Considerations in the extrapolation of drug toxicity between humans and dogs

Abstract

The dog is an important species used in preclinical studies in support of human drug product development. Likewise, because of the many active pharmaceutical ingredients (APIs) with therapeutic relevance to both humans and dogs, extrapolation can also occur in the reverse, from human to dog. In either situation, it is important to appreciate species-specific factors influencing drug pharmacokinetics (absorption, metabolism, disposition, and elimination) and the potential impact of disease on the applicability of these extrapolations. Furthermore, tools such as physiologically based pharmacokinetic (PBPK) models not only enable investigators to extrapolate species-specific data on systemic or organ exposure to the parent compound and metabolite(s) but also facilitates an interrogation of factors that can lead to species-specific differences in drug effectiveness and toxicity. In this review, we explore the factors and tools that comprise our current arsenal for understanding and predicting human-canine comparative toxicity.

Comparison of Canine and Human Physiological Factors: Understanding Interspecies Differences that Impact Drug Pharmacokinetics

“…Gastric Crushing Force Dogs and humans exhibit similar area-normalized torque (approximately 3700 dynes/cm 2 ), reflecting comparable 2dimensional rotational force, but very different 3-dimensional crushing force (8). Using identical pressure sensitive pills in dogs and humans, the area-normalized gastric emptying force (dynes/cm 2 ) was 606 and 962 in fasted and fed humans and was 3858 and 3639 dynes/cm 2 for fasted and fed dogs (16).…”

“…To support these important interspecies extrapolations, there is a need to understand the respective physiological differences that can exist in drug absorption, distribution, metabolism, and elimination. Such information can also help predict interspecies differences in drug toxicity (5)(6)(7)(8)(9). Therefore, this review provides a comparison of canine vs. human physiological characteristics, transporter abundance, activity and location, and enzyme abundance, activity, and location.…”

Cyanotoxins Associated with Macrophytes in Berlin (Germany) Water Bodies – Occurrence and Risk Assessment

“…Consequently, dogspecific guideline values as proposed by the Oregon Health Authority are 50-fold lower compared to those proposed for humans (Farrer et al, 2015). In this context, it is worth noting that dogs may be more susceptible to anatoxins than humans: the pharmacokinetics of other alkaloids such as theobromine in chocolate show significantly lower half-life times in dogs (Martinez et al, 2020) resulting in frequent consultations for "chocolate poisoning" in veterinary clinics (Cortinovis and Caloni, 2016;Weingart et al, 2021). Another aspect is that taste and odour substances coproduced with toxins (Gaget et al, 2022;Li et al, 2022) may attract dogs (Codd et al, 1992) and possibly lead to a selective intake of potentially toxic cyanobacteria.…”