Integration and modelling of pharmacokinetic and pharmacodynamic data to optimize dosage regimens in veterinary medicine

In veterinary drug development procedures, pharmacokinetic (PK) and pharmacodynamic (PD) data have generally been established in separate, parallel studies to assist in the design of dosage schedules for subsequent evaluation in clinical trials. This review introduces the concept of PK/PD modelling, an approach in which PK and PD data are generated in the same study, and used to derive numerical values for PD parameters based on drug plasma concentrations. The PD parameters define the efficacy, potency and slope (sensitivity) of the concentration-effect relationship. It is proposed that the parameters derived from PK/PD modelling may be used as an alternative and preferred approach to dose titration studies for selecting rational dosage regimens (both dose and dosing interval) for further evaluation in clinical trials. In PK/PD modelling, the explicative variable for effect is the plasma concentration profile. The PK/PD approach provides several advantages over dose-titration studies, including determination of a projected dosage regimen by investigation of a single dose, in contrast to dose-ranging studies which by definition require testing of multiple dosage. Implementation of PK/PD modelling in the veterinary drug development process is currently constrained by the limited number of veterinary studies performed to date, and the consequently limited understanding of PK/PD concepts and their absence from regulatory authority guidelines. Nevertheless, PK/PD modelling has major potential for rational dosage regimen determination, as it considers and quantifies the two main sources of interspecies variability (PK and PD). It is therefore applicable to interspecies extrapolation and to multiple species drug development. As well as the currently limited appreciation of PK/PD principles in the veterinary scientific community, a further constraint in implementing PK/PD modelling is the need to validate PK/PD approaches and thereby gain confidence in its value by pharmaceutical companies and regulatory authorities.     

A pharmacokinetic/pharmacodynamic approach vs. a dose titration for the determination of a dosage regimen: the case of nimesulide, a Cox-2 selective nonsteroidal anti-inflammatory drug in the dog

The present experiment was designed to determine a dosage regimen (dose, interval of administration) in the dog for nimesulide, a nonsteroidal anti-inflammatory drug with in vitro selectivity for the inhibition of cyclo-oxygenase 2 (Cox-2), using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The PK/PD results were compared with those obtained using a classical dose titration study. In the PK/PD experiment, 11 dogs were subjected to Freund's adjuvant arthritis characterized by permanent hyperthermia. Nimesulide (5 mg/kg, oral route) was tested during the secondary phase of the inflammatory response. In the dose titration study, nimesulide (0, 3, 6 and 9 mg/kg, oral route) was tested in eight other dogs using a reversible urate crystal arthritis in a 4-period crossover design. Different PD endpoints (including lameness assessed by force plate and hyperthermia) were regularly measured during the PK/PD experiment, and plasma samples were obtained to determine the plasma nimesulide concentration. The data were modeled using an indirect effect model. The IC50 of nimesulide for lameness was 6.26 +/- 3.01 microg/mL, which was significantly higher than the EC50 value obtained for antipyretic effect (2.72 +/- 1.29 microg/mL). The ED50 estimated from the classical dose titration study were 1.34 mg/kg (lameness) and 3.0 mg/kg (skin temperature). The PK/PD parameters were used to simulate different dosage regimens (dose, interval of administration). The antipyretic and anti-inflammatory effects were calculated from the model for the recommended dosage regimen (5 mg/kg/24 h). It was apparent from this approach, that this dosage regimen enabled 76% of the theoretical maximal drug efficacy to be obtained for pyresis and 43% for lameness. It was concluded from the comparison of in vivo and in vitro IC50, that nimesulide is a potent NSAID for which some Cox-1 inhibition is required to obtain clinically relevant efficacy.     

Oral pharmacokinetic and pharmacodynamic effects of FTY720 in cats

The aim of the study was to determine pharmacokinetic and pharmacodynamic profiles of FTY720 in cats and identify any toxic side effects. Six adult cats were used for the experimental study. Single oral dosages were tested at 0.05, 0.3 and 1.0 mg/kg. Whole blood drug concentration, total white blood cell and differential counts were monitored. Flow cytometry evaluated the effects on lymphocyte subsets. A toxicity study consisted of cats receiving a dose of 0.15 mg/kg daily for 30 days. Daily observation, physical examination and bloodwork were evaluated to assess for toxicity. All single doses resulted in > or =80% reduction in circulating lymphocytes within 12 h after administration, with the duration of lymphopenia being dose dependent. CD4+ and CD5+ T cells were specifically depleted. Peripheral neutrophils declined by approximately 70% at all dosages tested. No other toxic side effects were observed. Results of this study suggest that FTY720 is effective at inducing a peripheral lymphopenia in cats without any toxic side effects. Currently, cats appear to be the only species in which FTY720 induces a neutropenia. This study provides the foundation for future clinical transplantation trials using FTY720 in cats. By using combination therapy of FTY720 and low dose cyclosporine, the incidence of serious side effects may be reduced while still preventing allograft rejection.     

Use of a pharmacokinetic/pharmacodynamic approach in the cat to determine a dosage regimen for the COX-2 selective drug robenacoxib

This study investigated the analgesic, anti-inflammatory and antipyretic efficacy of the new COX-2 selective inhibitor robenacoxib in the cat and established pharmacodynamic (PD) parameters for these effects. Robenacoxib, at a dosage of 2 mg/kg administered subcutaneously, was evaluated in a kaolin-induced paw inflammation model in 10 cats, using both clinically relevant endpoints (lameness scoring, locomotion tests) and other indicators of inflammation (body and skin temperature, thermal pain threshold) to establish its pharmacological profile. A pharmacokinetic/pharmacodynamic (PK/PD) modelling approach, based on indirect response models, was used to describe the time course and magnitude of the responses to robenacoxib. All endpoints demonstrated good responsiveness to robenacoxib administration and both the magnitude and time courses of responses were well described by the indirect pharmacodynamic response models. Pharmacokinetic and clinically relevant pharmacodynamic parameters were used to simulate dosage regimens that will assist the planning of clinical trials and the selection of an optimal dosage regimen for robenacoxib in the cat.     

Disposition kinetics,urinary excretion and dosage regimen of kanamycin in buffalo calves following single intravenous administration

The disposition kinetics and appropriate dosage regimen for kanamycin were investigated in buffalo calves following a single intravenous dose of 10 mg/kg body weight. The distribution and elimination half-lives were 0.12±0.01 h and 1.94±0.11 h, respectively. The apparent volume of distribution and total body clearance were 0.2±0.01 L/kg and 92.9±3.69 ml/kg/h, respectively. About 74% of the administered dose was excreted in urine in 24 h. A suitable dosage regimen for the intravenous administration of kanamycin was also calculated.Abbreviation SEM standard error of the mean     

Oral dosage regimen in the nonlinear pharmacokinetics of sulphadimethoxine in pigs

Summary

An oral high dosage regimen of sulphadimethoxine (SDM) was examined in pigs. The dose (50 mg/kg) in the therapeutic range, showed nonlinear pharmacokinetics, and administered by drench once a day for 4 days. The unbound plasma concentration‐time profile was compared with that of the dosage regimen based on nonlinear pharmacokinetics, where a pharmacokinetic model and parameters were used except for the first order absorption rate constant (ka) and bioavailability (F). F and ka were obtained from oral and intravenous administration of 20 and 10 mg/kg of SDM. The unbound plasma concentration was observed almost within the setting range by the dosage regimen through the experimental period. This result suggested that the dosage regimen, based on the nonlinear pharmacokinetic model, resulted in an appropriate effect in the clinical use.     

Oral dosage regimen in the nonlinear pharmacokinetics of sulphadimethoxine in pigs

An oral high dosage regimen of sulphadimethoxine (SDM) was examined in pigs. The dose (50 mg/kg) in the therapeutic range, showed nonlinear pharmacokinetics, and administered by drench once a day for 4 days. The unbound plasma concentration-time profile was compared with that of the dosage regimen based on nonlinear pharmacokinetics, where a pharmacokinetic model and parameters were used except for the first order absorption rate constant (ka) and bioavailability (F). F and ka were obtained from oral and intravenous administration of 20 and 10 mg/kg of SDM. The unbound plasma concentration was observed almost within the setting range by the dosage regimen through the experimental period. This result suggested that the dosage regimen, based on the nonlinear pharmacokinetic model, resulted in an appropriate effect in the clinical use.     

Nonlinear pharmacokinetics of intravenous sulphadimethoxine and its dosage regimen in pigs

The time courses of the total (Ct) and unbound plasma (Cf) concentration after the i.v. injection of 20, 50 and 100 mg/kg of sulphadimethoxine (SDM) were examined in pigs. The area under the Ct-time curve per unit dose decreased dose-dependently. Vdarea and total body clearance of Ct increased dose-dependently. The concentration-dependent plasma protein binding of SDM was evident after 50 and 100 mg/kg. The time courses of Cf en Ct after 3 doses were analyzed by a one compartment open model with nonlinear plasma protein binding. The agreement between calculated curves of Cf and Ct and the observed values, and relative constancy of pharmacokinetic parameters were obtained over 3 doses. These results suggested that the nonlinear pharmacokinetics of SDM was caused by saturable plasma protein binding. The multiple i.v. dose of SDM was based on the dosage regimen using the nonlinear pharmacokinetic model (50 mg/kg, 24 hour interval, 4 days). The observed Cf was maintained in the intended range by the dosage regimen. Therefore, the dosage regimen based on the nonlinear pharmacokinetics may allow the unbound concentration after i.v. injection of SDM in pigs to be controlled.     

Plasma concentrations and therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse: pharmacokinetic/pharmacodynamic modelling

The purpose of the present study was to establish in the horse the relationship between plasma concentration profiles of phenylbutazone (PBZ) and flunixin meglumine (FM) and their pharmacological effects in order to build a predictive pharmacokinetic/pharmacodynamic (PK/PD) model. In five horses, an experimental arthritis was induced by injecting Freund's adjuvant into a carpal joint. PBZ (4 mg/kg) and FM (1 mg/kg) were injected by the intravenous route as a single intravenous dose in two different trials. Five pharmacodynamic end-points were regularly measured after test article injection using standardized procedures: local skin temperature, stride length, the rest angle flexion and the maximal carpal flexion of the injured leg and circumference of the inflamed joint. Plasma drug concentrations and pharmacodynamic data were analysed according to an integrated PK/PD model: for the stride length, the PBZ ECSOr i.e. the plasma concentration for which half the maximum effect could be obtained, was 3.6 ± 2.2 yglml and the maximum potential effect was 10.7 ± 9.4% above the control value. For FM, the corresponding values were 0.93 ± 0.35 μg/ml and 16.3 ± 4.6%. ECSO values for rest angle flexion and local skin temperature were similar to that obtained for stride length. Maximal carpal flexion was an unreliable end-point, and circumference of the joint did not display significant response to the drugs. Using these experimental parameters, a dose-effect relationship was simulated for both drugs: it was shown for PBZ that the model predicts an absence of effect for a 1 mg/kg dose and a maximum effect at about 2 mg/kg: at higher PBZ doses, the maximum effect was not modified, but its duration was increased from 8 h with a 2 mg/kg dose to about 24 h with an 8 mg/kg dose. For FM the model predicts that a dose of 0.5 mg/kg will be without significant effect, whereas a 1 mg/kg dose allows a nearly maximal effect with a return to the control value after a delay of 16 h. A 2 mg/kg dose allows the effect to be maintained for 24 h. It is concluded that PK/PD is a tool of potential value for the preclinical screening of a dosage regimen.     

Nonlinear pharmacokinetics of intravenous sulphadimethoxine and its dosage regimen in pigs

Summary

The time courses of the total (Ct) and unbound plasma (Cf) concentration after the i.v. injection of 20, 50 and 100 mg/kg of sulphadimethoxine (SDM) were examined in pigs;

The area under the Ct‐time curve per unit dose decreased dose‐dependently. Vd_area and total body clearance of Ct increased dose‐dependently.

The concentration‐dependent plasma protein binding of SDM was evident after 50 and 100 mg/kg.

The time courses of Cf en Ct after 3 doses were analysed by a one compartment open model with nonlinear plasma protein binding. The agreement between calculated curves of Cf and Ct and the observed values, and relative constancy of pharmacokinetic parameters were obtained over 3 doses. These results suggested that the nonlinear pharmacokinetics of SDM was caused by saturable plasma protein binding.

The multiple i.v. dose of SDM was based on the dosage regimen using the nonlinear pharmacokinetic model (50 mg/kg, 24 hour interval, 4 days). The observed Cf was maintained in the intended range by the dosage regimen. Therefore, the dosage regimen based on the nonlinear pharmacokinetics may allow the unbound concentration after i.v. injection of SDM in pigs to be controlled.     

Pharmacokinetics of etodolac in the horse following oral and intravenous administration

The purpose of this study was to determine the pharmacokinetics of etodolac following oral and intravenous administration to six horses. Additionally, in vitro cyclooxygenase (COX) selectivity assays were performed using equine whole blood. Using a randomized two-way crossover design, horses were administered etodolac (20 mg/kg) orally or intravenously, with a minimum 3-week washout period. Plasma samples were collected after administration for analysis using high pressure liquid chromatography with ultraviolet detection. Following intravenous administration, etodolac had a mean plasma half-life (t(1/2)) of 2.67 h, volume of distribution (Vd) of 0.29 L/kg and clearance (Cl) of 234.87 mL/h kg. Following oral administration, the average maximum plasma concentration (Cmax)) was 32.57 mug/mL with a t(1/2) of 3.02 h. Bioavailability was approximately 77.02%. Results of in vitro COX selectivity assays showed that etodolac was only slightly selective for COX-2 with a COX-1/COX-2 selectivity ratio effective concentration (EC)50 of 4.32 and for EC80 of 4.77. This study showed that etodolac is well absorbed in the horse after oral administration, and may offer a useful alternative for anti-inflammatory treatment of various conditions in the horse.     

Pharmacokinetics of amikacin in the horse following intravenous and intramuscular administration

The pharmacokinetics of amikacin sulfate (AK) were studied in the horse after intravenous (i.v.) and intramuscular (i.m.) administration. Serum (Cs), synovial (Csf) and peritoneal (Cpf) fluid concentrations of the drug were measured. Doses of 4.4, 6.6 and 11.0 mg/kg were given. The concentrations at 15 min following i.v. injection were 30.3 +/- 0.3, 61.2 +/- 6.9 and 122.8 +/- 7.4 micrograms/ml, respectively, for the 4.4, 6.6 and 11.0 mg/kg doses. Mean peak Cs values after the intramuscular injections occurred at 1.0 h post-injection and were 13.3 +/- 1.6, 23.0 +/- 0.6 and 29.8 +/- 3.2 micrograms/ml, respectively. The t 1/2 of amikacin was 1.44, 1.57 and 1.14 h for the 4.4, 6.6 and 11.0 mg/kg doses, respectively. In this study, minimum inhibitory concentrations (MIC) of amikacin sulfate were determined for six pathogens. Based on the MIC and the pharmacokinetic parameters, it would appear that the usual therapeutic dose of amikacin would be between 4.4 and 6.6 mg/kg twice daily and, for the more serious life-threatening infections, dosing three times a day.     

Toxicokinetics of ergovaline in the horse after an intravenous administration

The toxicokinetics of ergovaline (an ergopeptine mycotoxin present in some grasses infected with endophytic fungus of the genus Neotyphodium) were studied after intravenous administration of a single dose of 15 microg/kg bwt in four gelding horses. Plasma ergovaline concentrations were measured by high performance liquid chromatography, and the kinetic data were described by a three-compartment model. The elimination half-life and the total clearance of ergovaline were found to be 56.83 +/- 13.48 min and 0.020 +/- 0.004 L/min x kg, respectively. According to the toxicological data previously reported in the horse, and in spite of the very low dose administered, clinical signs were observed, including excessive coolness of the ears and the nose, excessive sweating and prostration.     

The pharmacokinetics of orbifloxacin in the horse following oral and intravenous administration

The purpose of this study was to determine the pharmacokinetics and physicochemical characteristics of orbifloxacin in the horse. Six healthy adult horses were administered oral and intravenous orbifloxacin at a dose of 2.5 mg/kg. Plasma samples were collected and analyzed by high-pressure liquid chromatography with ultraviolet detection. Plasma protein binding and lipophilicity were determined in vitro . Following i.v. administration, orbifloxacin had a terminal half-life ( t _1/2) of 5.08 h and a volume of distribution (V_d(ss)) of 1.58 L/kg. Following oral administration, the average maximum plasma concentration ( C _max) was 1.25  μ g/mL with a t _1/2 of 3.42 h. Systemic bioavailability was 68.35%. Plasma protein binding was 20.64%. The octanol:water partition coefficient (pH 7.4) was 0.2 ± 0.11. No adverse reactions were noted during this study. Dosage regimens were determined from the pharmacokinetic–pharmacodynamic parameters established for fluoroquinolone antibiotics. For susceptible bacteria, an oral dose of approximately 5 mg/kg once daily will produce plasma concentrations within the suggested range. This dose is suggested for further studies on the clinical efficacy of orbifloxacin for treatment of susceptible bacterial infections in the horse.     

Oral administration of tepoxalin in the horse: a PK/PD study

Tepoxalin is a non-steroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties and has been recently introduced into veterinary medicine. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profile of tepoxalin to assess whether it would be suitable for clinical use in horses. Six female fasting/fed horses were given 10mg/kg tepoxalin orally in a cross-over study. After administration, tepoxalin underwent rapid and extensive hydrolytic conversion to its carboxylic acid metabolite RWJ-20142. In animals that had been fed, the plasma concentrations of tepoxalin were undetectable, whereas in fasting animals they were close to the limit of quantification of the method. No differences between the fasting/fed groups in RWJ-20142 plasma concentrations were shown. Tepoxalin showed a strong and long-lasting ex vivo inhibitory activity against cyclooxygenase (COX)-1, mainly due to its main metabolite RWJ-20142. Tepoxalin and RWJ-20142 do not seem to possess either COX-2 or 5-lipoxygenase inhibitory activity in the horse. These features suggest that the drug is a selective COX-1 inhibitor in horses, with no significant anti-inflammatory activity. Thus, its long term use in equine practice could be of concern.