Chihuahuas to mastiffs: therapeutics and body size (Proceedings)
Small animal practitioners are well aware that "cats are not small dogs". However, are small dogs just miniaturized versions of their larger brothers and sisters? What about the effect of breed on therapeutics? The incredible diversity of dog breeds presents veterinarians with problems and opportunities inherent to the medical care for such a highly variable species.
Given the wide range of body weights associated with breed, from a 2 kg Chihuahua to an 80 kg Mastiff, adjustments at the extremes of body size are of particular importance in dogs. Many anatomical parameters, such as blood volume, hematocrit, red blood cell size and capillary diameter, are either directly proportional to or independent of body weight.1 However, numerous physiological and anatomical parameters are not related to body weight in a directly proportional, or isometric, manner. Changes in body weight result in disproportionate or allometric changes in characters such as organ weight, heart rate, cardiac output, hepatic blood flow, renal blood flow, respiratory rate, and metabolic rate.2,3 Such parameters are said to be allometrically related to body weight. Scalable parameters are usually best-described by the generalized relationship: y=a · w b, where y is the scalable parameter, a is the mass coefficient, W is body weight, and b is the mass exponent.
In addition to anatomical and physiological factors, longevity is subject to body size effects, with the well-recognized general relationship between small body weight and longer lifespan in dogs.4 Although lifetime energy expenditure has been suggested in differential longevity in dogs of different sizes, endocrine and other factors may actually be more important. However, the study of bioenergetics began as a physiological pursuit that ultimately revealed surprising anatomic implications and present some of the most robust examples of scalable parameters. As an animal's mass increases, its metabolic rate increases less than does the animal size: size and metabolic rate are not directly proportional.5 The power function relating metabolic rates to mass has been used to describe the relationship existing between the increase in metabolic rate as a function of body size in animals ranging from unicellular organisms to large mammals.6 When the metabolic rates of many animal species are considered together, the resulting mass exponent is approximately 0.67, the basis of the "surface area rule" that implicates surface to volume relationships as the major predictor of mass exponents. The mass exponent, "b," has alternatively been described as approximately 0.75, and the accumulation of larger amounts of data have generally supported the use of the 3/4 exponent, at least when animals from multiple species are examined. Metabolic rate has also been specifically examined within dogs, and found to scale with exponents between 0.67 and 0.75.7Kidney function is a physiological parameter that clearly requires some kind of non-proportionality adjustment for estimation of normal values in healthy animals. In comparison to dogs, cats vary little in body size, so normalization to body weight is all that is necessary for estimation of glomerular filtration rate (GFR) in healthy animals.8 However, when dogs of sufficient size range are examined, normalization of GFR to body surface area (BSA) is necessary to accommodate non-proportional increases in GFR with body size.8 Although the ramifications of such non-proportionality on the doses of drugs subject to renal-excretion have been poorly studied, it is likely that similar dose adjustments of renally cleared drugs with narrow therapeutic indices are warranted. It is also likely that drugs cleared by processes other than renal clearance, such as tubular secretion, will also be best dosed by considering non-proportionality. Such adjustments are likely to be most important for drugs with narrow therapeutic indices, where an excess of drug may be toxic and too little will be similarly harmful. Dogs at the extremes of body size, such as the 2 kg Chihuahua and the 80 kg mastiff, are also most likely to benefit from such dose adjustments.
Practitioners may be most familiar with scaling of drug doses from the practice of adjusting the dose of cytotoxic anticancer drugs on the basis of the patient's body surface area (BSA). Due to the unique dosing concerns inherent to the use of cytotoxic drugs, clinicians have calculated doses of these agents as a function of body surface area since the late 1950's. The BSA dosing method was partly based upon earlier studies in which metabolic rate appeared to be directly proportional to BSA, and thus vary allometrically with body weight. Clinicians and medical researchers likewise found that the disposition of some drugs could be more accurately described as a function of BSA than of body weight. From these studies, a rational theory relating body weight, metabolic rate, BSA, and drug disposition emerged: BSA varies with body weight by the 2/3 power due to surface area to volume ratios, which are inherent to geometrically similar objects. As a consequence, smaller individuals also exhibit higher surface area to volume ratios, resulting in greater heat loss, or metabolic rate, per unit volume. The relatively higher metabolic rates of these smaller bodies results in higher rates of drug metabolism and excretion. Therefore, to produce the same extent of drug exposure, smaller individuals require larger dosages on a body weight basis than do larger individuals. Finally, both BSA and drug clearance depend on body weight with the 2/3 power, resulting in the correlation of clearance and BSA. Early studies supported the BSA theory of drug dosing, and the system was ultimately adopted in the selection of initial doses of anticancer drugs for Phase I studies. Despite inaccuracies that have subsequently been associated with the BSA dosing methodology, most notably for the administration of doxorubicin in dogs, the normalization of anticancer drug dose to BSA remains the standard of care for most cytotoxic drugs.9,10
While anticancer drugs are the most visible means of adjusting drug dosages, other examples of body size adjustment abound in small animal practice. For example, the scientists and clinicians who first investigated the use of medetomidine as a sedative agent in dogs quickly realized that weight-proportional dosing was insufficient to control variable responses to this agent in dogs of different breeds. The final FDA label approved for medetomidine and now the newer agent, dexmedetomidine, as a sedative in dogs instead advocates dosing this drug as a proportion of BSA, as a range of doses/m2. As a fine example of the ramifications of BSA dosing, the package insert for dexmedetomidine points out that, "the mcg/kg dosage decreases as body weight increases. For example, dogs weighing 2 kg are dosed at 28 mcg/kg dexmedetomidine IV, compared to dogs weighing 80 kg that are dosed at 9 mcg/kg." Would the reliability and safety of other sedative and anesthetic agents benefit from adjustment to body surface area, or some other surrogate of non-proportionality in the metabolism of drugs?
Although adjustments for body size may be valuable for anesthetic agents and other drugs with a narrow therapeutic index, other adjustments for anesthetic agents are clearly dependent on breed-specific polymorphisms. For examples, the lean greyhound has long been recognized to be particularly sensitive to the effects of some injectable anesthetic agents that require redistribution into fat for termination of effect.11 However, more recent evidence points to polymorphisms in the greyhound hepatic cytochrome P450 system that is responsible for metabolizing most anesthetic agents, such as propofol.12 Although largely unexplored at this time, such differences are also likely to be important in the handling of other drugs by greyhounds and other sighthounds. Even the familiar beagle, bastion of both human and veterinary preclinical pharmacokinetic and toxicity studies, has been found to exhibit genetic polymorphisms in cytochrome P450 that differentiate it from the "typical" dog.13 Other breeds exhibit other polymorphisms that will likely impact the practitioner's ability to safely and effectively administer appropriate drug therapy. The collie and related breeds are now well-recognized to differ from typical dogs in the proportion of dogs that exhibit deficiencies in p-glycoprotein expression, most famously allowing ivermectin and related drugs to accumulate in the central nervous system.14 Given the importance of p-glycoprotein to many other drug handling processes, such as oral absorption and biliary excretion, the importance of the multi-drug resistance mutation (ABCB1 gene) on the use of numerous classes of drugs is likely, but poorly understood.15 Accommodation of diverse breed differences requires a knowledge of how both body size and genetic polymorphisms affect drug handling. Although undoubtedly of clinical importance, rational adjustments to individual differences within dogs are nearly in its infancy.