scholarly journals Principles of dose-setting in toxicology studies: the importance of kinetics for ensuring human safety

2021 ◽  
Author(s):  
C. J. Borgert ◽  
C. Fuentes ◽  
L. D. Burgoon
Keyword(s):  
Blood Level ◽  
Maximum Dose ◽  
Dose Range ◽  
Chemical Toxicity ◽  
Regulatory Toxicology ◽  
Toxic Dose ◽  
Kinetic Relationship ◽  
Chemical Hazard ◽  
Pharmacology And Toxicology ◽  
Safe Dose

AbstractRegulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals—i.e., the field of kinetics—often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.

Phase 1 Clinical Trials of Small Molecules: Evolution and State of the Art

2021 ◽  
Vol 16 ◽  
Author(s):  
John J. Sramek ◽  
Michael F. Murphy ◽  
Sherilyn Adcock ◽  
Jeffrey G. Stark ◽  
Neal R. Cutler
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Healthy Volunteers ◽  
Small Molecules ◽  
Phase 1 ◽  
Dose Range ◽  
Pharmacodynamic Modeling ◽  
Inpatient Setting ◽  
Conducting Phase ◽  
Safe Dose

Background: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound, and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. Methods: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including “healthy volunteers”, “Phase 1”, and “normal volunteers” , and also based on the authors’ own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. Results: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. Conclusion: Phase 1 studies can yield critical insights to the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

SENSITIVITY OF THE RAT TO INCREASING DOSES OF DEXTRAN

1962 ◽  
Vol 40 (6) ◽  
pp. 697-702 ◽  
Author(s):  
Gaetan Jasmin ◽  
Pierre Bois ◽  
Mai-Shian Su
Keyword(s):  
Toxic Effect ◽  
Intravenous Injection ◽  
Dose Response ◽  
Dose Range ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Toxic Dose ◽  
Lower Dose Range ◽  
Higher Doses ◽  
Adrenalectomized Rats

Increasing doses of dextran, a commercial 6% solution, were injected intravenously into both intact and adrenalectomized rats to evaluate the dose–response relationship. The minimum dose capable of producing an edema with 100% incidence was approximately 30 mg/kg in intact and only 4 mg/kg in adrenalectomized rats. Lower doses produced responses of decreasing intensity and incidence with a longer period of onset. Conversely, higher doses resulted in a shorter period of onset and a more intense reaction until a toxic dose was reached, beyond which cyanosis and shock appeared. Adrenalectomized rats reacted similarly to intact ones except that their response occurred at a lower dose range; they could not withstand the toxic effect of higher doses and died of circulatory failure. The fact reported by other workers that the edema is more intense and appears more rapidly after intravenous injection of minute rather than large quantities of dextran was not confirmed; the existence of a "critical dose" that does not produce any edema was not substantiated.

Metoclopramide: dose-related toxicity and preliminary antiemetic studies in children receiving cancer chemotherapy.

1985 ◽  
Vol 3 (8) ◽  
pp. 1136-1141 ◽  
Author(s):  
J C Allen ◽  
R Gralla ◽  
L Reilly ◽  
M Kellick ◽  
C Young
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Cancer Chemotherapy ◽  
Randomized Clinical Trials ◽  
Dose Range ◽  
Toxicity Study ◽  
Dose Increase ◽  
Younger Adults ◽  
Nonrandomized Trial ◽  
Safe Dose

Prior studies in adults have shown that metoclopramide (MCP), when given in high intravenous (IV) doses (2 mg/kg), is a highly effective antiemetic for chemotherapy-induced vomiting. It is well-tolerated in older adults, but younger adults have an increased disposition to acute extrapyramidal reactions (EPRs). Before studying the efficacy of MCP as an antiemetic in children, we first had to establish the safe dose range. We performed a dose-increase MCP toxicity study in children receiving highly emetic chemotherapy such as cisplatin (120 mg/m2) or cyclophosphamide (greater than 900 mg/m2), beginning with a dose of 0.2 mg/kg and increasing the dose in nine steps to 3 mg/kg. MCP was given every two hours for four doses beginning one-half hour before chemotherapy. To reduce the incidence of EPRs, we added concomitant diphenhydramine. In MCP doses less than 2 mg, toxicity was minimal. In doses greater than or equal to 2 mg, 4/27 (15%) had EPRs and 9/27 (33%) had akathisia. Children who received two consecutive days of MCP had a higher frequency of EPRs. Metoclopramide (2 mg/kg) had promising antiemetic efficacy in a preliminary nonrandomized trial. Chemotherapy-experienced children vomited fewer than five times in 9/21 (43%) trials, and new patients vomited fewer than five times in 7/10 (70%) trials. MCP will become more useful as an antiemetic in children if better measures to prevent EPRs can be developed. Chemotherapy-induced emesis has the same negative implications in children as it does in adults and optimum antiemetic regimens can only be discovered by conducting randomized clinical trials in children.

scholarly journals Subacute Toxicity Study of Nicotinamide Mononucleotide via Oral Administration

2020 ◽  
Vol 11 ◽  
Author(s):  
Yingnan You ◽  
Yang Gao ◽  
Han Wang ◽  
Jingshu Li ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Uric Acid ◽  
Oral Administration ◽  
Dose Range ◽  
Cellular Level ◽  
Toxicity Study ◽  
Beagle Dogs ◽  
Subacute Toxicity ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Safe Dose

Nicotinamide mononucleotide (NMN), a key precursory metabolite of NAD+, has been shown to elevate the cellular level of NAD+ and ameliorate various age-related diseases. Despite these progresses, systemic evaluation pertaining to the subacute toxicity of NMN remains to be determined. Here, we examine the subacute toxicity of NMN in mice and beagle dogs. Mice were gavaged with a saturated concentration of NMN solution at the maximum intragastric dose once or twice per day for 7 days. Dogs were gavaged twice per day for 14 days. In mice, NMN administrated once per day for 7 days is well tolerated with minimal deleterious effects. Upon higher dosage, we observe slightly increased level of alamine aminotransferase, while other biomarkers remain unchanged. Consistently, administration of NMN in beagle dogs only results in mild increases in creatinine and uric acid. Together, our study highlights the safety of NMN, providing a possible safe dose range for oral administration of NMN.

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