Modelling concentrations of antimicrobial drugs: comparative pharmacokinetics of cephalosporin antimicrobials and accuracy of allometric scaling in food-producing and companion animals
Pharmacokinetics of cephalosporins
The collected pharmacokinetic data on cephalosporins are presented in Additional file
1: Table S1. Pharmacokinetics of 1st and 2nd generation cephalosporins for the included
animal species were available from 15 studies (horses n?=?7, dogs n?=?4, cats n?=?2 and cattle n?=?2) involving 5 different cephalosporins (cefadroxil, cefazolin, cefapirin, cefalexin
and cefoxitin). An interspecies difference was observed for plasma protein binding
between horses and cattle for cefazolin (75 % in cattle, compared to 8.3 % in horses).
Comparing different cephalosporins over all species, cefazolin had the shortest elimination
half-life (ranging from 0.62 h in cattle to 1.23 h in dogs) and cefalexin the longest
(1.38 h in dogs to 2.02 h in horses). Volume of distribution was limited for all cephalosporins
(ranging from 0.135 L/kg (cefazolin in horses) to 0.374 L/kg (cefadroxil in horses)).
Clearance ranged from 0.140 L/kg/h (cefalexin and cefoxitin in cats) to 0.598 L/kg/h
(cefapirin in horses). Data was too limited for comparison of different cephalosporins
within each animal species, except in horses. No substantial differences exist between
pharmacokinetics of different cephalosporins in horses; t½ is short (ranging from
0.63 to 2.02 h), volume of distribution is limited (0.135–0.374 L/kg) and excretion
is mainly through renal mechanisms for all compounds with a clearance of 0.204–0.598 L/kg/h.
For 3rd and 4th generation cephalosporins 38 studies (cattle n?=?9, chickens n?=?2, pigs n?=?3, horses n?=?10, dogs n?=?9, cats n?=?4 and rabbits n?=?4) met the inclusion criteria. Some studies covered multiple animal species. Clinically
relevant interspecies differences in elimination half-life were observed for ceftiofur,
half-life ranged from 4.23 h in chicken to 21.5 h in horses. Intermediate half-lives
were found for calves (16.1 h), pigs (11.01 h) and foals (5.17–8.08 h). In general,
elimination half-life was short for the other cephalosporins (except cefovecin) with
limited interspecies differences: cefoperazone 0.50–2.13 h, ceftazidime 0.73–2.31 h,
ceftriaxone 0.81–3.25 h, cefotaxime 0.60–3.48 h, cefquinome 0.85–2.77 h, cefepime
1.09–2.38 h and cefpirome 0.79–1.48 h.
Excretion of 3rd and 4th generation cephalosporins is mainly renal and unchanged.
Two 3rd and 4th generation cephalosporins are not excreted unchanged. These are ceftiofur,
which is metabolized by the liver to active desfuroylceftiofur and cefotaxime which
is metabolized to active desacetylcefotaxime (see Additional file 1: Table S1). Depending on the cephalosporin, elimination can be through glomerular
filtration with or without the addition of tubular secretion. For ceftazidime it was
reported for cats 16] that glomerular filtration is the mechanism of excretion. This is confirmed by comparing
the clearance for ceftazidime in cats (0.190 L/kg/h) to the glomerular filtration
rate (GFR) measured in cats (renal inulin clearance) of 0.182 L/kg/h) 17]. For ceftriaxone it is reported that the mechanism of excretion in cats is through
glomerular filtration and tubular secretion and/or non-renal excretion with a clearance
of 0.370 L/kg/h 18], which exceeds the GFR in cats. In dogs the measured GFR (renal inulin clearance)
is 0.235 L/kg/h 17]. The clearance of ceftazidime in dogs is reported to be 0.192 L/kg/h 19] and 0.228 L/kg/h 20]. This relates very well to the GFR in dogs. The reported clearance of ceftriaxone
is 0.217 L/kg/h 21] in dogs, which is also close to the GFR. This might indicate that ceftazidime is
excreted exclusively through glomerular filtration in both dogs and cats, yet, for
ceftriaxone this only seems to be the case for dogs and not for cats. The renal clearance
of cefquinome ranges from 0.191 to 0.221 L/kg/h 22] in dogs. Although the mechanism of excretion is not mentioned in the study, it correlates
so well to the GFR in dogs that also cefquinome is probably excreted exclusively through
glomerular filtration in dogs. Data on cats is not available.
Allometric analysis
Sufficient pharmacokinetic data to apply allometric analysis was available for five
cephalosporins, cefquinome, ceftriaxone, ceftazidime, ceftiofur and cefepime. The
results of the allometric scaling regression analysis (allometric coefficient, allometric
exponent and correlation (R
2
)) of volume of distribution, clearance and elimination half-life are shown in Table 1. Graphs on the allometric scaling of ceftazidime (including human data) and cefquinome
(exclusively veterinary use) are presented in Fig. 1. The allometric analyses of cefepime, ceftriaxone and ceftiofur are shown in Additional
file 1: Figure S1 t/m S3. Additional file 1: Figure S4 shows the allometric analysis for ceftazidime excluding human data. For
ceftazidime, ceftiofur, cefquinome and cefepime (but not ceftriaxone) correlations
between body weight and both parameters volume of distribution and clearance were
high (R 2
??0.97 and R 2
??0.95 respectively). The allometric exponent for all five cephalosporins ranged
from 0.80 to 1.31 for Vd and 0.83 to 1.24 for Cl. Half-life proved to be less predictable
using allometric scaling with R
2
0.067–0.655 based on the values for half-life retrieved from literature. Calculating
half-life (t½?=?(ln2*Vd)/Cl) improved correlation to a range of R
2
0.102–0.876. The calculated half-life per study is available in Additional file 1: Table S1. For cefepime correlation improved the most after calculating (from R
2
0.628 to 0.876). Correlations for ceftriaxone and ceftazidime remained almost equal
(R
2
0.067 versus 0.102 and R
2
0.655 versus 0.662 respectively) and dropped for ceftiofur and cefquinome (R
2
0.481 versus 0.128 for ceftiofur and R
2
0.388 versus 0.243 for cefquinome).
Table 1. Allometric scaling of pharmacokinetics of different cephalosporins in animals
Fig. 1. Two examples of allometric analysis performed on pharmacokinetic data of cephalosporins.
Figure shows clearance, volume of distirubution and half-life of ceftazidime (3rd
generation cephalosporin) and cefquinome (4th generation cephalosporin). Ceftazidime
is also used in human medicine, human data are included in this figure and the equation
and R
2
shown are based on allometric analysis including human data
To further assess accuracy of extrapolation of pharmacokinetics to humans for ceftriaxone,
ceftazidime and cefepime, two human pharmacokinetic studies per cephalosporin were
used to compare extrapolated pharmacokinetics to observed data. For ceftazidime allometric
scaling was repeated with the human data included, to assess the changes to the allometric
equation and correlation coefficient. The scaling including human data is shown in
Fig. 1 (without human data in Additional file 1: Figure S4). As can be seen in the figures and Table 1 the correlation drops for all three pharmacokinetic parameters, especially for the
elimination half-life (from R
2
0.655 to 0.472). For ceftriaxone and cefepime no allometric scaling including human
data was performed. All studies were performed on healthy volunteers, as pharmacokinetics
used for the allometric model were also mostly assessed in healthy animals. For ceftiofur
three additional animal species were used with a wide range of body weights, namely
goats, camels and Asian elephants. For cefquinome studies in ducks and buffalo were
used. Data and results are presented in Table 2. Pharmacokinetics for cefepime could be extrapolated to humans with the animal based
allometric equation. For ceftazidime the model overestimated the pharmacokinetic values.
Observed Vd was 30–40 % lower than the predicted value and observed Cl was 35–40 %
lower than predicted. For ceftriaxone the model overestimated the observed value for
Vd about 4 times (extrapolated 0.4 L/kg, observed 0.1 L/kg) and the value for Cl about
23 times (extrapolated 0.280 L/kg/h, observed 0.012 L/kg/h). Allometric scaling of
ceftiofur was only accurate for clearance in goats. Pharmacokinetic values for cefquinome
could be extrapolated to ducks with reasonable accuracy, but the clearance in buffalo
was overestimated (extrapolated 0.149 L/kg/h, observed 0.061 L/kg/h).
Table 2. Extrapolated volume of distribution and clearance by allometric scaling versus volume
of distribution and clearance