Drug Development and the Use of Pharmacokinetics/Toxicokinetics in Selecting the First Dose of Systemically Administered Drugs in Humans—A Nonclinical Perspective
John C. Lipscomb, Edward V. Ohanian in Toxicokinetics and Risk Assessment, 2016
The selection of the first dose in humans depends on whether the population is considered healthy or whether it is a patient population with moderate or serious disease. More toxicity in patients is acceptable for more serious conditions. For normal volunteers, the first dose is generally determined by extrapolation from a NOAEL for a dose-limiting effect in the most sensitive species, followed by conversion to a HED with allometric scaling based on BSA. The recommended safety factor is 10, which may be increased or decreased under certain conditions (9). However, sometimes Cmax or AUC values in all the species tested suggest that correlation is better with dose in mg/kg or something else. The safety factor might be increased if there is a steep dose response for serious toxicity, especially if the steep dose response is seen in multiple species, or if there are severe nonmonitorable toxicities (such as cardiac necrosis, brain vacuolization, or nonimmune vasculitis) or toxicities without premonitory signs (sudden death with no warning that the patient is about to die). The safety factor might be reduced if the drug is a member of a well-characterized class with similar metabolic profile, bioavailability, and toxicity across all species, including in humans for other members of the class, and the dose response for toxicity is moderate to shallow and is consistent across tested species with regard to appropriately scaled dose and exposure. Nonclinical data on bioavailability, the metabolite profile, and plasma drug levels associated with toxicity may influence the selection of the NOAEL. Other types of scaling could be based on what is known about a class of drugs.
Hierarchical Modeling and Aggregation
Song S. Qian, Mark R. DuFour, Ibrahim Alameddine in Bayesian Applications in Environmental and Ecological Studies with R and Stan, 2023
The hypothesis testing based assessment rules, when presented with the Magnitude-Duration-Frequency components (see Section 1.4.4), are often confusing and difficult to interpret. For example, the TP criterion for the Central Florida Bay is expressed as: “the annual geometric mean TP concentration shall not surpass 0.019 mg/L more than once in a three-year period” [FDEP, 2011]. That is, the criterion has a magnitude of 0.019, a duration of 1 year, and a frequency of 1/3. After a careful read of the criterion development document, however, we learned that the criterion is developed to ensure that the long-term (geometric) mean TP concentration is around 0.014 mg/L, a value established as the “healthy existing condition” of the water. In order to derive a rule with a frequency component, Florida Department of Environmental Protection (FDEP) argued that the 80th percentile of the annual geometric mean distribution should be used as the magnitude of TP criterion. This is a level of protection similar to the commonly used engineering practice of adding a safety factor. The frequency of one in three years is based in the binomial test with null hypothesis . (FDEP calculated the 0.8 quantile to be 0.019 using a data set representing the “reference condition.”) The null hypothesis can be rejected with a significance level of when more than one exceedance is observed in three trials, where p is the exceedance probability. (If the true exceedance probability is 0.2, the probability of observing 0 or one exceedance in three trials (years) is 0.896). Such a rule attempts to “evaluate a statistical feature that requires the law of large numbers using a sample size of three” [Guttorp, 2006].
Evaluation of complementary and alternative therapies
Peter R Wilson, Paul J Watson, Jennifer A Haythornthwaite, Troels S Jensen in Clinical Pain Management, 2008
The extremely high dilutions of homeopathic remedies suggest the absence of risk. However, the use of toxic agents such as heavy metals, arsenic, bromide, etc., combined with improper handling, can result in adverse effects.65 The reliability of the manufacturer is therefore an important safety factor. Avoiding remedies that use heavy metals, such as mercury or cadmium, may also be a warranted safety measure.
Biomechanical assessment of screw safety between far cortical locking and locked plating constructs
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2021
Yuping Deng, Hanbin Ouyang, Pusheng Xie, Yanfang Wang, Yang Yang, Wenchang Tan, Dongliang Zhao, Shizhen Zhong, Wenhua Huang
The safety factor is a ratio of yield strength to intended load for the actual item that was designed (Macciotta 2018). The allowable strength design method and probability ultimate-state design method have been used in mechanical engineering and civil engineering (Committee 1988), and these methods should be used for assessing and designing medical instruments as well. In our results, the stress of the FCL constructs was significantly higher than that of the LP constructs at all locations, and the von Mises stress of the FCL screw exceeded the allowable stress of the material. However, the critical threshold stress causing bone resorption remained unclear and human bones will grow and heal by themselves, fracture healing models at bone-screw interface are always irreproducible in the laboratory and almost impossible to perfectly validate. There is currently no definitive mathematical or mechanical model of fracture healing for computational simulation as the fracture healing models at bone-screw interface. Fracture fixation is a tradeoff between fracture healing and constructs failure. And considering models under high cycle fatigue loading conditions would make the true failure mechanism more complex and unpredictable. Thus, we focused on assessment of the screws and metal implant safety issues only. Further investigation should pay more attention to the bone-screw interface stress issues for the far cortical constructs
Railway safety climate: a study on organizational development
Published in International Journal of Occupational Safety and Ergonomics, 2019
Factor 3: safety management comprises the following 12 items: (a) the safety deputy’s suggestions are taken seriously by management; (b) information about undesirable incidents is effective in preventing their recurrence; (c) emergency preparedness is good; (d) the safety deputies are good; (e) the organization conducts safety inspections frequently; (f) the organization investigates safety problems quickly; (g) the organization provides safety equipment; (h) the organization provides safe working conditions; (i) the organization always responds quickly to safety concerns; (j) the organization keeps employees informed of hazards; (k) the organization has explicit safety targets; (l) the organization has a section responsible for safety management. Most items are related to safety management. The factor loading of these 12 items is in the range of 0.5–0.7. ‘Emergency preparedness is good’ has the highest factor loading in this dimension. Factor 3 accounts for 17.88% of total variance.
Design approaches and challenges for biodegradable bone implants: a review
Published in Expert Review of Medical Devices, 2021
A successful biodegradable implant that is pretty much capable of avoiding painful re-surgeries must satisfy the below mentioned requirements: Adequate strength and other mechanical properties that depend on material optimization and processing techniques.Appropriate biodegradation rate that can strike a balance between the strength or support requirement, and complete biodegradation. Higher than the desirable biodegradation rate is likely to defeat the basic support purpose, whereas lower than the desired biodegradation rate will prolong the degradation cycle and will consequently give rise to health issues, increased probability of re-surgery, etc. If maximum possible plate thickness is resorted to then complete degradation of the implant within 9–15 months from implantation will be difficult. On the other hand, lower thickness of the implant plate is likely to lower the value of factor of safety (FS).Minimum possible equivalent stress so that the factor of safety decreases to the extent possible, without compromising the support function.Maximum possible thickness to result in best possible factor of safety in design while going through complete degradation within 9–15 months and that too without adversely affecting human body.
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