies that inform a chemical compound’s potency, mode of action, or TK. However, human exposure information, such as routes, length, and daily range, can provide additional line of support for proper dose range determination that would induce a biological response compared to what could be expected in humans and confirm the dose-response range that is relevant to human exposure.

Under REACH at EU, several models, e.g., the Centre for Chemical Safety Assessment (ECETOC) Targeted Risk Assessment (TRA) tool and the European Solvents Industry Group (ESIG) Generic Exposure Scenario (GES) Risk and Exposure Tool (EGRET), were used as screening tools to estimate the human exposures via inhalation, dermal, and oral exposure routes to a wide range of chemical substances, to support chemical safety assessment. The analysis demonstrated the margin between predicted human exposure levels and the dose levels used in repeated-dose animal studies, which were typically orders of magnitude lower than no-observed-adverse-effect levels/lowest-observed-adverse-effect levels (NOAELs/LOAELs).

A weight of evidence approach considering all the information as discussed above can be recommended to identify the top dose and appropriate dose regimen in animal study design.

10/28/2023

Evaluation of Thermal Degradation Products in E(N)NDS

The Committee on Toxicology of Chemicals in Food, Consumer Products and the Environment (COT) in UK has developed a framework for risk assessment of flavoring compounds for the electronic ni****ne (and non-ni****ne) delivery systems [E(N)NDS – e-cigarettes]. This framework includes consideration of the toxicological consequences of thermal degradation or reaction due to heating and v***rizing the formulation of ni****ne and excipients (including flavorings) during the normal use of the product. Analytical chemistry data should be used to confirm the compounds present in the v***r produced by E(N)NDS under its normal operating conditions.

Literature review is often performed to capture the studies and identify the potential thermal degradation products of the ingredients in ENDS. However, a large number of results can be found irrelevant, which needs to be critically reviewed for information specific to the thermal degradation of the ingredients in the products under normal use conditions.

To further support the findings of this literature review, a computational modeling should be conducted to identify potential thermal degradation products based on the chemical structure of each ingredient and predictions of the possible chemical pathways and degradants. The selected model should consider such transformations as condensations and additions, eliminations and fragmentations, hydrolysis, isomerization and rearrangement, oxidation, and photochemical reactions, take into account a variety of degradation conditions.

Ultimately across computational modeling and literature reviews, those unique potential degradants identified should be added to aerosol testing in addition to HPHCs. Their toxicological profile and health risk at relevant exposure levels and all routes of exposure must be fully assessed for the ENDS to inform the weight of benefit over risk for intended user population.

09/19/2023

What are the appropriate animal models for COVID-19? Most have been directed toward rodents, transgenic rodents, and non-human primates. In these models the angiotensin-converting enzyme 2 (ACE2) is the host cell receptor for SARS-CoV-2 necessary for the infection. The affinity between the SARS-CoV spike protein and ACE2 is a major determinant for the susceptibility of the host to SARS-CoV infection. The ACE2 from human, bat, pig, and civet but not from mouse and rat, supported cellular uptake of SARS-CoV-2. high affinity between SARS-CoV-2 and the ACE2 protein correlates with susceptibility of the species to SARS-CoV-2 infection.

In an existing SARS-CoV models such as the Syrian hamster, SARS-CoV-2 has been reported to propagate and cause respiratory disease but only “mild SARS-CoV-2 infection” was obtained. Ferrets are well-known models for influenza and get infected with SARS-CoV-2, however only moderate disease is obtained. Non-human primates are an obvious choice based on closeness to humans genetically and a study reporting asymptomatic lung pathology after SARS-CoV-2 infection in cynomolgus macaques has appeared. Similarly, mild symptoms in rhesus macaques with weight loss and signs of pneumonia but no fever were observed following SARS-CoV-2 inoculation.

A group of scientists (Heegaard et al) urged to consider the obese Ossabaw pig model as a highly relevant animal model of severe COVID-19. The severe COVID-19 cases occur in people with chronic comorbidities such as diabetes, obesity, and/or cardiovascular disease. The metabolic syndrome, E.G., the persistent inflammation, increases the risk of a cytokine storm during coronavirus infection linking an aberrant metabolic state to severe COVID-19. The Ossabaw pig can reproducibly be made obese and show most aspects of the metabolic syndrome, thus resembling the critically ill COVID-19 patients admitted to hospitals.

08/05/2023

Functional Observational Battery (FOB)

As one of the 3 categories of pharmacology studies, safety pharmacology studies focus on investigating the potential undesirable pharmacodynamic (PD) effects of a compound on vital functions in relation to exposure in the therapeutic range and above. The functions of vital organ systems (e.g., central nervous, cardiovascular, and respiratory systems) are the most critical ones to assess in the studies.

The dose range should be appropriate to define the dose-response relationship of the adverse effect observed in consideration of the doses eliciting the primary PD effect in the test species or the proposed therapeutic effect in humans. Due to species differences in PD sensitivity, doses should include and exceed the primary PD or therapeutic range. In case of absence of an adverse effect on the safety pharmacology parameters, the highest tested dose should be a dose that produces moderate adverse effects (e.g., dose-limiting PD effects or other toxicity) in studies of similar route and duration of administration.

Investigation of the effects of a compound on the CNS is one assay of the core battery of safety pharmacology. Motor activity, behavioral changes, coordination, sensory/motor reflex responses and body temperature should be evaluated. For example, as a screening for behavioral toxicity, or neurotoxicity, FOB has become standard practice in preclinical safety pharmacology and toxicology. The FOB is derived from protocols used in pharmacology, toxicology, and psychology, with a focus on detailed observations and specific tests of reflexes and responses to assess autonomic, neuromuscular, and sensory function, as well as levels of activity and excitability.

FOB Has been shown to be valid in detecting expected effects of known neurotoxicants. From each study the data needs proper statistical analyses, and the data interpretation is based on the information from individual endpoints as well as the profile or pattern observed.

06/18/2023

Control of Nitrosamine Impurities

The nitrosamine impurities, which are probable or possible human carcinogens by the International Agency for Research on Cancer (IARC), were found in human drugs such as ranitidine, nizatidine, and metformin, etc. The drug substance and drug product manufacturers have conducted risk assessments and taken appropriate actions to reduce or prevent the presence of nitrosamines in drug substances and products.

How are Nitrosamine compounds formed? The compounds can form by a nitrosating reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions). Amines may be present in a manufacturing process. The API (or API degradants), intermediates, or starting materials may contain secondary or tertiary amine functional groups. Tertiary and quaternary amines may also be added intentionally as reagents or catalysts. Nitrites have been reported in many excipients at ppm levels, which may lead to nitrosamine impurities forming in drug products during the drug product manufacturing process and shelf-life storage period. All the types of amines can react with nitrous acid or other nitrosating agents to form nitrosamines. FDA has identified seven nitrosamine impurities that theoretically could be present in drug products: NDMA, N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethylphenylamine (NMPA).

How are Nitrosamine acceptable risk levels calculated? Based on ICH guidance M7(R1), a compound-specific acceptable intake (AI) can be calculated based on rodent carcinogenicity potency data such as TD50 values identified in the public literature or the Carcinogenicity Potency Database (CPDB). Linear extrapolation to an accepted lifetime risk level of 1 in 100,000. The AI (in mg/kg/day units) can then be converted to mg/day by multiplying by the human body weight. Linear extrapolation from a TD50 value is considered appropriate to derive an AI for M7 Class 1 impurities (known mutagenic carcinogens) with no established threshold mechanism. If more than one of the nitrosamine impurities identified and detected, the total quantity of nitrosamine impurities should be controlled typically not to exceed the AI for the most potent nitrosamines based on the maximum daily dose.

It’s the Agency’s recommendation that the drug substance and product Manufacturers should refer to the ICH guidance Q9 Quality Risk Management for details related to quality risk identification, analysis, and management, take appropriate measures to prevent unacceptable levels of nitrosamine impurities in human drugs.

05/28/2023

Unexpected vs. Anticipated Adverse Event Determination in IND Safety Reporting

How “Unexpected" is defined when adverse events are reviewed for IND safety reporting purposes? According to the FDA, an (suspected) adverse event is considered “unexpected” if it is not listed in the investigator brochure (IB) or is not listed at the specificity or severity that has been observed; or is not consistent with the risk information (nature, frequency, severity, specificity, mechanism, MOA) described in the general investigational plan when IB is yet to be developed. Under this definition, myocardial infarction, for example, would be unexpected (by virtue of nature, mechanism, specificity, and severity) if the IB referred to Lactate Dehydrogenase Deficiency. In circumstance that an adverse event is not specifically mentioned as occurring with the candidate drug under investigation though it is mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, it is Unexpected.

There has been some confusion with the term “Expected” versus “Anticipated” for the disease being treated in clinical trials or population studies. Certain serious adverse events can be anticipated to occur in the study population independent of drug exposure. Such events include known consequences of the underlying disease or condition under investigation (e.g., symptoms, signs, disease progression), and events unlikely to be related to the underlying disease or condition under investigation, but events anticipated from any background regimen, events common in the study population, or re-emergence or worsening of a condition relative to pretreatment baseline independent of drug therapy (e.g., diabetics in over weighted population, or cardiovascular events in an elderly population). Although these serious adverse events meet the definition of Unexpected as they are not listed in the IB, they do not meet the criteria for expedited reporting.

In general, a limited number of occurrences of such an adverse event in a study population in which occurrences of the event are anticipated is not an adequate basis to conclude that the event is a suspected adverse reaction (i.e., that there is a reasonable possibility that the drug caused the event). Such events do not warrant expedited reporting as individual cases because it is not possible, based on a single case, to determine that there is a reasonable possibility that the candidate drug caused the event. However, such anticipated adverse events should be monitored at appropriate intervals, and the numbers of events in each arm of a controlled study should be compared. The adverse event must be reported to FDA expeditiously as an IND safety report if there is an imbalance between arms suggesting there is a reasonable possibility that the drug caused the adverse event.

04/09/2023

A Few Considerations When You Design A Preclinical Safety Assessment Program For Biopharmaceuticals:

One of the safety concerns arises from the presence of impurities or contaminants in a biopharmaceutical. For instances, the presence of cellular host contaminants derived from bacteria, yeast, insect, plants, and mammalian cells can result in allergic reactions and other immunopathological effects, the nucleic acid contaminants may be integrated into the host genome. Thus a purification process is necessary at first place to remove the impurities and contaminants, and the product should be sufficiently characterized to allow an appropriate design of a preclinical testing program.

The product used in the pharmacology and toxicology studies should be comparable to the product proposed for the clinical studies. To demonstrate the comparability of the test material when a new or modified manufacturing process is developed or other significant changes in the product or formulation are made during product development, the biochemical and biological characterization (i.e., identity, purity, stability, and potency) can be evaluated, or additional studies (i.e., pharmacokinetics, pharmacodynamics and/or safety) conducted to provide the scientific rationale.

The biological activity together with species and/or tissue specificity of many biopharmaceuticals preclude standard toxicity testing designs in commonly used species (e.g., rats and dogs). To select relevant animal species for toxicity testing, in vitro cell lines derived from mammalian cells can be used to predict specific aspects of in vivo activity and to assess quantitatively the relative sensitivity of various species (including human) to the biopharmaceutical. Such studies may be designed to determine, for example, receptor occupancy, receptor affinity, and/or pharmacological effects, and to assist in the selection of an appropriate animal species for further in vivo pharmacology and toxicology studies. The combined results from in vitro and in vivo studies assist in the extrapolation of the findings to humans, and to support the rationale of the proposed use of the product in clinical studies. When no relevant species exists, the use of relevant transgenic animals expressing the human receptor, or the use of homologous proteins should be considered.

Immunogenicity is a potential concern for biopharmaceuticals. Many biopharmaceuticals intend to stimulate or suppress the immune system and may affect not only humoral but also cell-mediated immunity. One aspect of immunotoxicological evaluation includes assessment of potential immunogenicity. Immunotoxicological testing strategies may require screening studies followed by mechanistic studies to clarify such issues. Routine tiered testing approaches or standard testing batteries, however, are not recommended for biopharmaceuticals. Measurement of antibodies should be performed when conducting repeated dose toxicity studies in order to aid in the interpretation of these studies. Antibody responses should be characterized (e.g., titer, number of responding animals, neutralizing or non-neutralizing) and their appearance should be correlated with any pharmacological and/or toxicological changes. Specifically, the effects of antibody formation on pathological changes, pharmacokinetic/pharmacodynamic parameters, incidence and/or severity of adverse effects, complement activation, or the emergence of new toxic effects should be considered. The induction of antibody formation in animals is not predictive of a potential for antibody formation in humans. Humans may develop serum antibodies against humanized proteins, and frequently the therapeutic response persists in their presence. The occurrence of severe anaphylactic responses to recombinant proteins is rare in humans.

03/12/2023

To support human clinical trials for a pharmaceutical, nonclinical safety studies should be adequately conducted to characterize the toxic effects to target organs, dose dependence, relationship to clinical exposure, potential reversibility, and to provide the estimation of an initial safe starting dose and dose range for the trials.

How to select the high dose for general toxicity studies? In general, the effects that are potentially clinically relevant can be adequately characterized using doses up to the maximum tolerated dose (MTD) in toxicity studies. To prevent overdoing animals that would not add value to predicting clinical safety, other options of limit doses include use of the maximum feasible dose (MFD), or those at saturation of exposure or that achieve large exposure multiples.

Limit dose of 1000 mg/kg/day is considered appropriate for acute, sub-chronic, and chronic toxicity studies for rodents and nonrodents in most cases. In the few situations where a dose of 1000 mg/kg/day does not result in a mean exposure margin of 10x to the clinical exposure and the human dose exceeds 1 g/day, the doses in the toxicity studies should be a dose of 2000 mg/kg/day, MFD, or limited by a 10x exposure margin, whichever is lower. In situations in which the dose of 2000 mg/kg/day is less than the human dose, testing up to the MFD should be considered.

Based on the group mean AUC of the API to the clinical systemic exposure, doses providing a 50x margin of exposure are considered acceptable as the maximum dose for acute and repeated-dose toxicity studies in general. Dose-limiting toxicity should be identified in at least one species using the 50x margin of exposure as the limit dose, or characterized in a study of 1 month or longer duration in one species dosed at 1000 mg/kg, MFD or MTD (whichever is lowest), or a study of a shorter duration at doses higher than the 50x exposure margin. If genotoxicity endpoints are to be incorporated into a general toxicity study, then an appropriate maximum dose should be selected based on a MFD, MTD, or limit dose of 1000 mg/kg/day.

02/18/2023

The thresholds of toxicological concern (TTCs) are defined as the limits for substances with unknown toxicity below which the intake is considered to be of no concern to human health. A review of the articles published by Carthew et al (2009), Munro et al (1996), and Escher et al (2010) reaffirms the understanding that the inhalation thresholds for Cramer classes 1, 2, and 3 chemicals can be considerably lower than the oral thresholds. What is the scientific rationale behind the findings of the lower thresholds derived for inhalation compared to the oral route?

One of the reasons for the difference is the higher sensitivity of the respiratory tract to local effects than the digestive tract. The substance itself may be more toxic in the respiratory tract due to its irritating properties and/or differences in metabolism/bioactivation in the lung compared to the liver (first pass effect). It is also noticed that classical systemic targets such as liver or kidney are affected less frequently in determining the no observed effect concentrations (NOECs) compared to local target organs such as nose or lung after inhalation exposure. Indeed, the local effects in the respiratory tract play a role in determining the NOECs that may trigger the low threshold values.

It is also observed that NOECs differ between local and systemic toxicities, i.e., the threshold values are lower for ‘‘local” toxicity than ‘‘systemic” toxicity. The studies (Carthew et al 2009, and Escher et al 2010) revealed that there were particular structural features that account for large differences between systemic and local NOEC values in inhalation studies. The most frequently occurring structural class is that of carboxylic esters, α, β-unsaturated carbonyls, aliphatic ethers, acyl halogenides, diisocyanates, diketones, and secondary amines in the dataset these investigators analyzed. Thus, the NOECs and the 5th percentiles of NOECs and TTCs based on local effects in the respiratory tract are lower than those derived from systemic toxicity. The analysis from these investigators provides solid support to the finding that the sensitivity of the respiratory tract leads to lower inhalation TTCs compared to oral TTCs.

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