BACKGROUND
non-steroidal anti-inflammatory drugs  constitute an essential therapeutic class both in human and veterinary medicines.
it is now well established that most side effects of nsaids are related to their anti-cyclooxygenase- <dig>  activity while the therapeutic effects are mainly associated with cox- <dig> inhibition.
this has led to the development of preferential or selective cox- <dig> inhibitors among which are the diarylimidazol derivatives  in an attempt to overcome the side effects especially those of the gastro-intestinal tract .
one of these substances was recently developed for therapeutic use in dogs: cimicoxib which is a sulfonamide, like celecoxib, mavacoxib and firocoxib.
high in vitro potency of cimicoxib was measured for cox- <dig> inhibition using a human whole blood assay  66nm or 25 ng/ml).
in vivo effects were demonstrated in rats in adjuvant-induced arthritis, and in air pouch and hyperalgesia models  <cit> .
in fact, the coxib class is not homogenous regarding the cox-1/cox- <dig> selectivity and some of its members such as deracoxib and mavacoxib are classified as preferential and moderately selective cox- <dig> inhibitors while others like firocoxib and robenacoxib are classified as highly selective cox- <dig> inhibitors with a more than 100-fold greater potency for cox- <dig> inhibition and with little or no in vivo inhibition of cox- <dig>  <cit> .
usually, with highly selective coxib compounds, no gastro intestinal tract  ulceration or antiplatelet effects are expected even at a maximum plasma concentration while significant cox- <dig> inhibition may occur with preferential coxibs  <cit> .
for example, for deracoxib, the cox-1/cox- <dig> selectivity index  was about 50– <dig>  <cit>  and gastric ulcerations were reported following some overdosing of deracoxib or as a result of its association with other substances such as other nsaids or corticosteroids  <cit> .
this means that a cox-1/cox- <dig> selectivity index of  <dig> is not enough to guarantee a margin of g.i.t safety and more highly selective coxibs are desirable.
this is the case of firocoxib with a selectivity index of  <dig> in a whole blood assay  <cit>  and for which a favorable tolerability was shown in a large scale survey with a withdrawal rate associated with g.i.t side effects as low as  <dig> % of dogs  and no serious drug-related adverse events  <cit> .
however it was shown that firocoxib was able to slow down wound healing in a canine gastric mucosal injury model but by a mechanism independent of prostaglandin synthesis  <cit>  meaning that a high cox-1/cox <dig> selectivity is not the only pharmacodynamic  endpoint to consider when discussing nsaid g.i.t tolerability.
another factor of coxib tolerability is the selected dosage regimen; a dosage regimen depends on two pharmacokinetic  parameters  and of one pd parameter .
in addition, the dosage interval should also be rationally determined according to the plasma terminal half-life .
for the coxib class, the plasma clearances are very different among substances from a very low clearance for mavacoxib   <cit>  to a rather high clearance for robenacoxib   <cit>  and firocoxib   <cit>  which explains the large differences in half-lives namely  <dig>  days  for mavacoxib,  <dig>  h  for robenacoxib and  <dig>  h  for firocoxib.
such differences are reflected into the dosage regimen , with mavacoxib marketed at 2 mg/kg at one month intervals vs. 5 mg/kg daily for firocoxib and 1-2 mg/kg daily for robenacoxib.
it is expected that a very short half-life of about 1 h cannot maintain steady plasma concentrations over the entire daily dosage interval while a very long terminal half-life is ineluctably associated with a minimal delay  to achieve steady state conditions.
in addition a population pk survey for mavacoxib in osteoarthritic dogs, showed wide between-subject variability with a typical terminal half-life  of 44 days, but for some dogs  it exceeded 80 days with extreme values up to 140 days.
it was shown for mavacoxib that the pk differed considerably between young adult beagle dogs and the typical geriatric large-breed osteoarthritic patient  <cit>  indicating that considering only preclinical pk in young beagle dogs can be very misleading when rationally determining a dosage regimen for a coxib.
in the present paper this point was specifically addressed for cimicoxib by investigating the pk profiles in breeds other than beagle dogs.
the present study reports how the dosage regimen of cimicoxib  was established using pk/pd concepts  <cit>  and provides preliminary information on the interbreed variability of cimicoxib pk.
RESULTS
study 1
the time course of cimicoxib plasma concentrations vs. time  following oral administration is presented in figure  <dig>  visual inspection of the graph suggests the existence of two subgroups of dogs regarding the terminal half-life, with  <dig> dogs having a long terminal half-life  while the  <dig> other dogs exhibited a short terminal half-life  p <  <dig> ).
plasma terminal half-life is a hybrid parameter controlled by plasma clearance and volume of distribution and the difference in the rate of elimination between the two groups of dogs was suggestive of a difference in their capacity to metabolize the cimicoxib i.e.
of a difference in plasma clearance.
to verify this hypothesis, the pk parameters of cimicoxib were also estimated for the same twelve dogs after a single intravenous  cimicoxib administration .
the main iv pk parameters are summarized in table  <dig> and showed a significant difference between the two groups of dogs for cimicoxib half-life  and clearance  while the volumes of distribution were not significantly different .
by analogy to the terminology adopted for celecoxib  <cit> , another coxib for which a bimodal repartition of a beagle dog population was observed, we designated the group of beagle dogs rapidly eliminating cimicoxib as “extensive metabolizers ” and the group of dogs slowly eliminating cimicoxib as “poor metabolizers ”, even if the cimicoxib metabolism per se was not directly investigated in the present experimentation.
data were analysed using non-compartmental approach; auc: area under the curve; v: volume of distribution; hl: plasma half- life; cl: plasma clearance.
*difference were significant between the two groups p <  <dig>  for hl and auc and p <  <dig>  for the cl.
for all clinical endpoints an improvement after cimicoxib administration was observed for the em and the pm dogs.
for the six pharmacodynamics endpoints investigated , the maximum effect was expressed as a percentage of improvement, a 100% effect indicating that the measures returned to control values  and a 0% effect indicating a complete lack of effect of the cimicoxib.
for the clinical lameness score, the effects were expressed using a score ranging from  <dig>  to  <dig> .
for each endpoint, the amplitude and duration of the maximum effect were described for each of the two groups of dogs .
the maximum effect on skin temperature could not be evaluated in the poor-elimination group because no plateau could be observed, with the improvement increasing constantly for this endpoint from 37% to 91%.
for the other endpoints, the maximal observed effect was similar for the two groups of dogs but the duration of a sustained maximal effect and the duration of the overall effect were systematically longer in the group of pm dogs .
the overall maximal effects for the two groups of dogs were 86% for the body temperature, 66% for the ground reaction vertical force and 76% for the creeping speed.
in contrast, the corresponding duration of effect for these endpoints was systematically longer in the pm group  .
for the analgesic effect of cimicoxib, it was observed that the tolerance threshold to the heat-induced pain was increased above those recorded under control conditions  to reach a maximum of 232 ± 45% for the em group and 152 ± 53% for the pm group  which is indicative of a cimicoxib analgesic effect that is not limited to an anti-inflammatory effect .
for the body temperature, the paw circumference, the creeping speed, the vertical normalised force obtained with a force plate and the analgesic effect, the maximal estimated effect was expressed as a percentage of control value, a 100% maximum effect indicating a return to control value .
analgesia was assessed by the paw withdrawal time to a heat stimulus and values higher than 100% indicate that there was an analgesic effect of cimicoxib independent of its anti-inflammatory effect i.e.
that the paw withdrawal time was longer after the cimicoxib administration than in control condition .
for the lameness, the clinical score ranged from  <dig>  to  <dig> : a score of  <dig> corresponding to a slight lameness and a score of  <dig> to an obvious lameness.
the duration of the effect  was directly obtained from raw data.
duration of total effect is the time when the effects of cimicoxib observed are superior to the placebo.
duration of maximal effect is duration during which a steady maximal effect was observed.
values are mean ± sd for the maximal effect and mean and range value for the duration of the maximum effect.
figure  <dig> shows the observed and fitted values of the four modelled endpoints for a representative dog.
the efficacy and potency parameters obtained for the four modelled pharmacodynamic endpoints are presented in table  <dig>  within a given group, the ec50/ic <dig>  values were relatively similar, ranging from 325 ng/ml for the ground reaction vertical force to 786 ng/ml for the lameness for the group of pm dogs but from  <dig> to 284 ng/ml for the em dogs .
<dig>
or ic
<dig>
parameters were estimated using indirect effect pk/pd models.
mean and range, emax: maximum effect, ec50: plasma concentration to obtain 50% of the emax, ic50: plasma concentration to obtain 50% of the imax, kin: the zero-order rate constant for the production of the response; kout: the first-order rate constant for the loss of the response; n: coefficient of hill that measures the slope of the concentration-effect relationship; n.a.
: not applicable.
the average pk and pd parameters obtained in the  <dig> dogs of the em subgroup  were used to simulate the plasma concentration profiles and the effects predicted by the pk/pd model of different dosing regimens of cimicoxib administered by the oral route .
for this simulation, a dose-linearity of the pk parameters was assumed but after the completion and submission of this work, we have had access to an unpublished experimental trial showing that the disposition of cimicoxib after an oral administration was not linear for doses ranging from  <dig> to 4 mg/kg due to the limited solubility of cimicoxib ; for a dose of 1 mg/kg, the plasma concentrations were higher than expected  and for the dose of 4 mg/kg, the plasma concentrations were lower than expected corresponding to a dose of  <dig>  mg/kg for our simulations; nevertheless the results of the simulations assuming linearity are shown in figure  <dig> because the conclusions that were drawn remained unchanged.
for rectal temperature, creeping speed, overall clinical lameness score and ground reaction vertical force, a nearly maximal effect of cimicoxib was predicted to occur for doses of  <dig>   <dig> ,  <dig>  and 3 mg/kg, respectively.
for higher cimicoxib doses, only the duration of the maximum effect was increased.
however, considering ground reaction vertical force, the magnitude of the simulated effect increased at doses > 2 mg/kg; a dose of 2 mg/kg was finally selected for confirmatory clinical trial and for that dose, the duration of the different pharmacological effects to mitigate a permanent inflammatory stimulus ranged between  <dig> to 15 h for rectal temperature, creeping test, vertical ground reaction force and clinical lameness score, with this duration being sufficient to provide satisfactory clinical results .
study 2
figure  <dig> shows the average terminal slope of cimicoxib after an oral administration of cimicoxib to  <dig> dogs belonging to four different breeds.
the half-life was computed and descriptive statistics are presented by breed in table  <dig>  mean values of plasma half-life were  <dig>  h,  <dig>  h,  <dig>  h and  <dig>  h for: cavalier king charles, anglo-french hounds, pointers, bernes moutain respectively .
the intra-breed variability of the terminal half-life was similar in each breed, with a coefficient of variation of 20-25%.
a,b,c : the values indexed by the same letter are not significantly different.
discussion
cimicoxib is a new coxib marketed in veterinary medicine and with a terminal half-life between  <dig> and 4 h; its pharmacokinetic profile is intermediary between that of robenacoxib  and that of firocoxib .
during this experiment in beagle dogs we identified two subgroups of subjects: one group of dogs eliminating cimicoxib from plasma at a rapid rate and a second group of dogs having a three-fold lower plasma clearance ; they were termed by others who observed the same phenomenon for celecoxib  <cit>  extensive metabolizers  and poor metabolizers .
the origin and mechanism of these different elimination patterns of cimicoxib were not investigated but are likely to be due to polymorphism of the enzymes cytochrome p <dig> 2d <dig>  in dogs, which have been shown to be involved in the polymorphism of canine celecoxib metabolism  <cit> .
for mavacoxib, broad variability in pharmacokinetics was also observed within laboratory beagle dogs with a typical half-life of 15–17 days while some of these beagle dogs had a half-life >30 days.
for mavacoxib it was postulated that there was polymorphism of a transporter involved in the biliary clearance even if different sub-populations could not be detected  <cit> .
no equivalent information has been published for firocoxib.
in the present experiment, in order to select the most relevant subpopulation of beagle dogs  regarding the future target dog population we conducted a pilot study in field conditions on four different dog breeds of different body size  and a rather short terminal half-life  was observed for the  <dig> dogs investigated and we decided that our subpopulation of em beagle dogs should be considered for the pk/pd dosage regimen determination.
for pk/pd investigations, a reversible kaolin paw inflammation model i.e.
an ethically acceptable inflammation model was used to determine the main pd parameters of cimicoxib for a set of clinically relevant endpoints able to reflect the antipyretic, analgesic and anti-inflammatory potential.
this model has been validated in our hands and is fully described elsewhere  <cit> .
for the current experiment, the duration of the cimicoxib effect was short enough to avoid having to model the time development of inflammation as was required for meloxicam using the same protocol  <cit> .
in other words, it was assumed that the natural progression of the inflammation following a kaolin administration  was not a relevant confounding factor to assess the cimicoxib effect.
in the model for the placebo period, body temperature, creeping time, and paw withdrawal time still were altered in first 56 h after kaolin administration .
this model  used to test daily administration will be preferred to model with short inflammation like sodium urate crystal ; model used for robenacoxib and firocoxib  <cit> .
using a classical pk/pd modelling approach, the cimicoxib efficacy  and the cimicoxib potency  were determined.
for the subgroup of em, ec50/ic <dig> for rectal temperature, creeping speed under a tunnel, vertical ground reaction force and a clinical lameness, scores were between  <dig>  and  <dig>  nmol/ml i.e.
slightly lower than those obtained for meloxicam that were between  <dig>  and  <dig>  nmol/ml using the same canine model and the same investigated endpoints indicating that cimicoxib is slightly more potent than meloxicam, a reference nsaid in dogs.
the efficacy parameters i.e.
imax were similar for cimicoxib and meloxicam  indicating that both drugs can totally or near totally suppress symptoms associated with the kaolin inflammation .
for the analgesic effect, it was shown that cimicoxib has two types of effect: a so-called anti-hyperalgesic effect  and also an increase to the pain tolerance threshold beyond that recorded during the control  period suggesting a mechanism of cimicoxib action independent from its anti-inflammatory effect.
a similar observation has already been seen with other coxibs.
for example, using a model of peripherally induced inflammatory pain  in rats, celecoxib given systemically induced a state of hypoalgesia where the  nociceptive threshold was raised above basal values.
this effect was not observed after treatment with non-selective inhibitors of cox .
as naltrexone was able to reverse this hypoalgesia, it was concluded that celecoxib could act centrally via an effect mediated by endogenous opioids rather than by inhibition of pg biosynthesis  <cit> .
recently in rat, it was demonstrated that analgesic central effects of celecoxib were prevented by selective μ- and δ-, but not ĸ- opioid antagonists, after intracerebroventricular administration  <cit> .
this genuine effect of coxibs should deserve attention because cimicoxib could have some advantages over non-coxib nsaids to treat some  conditions in which pain is unrelated to inflammation.
the ultimate goal of the present experiment was to assist in the selection of a dosage regimen for subsequent assessment in clinical trials.
for this purpose, dose-effect relationships were simulated using pk and pd parameters obtained in the em beagle dogs because their pk parameters were closer to those of the four non-beagle breed dogs.
as explained in the result section, our simulations assumed a linear disposition of cimicoxib.
however, the disposition of cimicoxib after an oral administration was subsequently shown to be not linear due to solubility saturation and the results of our simulations should only be considered as indicative.
visual examination of the simulated dose-responses  with the various pd endpoints , showed that a near-maximal effect was obtained with a dose of 2 mg/kg for all effects but the vertical force and that, above this dose, a further increase was only able to increase the duration of the cimicoxib effect.
visual inspection of the pk/pd simulations clearly showed that a full pharmacological effect of cimicoxib cannot be maintained over a 24 h dosage interval with a single daily dose.
however, it was considered that to split the daily dose was not in order given that for other short acting coxibs such as robenacoxib, a once daily administration  was shown to be clinically appropriate; clinical trials with cimicoxib supported this interpretation  and this is likely due to the fact that our experimental model is more severe that most of the clinical conditions encountered and also to the likely longer persistence of the cimicoxib in the synovial fluid of the target dog population as already shown for robenacoxib  <cit> .
higher concentration of coxib and longer residence times in inflammatory exudate compare to blood is likely a property of class  <cit>  and it is reasonable to assume that it is also true for cimicoxib.
to support this single cimicoxib daily dose, the company carried out field trials on peri-operative pain associated with orthopaedic or soft tissue surgery using carprofen as a comparator .
carprofen is as well-established nsaid with a half-life of about 9 h in dogs  <cit> , i.e.
a half-life well-suited for a single daily dose regimen.
the non-inferiority of cimicoxib was concluded in comparison to carprofen on pain during the first 24 hours using a composite pain clinical score and a 20% difference as the inferiority limit  <cit> .
for the relief of pain and inflammation associated with osteoarthritis, the non-inferiority of cimicoxib against firocoxib was also demonstrated with regard to the primary efficacy endpoint and an inferiority limit set to 20%  <cit> .
as cimicoxib administered once a day at a dose of 2 mg/kg was shown not to be inferior to carprofen and firocoxib, two drugs having a longer half-life than cimicoxib, the european agency concluded that although pk/pd data indicated that the duration of the effect was shorter than the proposed dosing interval, this was regarded as acceptable, given that appropriate information to this effect was included in the product literature.
CONCLUSIONS
cimicoxib is an efficacious anti-inflammatory and analgesic drug and thanks to a pk/pd approach, a rational dosage regimen of 2 mg/kg was selected for confirmatory clinical trials allowing in fine the claim that cimicoxib at a daily dose of 2 mg/kg is not inferior to two well-established comparators, namely carprofen and firocoxib.

 non-steroidal anti-inflammatory drugs constitute an essential therapeutic class both in human and veterinary medicines. it is now well established that most side effects of nsaids are related to their anti-cyclooxygenase- activity while the therapeutic effects are mainly associated with cox- inhibition. this has led to the development of preferential or selective cox- inhibitors among which are the diarylimidazol derivatives in an attempt to overcome the side effects especially those of the gastro-intestinal tract. one of these substances was recently developed for therapeutic use in dogs: cimicoxib which is a sulfonamide, like celecoxib, mavacoxib and firocoxib. high in vitro potency of cimicoxib was measured for cox- inhibition using a human whole blood assay 66nm or 25 ng/ml). in vivo effects were demonstrated in rats in adjuvant-induced arthritis, and in air pouch and hyperalgesia models. in fact, the coxib class is not homogenous regarding the cox-1/cox- selectivity and some of its members such as deracoxib and mavacoxib are classified as preferential and moderately selective cox- inhibitors while others like firocoxib and robenacoxib are classified as highly selective cox- inhibitors with a more than 100-fold greater potency for cox- inhibition and with little or no in vivo inhibition of cox-. usually, with highly selective coxib compounds, no gastro intestinal tract ulceration or antiplatelet effects are expected even at a maximum plasma concentration while significant cox- inhibition may occur with preferential coxibs. for example, for deracoxib, the cox-1/cox- selectivity index was about 50– and gastric ulcerations were reported following some overdosing of deracoxib or as a result of its association with other substances such as other nsaids or corticosteroids. this means that a cox-1/cox- selectivity index of is not enough to guarantee a margin of g.i.t safety and more highly selective coxibs are desirable. this is the case of firocoxib with a selectivity index of in a whole blood assay and for which a favorable tolerability was shown in a large scale survey with a withdrawal rate associated with g.i.t side effects as low as % of dogs and no serious drug-related adverse events. however it was shown that firocoxib was able to slow down wound healing in a canine gastric mucosal injury model but by a mechanism independent of prostaglandin synthesis meaning that a high cox-1/cox selectivity is not the only pharmacodynamic endpoint to consider when discussing nsaid g.i.t tolerability. another factor of coxib tolerability is the selected dosage regimen; a dosage regimen depends on two pharmacokinetic parameters and of one pd parameter. in addition, the dosage interval should also be rationally determined according to the plasma terminal half-life. for the coxib class, the plasma clearances are very different among substances from a very low clearance for mavacoxib to a rather high clearance for robenacoxib and firocoxib which explains the large differences in half-lives namely  days for mavacoxib,  h for robenacoxib and  h for firocoxib. such differences are reflected into the dosage regimen, with mavacoxib marketed at 2 mg/kg at one month intervals vs. 5 mg/kg daily for firocoxib and 1-2 mg/kg daily for robenacoxib. it is expected that a very short half-life of about 1 h cannot maintain steady plasma concentrations over the entire daily dosage interval while a very long terminal half-life is ineluctably associated with a minimal delay to achieve steady state conditions. in addition a population pk survey for mavacoxib in osteoarthritic dogs, showed wide between-subject variability with a typical terminal half-life of 44 days, but for some dogs it exceeded 80 days with extreme values up to 140 days. it was shown for mavacoxib that the pk differed considerably between young adult beagle dogs and the typical geriatric large-breed osteoarthritic patient indicating that considering only preclinical pk in young beagle dogs can be very misleading when rationally determining a dosage regimen for a coxib. in the present paper this point was specifically addressed for cimicoxib by investigating the pk profiles in breeds other than beagle dogs. the present study reports how the dosage regimen of cimicoxib was established using pk/pd concepts and provides preliminary information on the interbreed variability of cimicoxib pk.  study 1 the time course of cimicoxib plasma concentrations vs. time following oral administration is presented in figure  visual inspection of the graph suggests the existence of two subgroups of dogs regarding the terminal half-life, with dogs having a long terminal half-life while the other dogs exhibited a short terminal half-life p <  ). plasma terminal half-life is a hybrid parameter controlled by plasma clearance and volume of distribution and the difference in the rate of elimination between the two groups of dogs was suggestive of a difference in their capacity to metabolize the cimicoxib i.e. of a difference in plasma clearance. to verify this hypothesis, the pk parameters of cimicoxib were also estimated for the same twelve dogs after a single intravenous cimicoxib administration. the main iv pk parameters are summarized in table  and showed a significant difference between the two groups of dogs for cimicoxib half-life and clearance while the volumes of distribution were not significantly different. by analogy to the terminology adopted for celecoxib, another coxib for which a bimodal repartition of a beagle dog population was observed, we designated the group of beagle dogs rapidly eliminating cimicoxib as “extensive metabolizers ” and the group of dogs slowly eliminating cimicoxib as “poor metabolizers ”, even if the cimicoxib metabolism per se was not directly investigated in the present experimentation. data were analysed using non-compartmental approach; auc: area under the curve; v: volume of distribution; hl: plasma half- life; cl: plasma clearance. *difference were significant between the two groups p <  for hl and auc and p <  for the cl. for all clinical endpoints an improvement after cimicoxib administration was observed for the em and the pm dogs. for the six pharmacodynamics endpoints investigated, the maximum effect was expressed as a percentage of improvement, a 100% effect indicating that the measures returned to control values and a 0% effect indicating a complete lack of effect of the cimicoxib. for the clinical lameness score, the effects were expressed using a score ranging from to. for each endpoint, the amplitude and duration of the maximum effect were described for each of the two groups of dogs. the maximum effect on skin temperature could not be evaluated in the poor-elimination group because no plateau could be observed, with the improvement increasing constantly for this endpoint from 37% to 91%. for the other endpoints, the maximal observed effect was similar for the two groups of dogs but the duration of a sustained maximal effect and the duration of the overall effect were systematically longer in the group of pm dogs. the overall maximal effects for the two groups of dogs were 86% for the body temperature, 66% for the ground reaction vertical force and 76% for the creeping speed. in contrast, the corresponding duration of effect for these endpoints was systematically longer in the pm group. for the analgesic effect of cimicoxib, it was observed that the tolerance threshold to the heat-induced pain was increased above those recorded under control conditions to reach a maximum of 232 ± 45% for the em group and 152 ± 53% for the pm group which is indicative of a cimicoxib analgesic effect that is not limited to an anti-inflammatory effect. for the body temperature, the paw circumference, the creeping speed, the vertical normalised force obtained with a force plate and the analgesic effect, the maximal estimated effect was expressed as a percentage of control value, a 100% maximum effect indicating a return to control value. analgesia was assessed by the paw withdrawal time to a heat stimulus and values higher than 100% indicate that there was an analgesic effect of cimicoxib independent of its anti-inflammatory effect i.e. that the paw withdrawal time was longer after the cimicoxib administration than in control condition. for the lameness, the clinical score ranged from to: a score of corresponding to a slight lameness and a score of to an obvious lameness. the duration of the effect was directly obtained from raw data. duration of total effect is the time when the effects of cimicoxib observed are superior to the placebo. duration of maximal effect is duration during which a steady maximal effect was observed. values are mean ± sd for the maximal effect and mean and range value for the duration of the maximum effect. figure  shows the observed and fitted values of the four modelled endpoints for a representative dog. the efficacy and potency parameters obtained for the four modelled pharmacodynamic endpoints are presented in table  within a given group, the ec50/ic values were relatively similar, ranging from 325 ng/ml for the ground reaction vertical force to 786 ng/ml for the lameness for the group of pm dogs but from to 284 ng/ml for the em dogs. or ic parameters were estimated using indirect effect pk/pd models. mean and range, emax: maximum effect, ec50: plasma concentration to obtain 50% of the emax, ic50: plasma concentration to obtain 50% of the imax, kin: the zero-order rate constant for the production of the response; kout: the first-order rate constant for the loss of the response; n: coefficient of hill that measures the slope of the concentration-effect relationship; n.a.: not applicable. the average pk and pd parameters obtained in the dogs of the em subgroup were used to simulate the plasma concentration profiles and the effects predicted by the pk/pd model of different dosing regimens of cimicoxib administered by the oral route. for this simulation, a dose-linearity of the pk parameters was assumed but after the completion and submission of this work, we have had access to an unpublished experimental trial showing that the disposition of cimicoxib after an oral administration was not linear for doses ranging from to 4 mg/kg due to the limited solubility of cimicoxib; for a dose of 1 mg/kg, the plasma concentrations were higher than expected and for the dose of 4 mg/kg, the plasma concentrations were lower than expected corresponding to a dose of  mg/kg for our simulations; nevertheless the results of the simulations assuming linearity are shown in figure  because the conclusions that were drawn remained unchanged. for rectal temperature, creeping speed, overall clinical lameness score and ground reaction vertical force, a nearly maximal effect of cimicoxib was predicted to occur for doses of, and 3 mg/kg, respectively. for higher cimicoxib doses, only the duration of the maximum effect was increased. however, considering ground reaction vertical force, the magnitude of the simulated effect increased at doses > 2 mg/kg; a dose of 2 mg/kg was finally selected for confirmatory clinical trial and for that dose, the duration of the different pharmacological effects to mitigate a permanent inflammatory stimulus ranged between to 15 h for rectal temperature, creeping test, vertical ground reaction force and clinical lameness score, with this duration being sufficient to provide satisfactory clinical results. study 2 figure  shows the average terminal slope of cimicoxib after an oral administration of cimicoxib to dogs belonging to four different breeds. the half-life was computed and descriptive statistics are presented by breed in table  mean values of plasma half-life were  h,  h,  h and  h for: cavalier king charles, anglo-french hounds, pointers, bernes moutain respectively. the intra-breed variability of the terminal half-life was similar in each breed, with a coefficient of variation of 20-25%. a,b,c: the values indexed by the same letter are not significantly different. discussion cimicoxib is a new coxib marketed in veterinary medicine and with a terminal half-life between and 4 h; its pharmacokinetic profile is intermediary between that of robenacoxib and that of firocoxib. during this experiment in beagle dogs we identified two subgroups of subjects: one group of dogs eliminating cimicoxib from plasma at a rapid rate and a second group of dogs having a three-fold lower plasma clearance; they were termed by others who observed the same phenomenon for celecoxib extensive metabolizers and poor metabolizers. the origin and mechanism of these different elimination patterns of cimicoxib were not investigated but are likely to be due to polymorphism of the enzymes cytochrome p 2d in dogs, which have been shown to be involved in the polymorphism of canine celecoxib metabolism. for mavacoxib, broad variability in pharmacokinetics was also observed within laboratory beagle dogs with a typical half-life of 15–17 days while some of these beagle dogs had a half-life >30 days. for mavacoxib it was postulated that there was polymorphism of a transporter involved in the biliary clearance even if different sub-populations could not be detected. no equivalent information has been published for firocoxib. in the present experiment, in order to select the most relevant subpopulation of beagle dogs regarding the future target dog population we conducted a pilot study in field conditions on four different dog breeds of different body size and a rather short terminal half-life was observed for the dogs investigated and we decided that our subpopulation of em beagle dogs should be considered for the pk/pd dosage regimen determination. for pk/pd investigations, a reversible kaolin paw inflammation model i.e. an ethically acceptable inflammation model was used to determine the main pd parameters of cimicoxib for a set of clinically relevant endpoints able to reflect the antipyretic, analgesic and anti-inflammatory potential. this model has been validated in our hands and is fully described elsewhere. for the current experiment, the duration of the cimicoxib effect was short enough to avoid having to model the time development of inflammation as was required for meloxicam using the same protocol. in other words, it was assumed that the natural progression of the inflammation following a kaolin administration was not a relevant confounding factor to assess the cimicoxib effect. in the model for the placebo period, body temperature, creeping time, and paw withdrawal time still were altered in first 56 h after kaolin administration. this model used to test daily administration will be preferred to model with short inflammation like sodium urate crystal; model used for robenacoxib and firocoxib. using a classical pk/pd modelling approach, the cimicoxib efficacy and the cimicoxib potency were determined. for the subgroup of em, ec50/ic for rectal temperature, creeping speed under a tunnel, vertical ground reaction force and a clinical lameness, scores were between and  nmol/ml i.e. slightly lower than those obtained for meloxicam that were between and  nmol/ml using the same canine model and the same investigated endpoints indicating that cimicoxib is slightly more potent than meloxicam, a reference nsaid in dogs. the efficacy parameters i.e. imax were similar for cimicoxib and meloxicam indicating that both drugs can totally or near totally suppress symptoms associated with the kaolin inflammation. for the analgesic effect, it was shown that cimicoxib has two types of effect: a so-called anti-hyperalgesic effect and also an increase to the pain tolerance threshold beyond that recorded during the control period suggesting a mechanism of cimicoxib action independent from its anti-inflammatory effect. a similar observation has already been seen with other coxibs. for example, using a model of peripherally induced inflammatory pain in rats, celecoxib given systemically induced a state of hypoalgesia where the nociceptive threshold was raised above basal values. this effect was not observed after treatment with non-selective inhibitors of cox. as naltrexone was able to reverse this hypoalgesia, it was concluded that celecoxib could act centrally via an effect mediated by endogenous opioids rather than by inhibition of pg biosynthesis. recently in rat, it was demonstrated that analgesic central effects of celecoxib were prevented by selective μ- and δ-, but not ĸ- opioid antagonists, after intracerebroventricular administration. this genuine effect of coxibs should deserve attention because cimicoxib could have some advantages over non-coxib nsaids to treat some conditions in which pain is unrelated to inflammation. the ultimate goal of the present experiment was to assist in the selection of a dosage regimen for subsequent assessment in clinical trials. for this purpose, dose-effect relationships were simulated using pk and pd parameters obtained in the em beagle dogs because their pk parameters were closer to those of the four non-beagle breed dogs. as explained in the result section, our simulations assumed a linear disposition of cimicoxib. however, the disposition of cimicoxib after an oral administration was subsequently shown to be not linear due to solubility saturation and the results of our simulations should only be considered as indicative. visual examination of the simulated dose-responses with the various pd endpoints, showed that a near-maximal effect was obtained with a dose of 2 mg/kg for all effects but the vertical force and that, above this dose, a further increase was only able to increase the duration of the cimicoxib effect. visual inspection of the pk/pd simulations clearly showed that a full pharmacological effect of cimicoxib cannot be maintained over a 24 h dosage interval with a single daily dose. however, it was considered that to split the daily dose was not in order given that for other short acting coxibs such as robenacoxib, a once daily administration was shown to be clinically appropriate; clinical trials with cimicoxib supported this interpretation and this is likely due to the fact that our experimental model is more severe that most of the clinical conditions encountered and also to the likely longer persistence of the cimicoxib in the synovial fluid of the target dog population as already shown for robenacoxib. higher concentration of coxib and longer residence times in inflammatory exudate compare to blood is likely a property of class and it is reasonable to assume that it is also true for cimicoxib. to support this single cimicoxib daily dose, the company carried out field trials on peri-operative pain associated with orthopaedic or soft tissue surgery using carprofen as a comparator. carprofen is as well-established nsaid with a half-life of about 9 h in dogs, i.e. a half-life well-suited for a single daily dose regimen. the non-inferiority of cimicoxib was concluded in comparison to carprofen on pain during the first 24 hours using a composite pain clinical score and a 20% difference as the inferiority limit. for the relief of pain and inflammation associated with osteoarthritis, the non-inferiority of cimicoxib against firocoxib was also demonstrated with regard to the primary efficacy endpoint and an inferiority limit set to 20%. as cimicoxib administered once a day at a dose of 2 mg/kg was shown not to be inferior to carprofen and firocoxib, two drugs having a longer half-life than cimicoxib, the european agency concluded that although pk/pd data indicated that the duration of the effect was shorter than the proposed dosing interval, this was regarded as acceptable, given that appropriate information to this effect was included in the product literature.  cimicoxib is an efficacious anti-inflammatory and analgesic drug and thanks to a pk/pd approach, a rational dosage regimen of 2 mg/kg was selected for confirmatory clinical trials allowing in fine the claim that cimicoxib at a daily dose of 2 mg/kg is not inferior to two well-established comparators, namely carprofen and firocoxib. 
for both the oral and iv route of administration two groups of dogs to be identified namely poor metabolizers and extensive metabolizers.the terminal half-life after oral administration was ± h for the pm and ± h for the em groups, with the corresponding values after the iv route being ± h and ± h. cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of mg/kg daily was determined for confirmatory clinical trials. thus pharmacokinetic and pharmacodynamic parameters obtained from the em beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial. the cimicoxib half-lives in these dogs were of same order of the magnitude as those of the em beagle dogs. the plasma concentration corresponding to half the maximum of the indirect effect were μg/l for creeping speed, μg/l for the lameness score, μg/l for the ground reaction vertical force and μg/l for the body temperature. to determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin–induced paw inflammation was used. dosage regimens were established using pharmacokinetic/pharmacodynamic modeling approach. to document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to dogs.
 cimicoxib is a new coxib anti-inflammatory drug for use in the dog. to determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin–induced paw inflammation was used. dosage regimens were established using pharmacokinetic/pharmacodynamic modeling approach.  analgesic, anti-inflammatory and antipyretic endpoints investigated with the inflammation model established the efficacy of cimicoxib at a dose of mg/kg administered orally in beagle dogs. for both the oral and iv route of administration two groups of dogs to be identified namely poor metabolizers and extensive metabolizers.the terminal half-life after oral administration was ± h for the pm and ± h for the em groups, with the corresponding values after the iv route being ± h and ± h. the main pharmacodynamic parameters were estimated for four endpoints. the plasma concentration corresponding to half the maximum of the indirect effect were μg/l for creeping speed, μg/l for the lameness score, μg/l for the ground reaction vertical force and μg/l for the body temperature. to document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to dogs. the cimicoxib half-lives in these dogs were of same order of the magnitude as those of the em beagle dogs. thus pharmacokinetic and pharmacodynamic parameters obtained from the em beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial.  cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of mg/kg daily was determined for confirmatory clinical trials. pharmacokineticpharmacodynamiccimicoxibnsaiddogdosage regimen 