Hervé P. Lefebvre, DVM, PhD, DECVPT
UMR 181 Physiopathologie et Toxicologie Experimentales INRA, ENVT and Department of Clinical Sciences, National Veterinary School
Most of the practitioners use the fixed dose recommended on the product label whatever the patient. Some dogs/cats however may fail to respond to the prescribed treatment whilst others experience adverse effects. 'One drug or one dose does not fit all'. Dose individualization is the best method of reducing interindividual variability. In humans, more rational approaches to drug dosing, taking into account individual characteristics, such as pharmacogenetic factors, renal function or hepatic metabolism, have been proposed. In veterinary medicine, such drug individualization remains currently a difficult challenge because of the lack of knowledge on inter- and intraindividual factors of variation. Only the main physiological factors affecting individual drug response in the canine species will be presented here.
Pharmacokinetic and Pharmacodynamic Considerations
Dose individualization is the best method of reducing interindividual variability. The dose depends on several parameters:
Dose = (body clearance x therapeutic concentration)/bioavailability
Body clearance and bioavailability are generally determined by appropriate pharmacokinetic studies performed in healthy experimental Beagle dogs, which are not representative of the target population which includes diseased and non Beagle dogs. The 'average' value obtained for clearance and bioavailability is only an 'average' value and does not take into account the interindividual variability. For example, if the 'average' oral bioavailability of a drug is 40%, that means that when a 100 mg dose is given, only 40 mg will reach the systemic circulation. Nevertheless, if the mean+/-SD of bioavailability is 40+/-15%, that means that the actual bioavailability may be 25 and 55% in two individuals. Consequently, the exposure may change by 2-fold from one patient to another one. Another issue is intraindividual variability in drug pharmacokinetics (PK) which is unknown for most veterinary drugs. The dose depends also on the target therapeutic concentration which is generally poorly defined. The concentration-effect relationship should be documented, but it shows also interindividual variability.
Population PK modeling methods are promising approaches for drug individualization. Unfortunately, they have been rarely used in small animal pharmacology (Whittem, 1999). Population PK or pharmacodynamics (PD) is defined as the study of the variability in drug concentration or pharmacological effect between individuals when standard dose regimens are administered (Aarons, 1991). Such population analysis uses specific patient covariates (e.g., weight, age, disease state) to predict the interindividual variation. However, unexplained interindividual variability remains.
Physiological Factors of Variation
Variability in drug response can be related to physiological, pathological or drug-induced variation in the treated animal, or to variation between individuals in the target population. Practitioners are aware of potential alterations in drug PK or PD due to concomitant diseases, but often underestimate the effect of physiological factors.
This factor has been underestimated until recently. The breed is clearly a major determining factor of the variability in drug PK, PD and safety. This breed-dependent variability results mainly from physiological differences. This issue is a major concern as Beagle dogs are generally used for dose titration studies and are not representative of the canine breed diversity. One of the first observations reported in small animal veterinary literature was that thiobarbiturates induced longer anesthetic effects in Greyhound dogs than in mixed-breed dogs (Sams et al, 1985). Greyhound dogs also appear to be atypical for propofol pharmacokinetics because of breed differences in liver hydroxylase activity (Court et al, 1999). Intestinal absorption may also be different between breeds as shown for intestinal permeability between Greyhound and Golden retriever dogs (Randell et al, 2001). Gastric emptying and orocecal transit time are similar in small and large-breed pups (Weber et al, 2005). Glomerular filtration rate may vary considerably (up to 2-3 fold) according to the breed and the size of the dog (Lefebvre et al, 2006). Pharmacodynamic differences exist also between breeds. The dose-effect relationship of anticholinergics and prokinetics on gastric motility differ between Beagle dogs and Labrador retriever dogs (Burger et al, 2006).
The breed also may affect the drug safety. Collies and related breeds are highly sensitive to nervous toxicity of avermectins, due to a deletion mutation of multiple-drug-resistance gene (MDR1) coding for P-glycoprotein (Mealey et al, 2001).
Puppies should not be considered as adult dogs. Gastric emptying time of solids is shorter in small- and large-breed puppies than in adult dogs (Weber et al, 2002). Differences in hepatic drug metabolism probably occur. For example, the plasma elimination half-life of acetaminophen was about 4.5 fold shorter at 40- to 60-day-old puppies than that at 4 days of age (Ecobichon et al, 1988). Distribution is probably also different as water content is higher than that in adult dogs. Hepatic metabolism has not been investigated in pups. Glomerular filtration rate in 3-month old puppies is two-fold higher compared to that in adult dogs (Laroute et al, 2005). Specific dosage regimen need to be defined in neonate and pediatric canine populations.
Aging can also affect drug pharmacokinetics and pharmacodynamics. Oral absorption can be altered by decreased gastrointestinal motility, blood flow, and secretion. Effect of aging on drug distribution has not been investigated in dogs and cats. Nevertheless, in the aged dog, the lean body mass is decreasing and the fat content is increasing. These changes may affect drug distribution: Vd of drugs that primarily distribute to body water decreases, while Vd of lipid-soluble drugs increases. Alterations in hepatic metabolism is hypothesized in aged dogs and cats but is not clearly established. The clearance of propofol appears to be lower in aged dogs compared to that in young adults (Reid and Nolan, 1996). In humans, decreased renal excretion of drug is the major pharmacokinetic alteration observed during aging because there is a gradual decline in renal function with age. In the dog, recent data suggest that glomerular filtration remains stable or decreases only mildly (Queau et al, 2007). Therefore, empirical reduction of doses in the aged dog appears not to be appropriate. Pharmacodynamic modifications have been evidenced in the aged human patient, and they cannot be excluded in dogs and cats. The aged patient might be more sensitive to drug adverse effects than young adults. For example, in some geriatric dogs, a lower dose of propofol than that recommended was associated with post-induction apnea (Reid and Nolan, 1996).
Effect of Body Weight
The body weight (BW) is generally used for dose calculation but two individuals may have the same body weight and different body composition. In such conditions, drug distribution may be different. Moreover, change in body weight is not associated with proportional change in other physiologic process, especially those involved in drug pharmacokinetics. In other terms, a 20%-increase in BW does not mean that the total dose should be increased by 20% to maintain the drug response. Effects of weight gain on drug pharmacokinetics have not been investigated in dogs so that it is difficult to predict how to adjust the dose when the BW increases. Lean body mass cannot be easily estimated.
Body surface area is also used for dose calculation, especially for chemotherapeutic drugs, as it has been considered to correlate more closely to physiologic process than BW. However, such indexation is highly questionable as the current formula used to calculate BSA in dogs may be inaccurate and the assumption that BSA correlates with chemotherapeutic drug exposure is unfounded (Price and Frazier, 1998). For example, it is difficult to believe that a unique formula can be valid for all dogs. Moreover, doxorubicin concentrations and toxicity was greater in smaller dogs when the dose was calculated using BSA instead of BW (Arrington et al, 1994).
Effect of Other Physiological Factors
Sex may affect pharmacokinetics and pharmacodynamics as shown for example with moxidectin (Vanapalli et al, 2002), but sex effect is generally mild with the exception of reproductive hormones. Circadian variations in drug response may also exist as reported for cisplatin in dogs (Hardie et al, 1991). Food may considerably affect drug absorption. Interval between feeding and drug administration may be critical as shown for ampicillin (Kung et al, 1995). The absorption of celecoxib, a NSAID, is delayed by food, although systemic exposure increased by 3- to 5-fold (Paulson et al, 2001). Change in diet composition may alter response to treatment. Low-sodium diet may increase the acute hypotensive effects of angiotensin-converting enzyme inhibitors and high protein diet may affect gentamicin-induced nephrotoxicity (Grauer et al, 1994).
"The right dose for the right patient" concept is difficult to develop in small animal pharmacology because of the high number of potential factors affecting individual response which are currently poorly documented for most drugs. The concept "The right dose for the right population" would be probably more realistic.
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