5 Origin of Interspecies Differences in Dosage Regimens
For each drug in each species an efficacious and safe dosage regimen (dose level,
interval of administration, and dosing duration) should be determined. Dosage
regimens may vary markedly between species, even when doses are expressed by
kg of body weight. For xylazine, an alpha-2 agonist used as a sedative, the effective
dose is tenfold lower in cattle than in horses, despite similar PK profiles (Garcia-
Villar et al. 1981 ). For morphine, the effective dose is ten-fold lower in cats than in
dogs; for aspirin, dosage is approximately 40 times higher in cattle than in cats,
while for suxamethonium (succinylcholine), a depolarising neuromuscular blocker,
the dose in cattle is some 40 times lower than in cats. From these examples, it seems
that no generalisation can be established between interspecies variability and
certain physiological traits, such as herbivorous vs. carnivorous species or mono-
gastric species vs. ruminants. Rather, it should be realised that a dosage regimen is a
PK/PD hybrid variable with two major components: a PK and a PD component (1):
ED¼
ClearanceEC
Bioavailability; (1)
whereEDis an efficacious dose,Clearanceis the plasma (total) clearance,Bio-
availabilityis the extent of the systemic bioavailability (for extravascular routes of
drug administration) andECis the efficacious plasma concentration. Clearance is a
pharmacokinetic parameter expressing the overall capacity of the body to eliminate
the drug. Bioavailability is a PK variable expressing the percentage of drug that
actually reaches the systemic circulation after administration by an extravascular
route andECis the PD parameter expressing drug potency (Toutain 2009 ). Thus,
interspecies variability may have either a PK (as for aspirin or suxamethonium),
and/or a PD (as for xylazine) origin. It should be understood that the 3 factors
determining a dose are themselves hybrid parameters and recognising their
biological determinants helps to identify the different anatomical, physiological,
and/or behavioural sources of interspecies differences. For example, plasma clear-
ance is the sum of different clearances (2):
Clearancetotal¼CLhmþCLnhmþCLbþCLrþCLother; (2)where the total clearance is the sum of the hepatic (CLhm) and non-hepatic meta-
bolic clearance (CLnhm), the biliary clearance (Clb) and the renal clearance (CLr),
with other clearances (CLother) generally being negligible. Thus, the interspecies
variability in plasma clearance reflects differences in the relative importance of the
several potential pathways of drug elimination (liver and non-liver metabolism vs.
biliary elimination vs. renal elimination) and the capacity for any given mode of
elimination.
The molecular weight (MW) of a compound is a key factor determining the
extent of biliary vs. non-biliary excretion. Experiments in rats with compounds
30 P.-L. Toutain et al.