Pharmacokinetic-pharmacodynamic Integration Research Articles

Pharmacokinetic behaviour and pharmacokinetic-pharmacodynamic integration of doxycycline in rainbow trout (Oncorhynchus mykiss) after intravascular, intramuscular and oral administrations.

Doxycycline (DO) has been used in fish for a long time, but there are some factors that have not yet been clarified regarding its pharmacokinetic (PK) and pharmacodynamic (PD) properties. Therefore, the aim of this study was to investigate the PK and PK/PD targets of DO after 20mg/kg intravascular (IV), intramuscular (IM) and oral (OR) gavage administration in rainbow trout (Oncorhynchus mykiss). Plasma samples were collected at specific time points and subsequently analysed by HPLC-ultraviolet. The PK/PD indices were calculated based on the MIC90 (Aeromonas hydrophila and Aeromonas sobria) values obtained for the respective bacteria and the PK parameters obtained for DO following both IM and OR administration. After IV administration, the elimination half-life (t1/2 ʎz), area under the concentration vs. time curve (AUC), apparent volume of distribution at steady-state and total body clearance of DO were 34.81h, 723.82hµg/mL, 1.24L/kg and 0.03L/kg/h, respectively. The t1/2λz of the DO was found to be 37.39 and 39.78h after IM, and OR administration, respectively. The bioavailability was calculated 57.02% and 32.29%, respectively, after IM and OR administration. The MIC90 of DO against A. hydrophila and A. sobria was 4µg/mL. The PK/PD integration showed that DO (20mg/kg dose) for A. hydrophila and A. sobria with MIC90 ≤4µg/mL achieved target AUC/MIC value after IM administration. These results suggest that when rainbow trout was treated with 20mg/kg IV and IM administered DO, therapeutically effective concentrations were reached in the control of infections caused by A. hydrophila and A. sobria.

P4 | Pharmacokinetic‐pharmacodynamic integration of lincomycin against Actinobacillus pleuropneumoniae in swine

Journal of Veterinary Pharmacology and TherapeuticsVolume 46, Issue S1 p. 86-87 POSTER PRESENTATIONS P4 | Pharmacokinetic-pharmacodynamic integration of lincomycin against Actinobacillus pleuropneumoniae in swine First published: 11 June 2023 https://doi.org/10.1111/jvp.13283Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume46, IssueS1Special Issue: 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology held Bruges, Belgium, July 2–5, 2023June 2023Pages 86-87 RelatedInformation

Dosage Derivation of Marbofloxacin in Broiler Chickens based on Pharmacokinetic-Pharmacodynamic Integration

Marbofloxacin, a veterinary–exclusive antimicrobial drug of third–generation fluoroquinolone class, exhibits wide spectrum antimicrobial activity against Gram-negative as well as Gram-positive bacteria, and thus, is a promising agent to treat susceptible bacterial infections in poultry. Therefore, the present study was conducted to derive dosage regimen of marbofloxacin based on the results of intravenous and oral pharmacokinetic (PK) trial in sixteen healthy broiler chickens. Plasma concentrations of marbofloxacin were measured by optimized and in-house validated Ultra High Performance Liquid Chromatography (UHPLC) method. The PK parameters were calculated from plasma concentrations versus time data by non-compartmental analysis using ‘PK Solver 2.0’ software. Following oral administration of marbofloxacin at the dose rate of 5 mg/kg body weight, the mean maximal plasma concentration (Cmax: 2.193 µg/ml) was achieved at 1.68 h. Marbofloxacin showed long half-life (6.03 h), high volume of distribution (2.64 L/Kg) and good oral bioavailability (88.10 %). The average plasma concentration of marbofloxacin ≥ 0.32 µg/ml was maintained upto 12 h and 0.10 µg/ml at 24 h. Based on the values of PK-PD integrated indices, it is concluded that oral dose of marbofloxacin @ 5.0 mg/kg body weight, to be repeated at 24 h, would be efficient to treat common bacterial pathogens of broiler chickens having MIC ≤ 0.12 μg/ml.

Evaluation of the pharmacokinetic-pharmacodynamic integration of marbofloxacin in combination with methyl gallate against Salmonella Typhimurium in rats.

Fluoroquinolone resistance in Salmonella Typhimurium is becoming a major concern. Hence, an intervention to limit the growth in resistance is inevitable. One way to combat this challenge is through combination therapy. The combination of antibiotics with phytochemicals has become an ideal means of preventing antimicrobial resistance. Recently, in an in vitro study, the combination of methyl gallate (MG) with marbofloxacin (MAR) has shown to prevent Salmonella Typhimurium invasion. It is also worth to study the effects of plant extracts on the pharmacokinetics of antibiotics. Hence, the objective of this study was to determine the effect of MG on the pharmacokinetics of MAR and pharmacokinetics/pharmacodynamics integration of MG and MAR. The micro-broth dilution method was used to obtain the minimum inhibitory concentration (MIC), and fractional inhibitory concentration (FIC) of MAR and MG. Whereas, the pharmacokinetic was conducted in rats by administering either MAR alone or combined with MG through oral and/or intravenous routes. The results indicated that the MIC of MAR and MG against standard strain Salmonella Typhimurium (ATCC 14028) was 0.031 and 500 μg/mL, respectively. The FICindex of the combination of MAR and MG was 0.5. For orally administered drugs, the Cmax and AUC24h of MAR were 1.04 and 0.78 μg/mL and 5.98 and 6.11 h.μg/mL when MAR was given alone and in combination with MG, respectively. The intravenous administration of MAR showed a half-life of 3.8 and 3.9 h; a clearance rate of 1.1 and 0.73 L/h/kg and a volume of distribution of 5.98 and 4.13 L/kg for MAR alone and in combination with MG, respectively. The AUC24/MIC for MAR alone and in combination with MG was 192.8 and 381.9 h, respectively. In conclusion, MG has shown to increase the antimicrobial activity of MAR in vitro and ex vivo experiments without affecting the pharmacokinetics of MAR in rats.

Pharmacokinetic-pharmacodynamic integration and resistance of tiamulin against Mycoplasma hyopneumoniae in an in vitro dynamic model

Mycoplasma hyopneumoniae is the major pathogen of enzootic pneumonia in pigs. We established an in vitro dynamic model to investigate the relationship between the pharmacokinetic and pharmacodynamic (PK-PD) parameters of tiamulin against M. hyopneumoniae. Static time-killing curves showed that mycoplasmacidal activity (reduced 3.0 log10 (CFU/mL)) was achieved during 48 h when the drug concentration was 8 MIC, and with a maximum kill rate of 0.072/h. In dynamic time-killing studies, only the dose-fractionated regimen achieved mycoplasmacidal activity when drug concentration was 1.44 and 1.92 mg/L. The duration of post antibiotic effect (PAE) at 1 × MIC was 6.27 ± 0.11 h, and prolonged as the concentration of tiamulin increased. The cumulative percentage of time over a 48-h period that the drug concentration exceeds the MIC (%T > MIC) was the best PK-PD parameter to predict the antimicrobial activity of tiamulin against M. hyopneumoniae (R2 = 0.98). Tiamulin showed time-dependent and prolonged PAE activity. Two strains of M. hyopneumoniae (M1, M2) had acquired resistance to tiamulin as well as to valnemulin, tylosin and amikacin. The genome of strain ATCC 25934 was used as a reference for gene-mutation analysis. For strains M1 and M2, a A2058C mutation occurred in domain V of 23S rRNA. These data showed that tiamulin had excellent efficacy and concentration-dependent characteristics against M. hyopneumoniae in vitro. The lower dose was not safe because it could lead to enrichment of resistant bacteria.

The effects of Mannheimia haemolytica and albendazole on marbofloxacin pharmacokinetics in lambs.

The study aimed to define the effects of M. haemolytica and a single oral dose of albendazole on the single-dose pharmacokinetics of marbofloxacin in lambs. The pharmacokinetic-pharmacodynamic integration of marbofloxacin was applied to describe a 3mg/kg intramuscular dose in lambs. The 6 healthy and 12 naturally infected with M. haemolytica lambs (Akkaraman, males weighing 10-15kg and aged 2-3months) were used in this study. In the marbofloxacin group, 6 healthy lambs received marbofloxacin. In the albendazole group after 2weeks washout period, the same animals received marbofloxacin on 1h after albendazole. In the diseased marbofloxacin group, 6 lambs naturally infected with M. haemolytica received marbofloxacin. In the diseased albendazole group, 6 lambs naturally infected with M. haemolytica received marbofloxacin on 1h after albendazole. The marbofloxacin and albendazole were administered each as a single dose of 3mg/kg intramuscular and 7.5mg/kg oral, respectively, in the respective groups. Plasma concentration of marbofloxacin was measured with HPLC-UV and pharmacokinetic parameters were analyzed by non-compartmental model. Albendazole did not change the pharmacokinetic profiles of marbofloxacin in healthy and diseased lambs. However, M. haemolytica affected the pharmacokinetics of marbofloxacin in diseased lambs, AUC0-24/MIC90 ratio was not found to be higher than 125, but Cmax/MIC90 ratios was found to be higher than 10 for an MIC value of 0.25μg/mL in all groups. The marbofloxacin dose described in this study may not be effective for the treatment of infections due to M. haemolytica in lambs, with MIC ≤ 0.25μg/mL.

Pharmacokinetic-pharmacodynamic integration of marbofloxacin after single and repeated intravenous administration in goats

The single dose pharmacokinetics (PK) of marbofloxacin was compared with repeated intravenous (IV) administrations in six healthy goats at the dose rate of 2 mg/kg body weight at 24 h interval for 5 days. Blood samples were collected at times: 5, 15, 30 min and 1, 2, 4, 6, 9, 12, 24, 36, 48 and 72 h post drug administration. Plasma drug concentrations were determined by High Performance Liquid Chromatography and concentration-time data were subjected to non-compartment analysis. The MIC and MBC of marbofloxacin against Escherichia (E.) coli and Pasteurella (P.) multocida in Mueller Hinton Broth were determined by broth microdilution method. The t1/2elm = 4.37 ± 0.18 h and ClB = 0.29 ± 0.01 following single administration were not significantly different from t1/2elm = 5.11 ± 0.22 h and ClB = 0.26 ± 0.01 mL/kg/h after repeated administrations of marbofloxacin. Accumulation index (AI = 1.1) indicated no accumulation of marbofloxacin following repeated IV administrations up to 5 days. The respective MICs of marbofloxacin against E. coli and P. multocida were 0.03 μg/mL and 0.4 μg/mL. The AUC0–24h/MIC ratios were 226.64 ± 7.21 h for E. coli and 16.99 ± 0.541 h for P. multocida. PK/PD integration indicated that marbofloxacin daily dose of 2 mg/kg is appropriate for treating E. coli (MIC ≤ 0.03 μg/mL) infections. However, a higher dose of 6 mg/kg/day is suggested to obtain clinical cure against diseases caused by P. multocida having MIC90 = 0.12 μg/mL in goat species.

PK-PD Integration Modeling and Cutoff Value of Florfenicol against Streptococcus suis in Pigs.

The aims of the present study were to establish optimal doses and provide an alternate COPD for florfenicol against Streptococcus suis based on pharmacokinetic-pharmacodynamic integration modeling. The recommended dose (30 mg/kg b.w.) were administered in healthy pigs through intramuscular and intravenous routes for pharmacokinetic studies. The main pharmacokinetic parameters of Cmax, AUC0-24h, AUC, Ke, t1/2ke, MRT, Tmax, and Clb, were estimated as 4.44 μg/ml, 88.85 μg⋅h/ml, 158.56 μg⋅h/ml, 0.048 h-1, 14.46 h, 26.11 h, 4 h and 0.185 L/h⋅kg, respectively. The bioavailability of florfenicol was calculated to be 99.14% after I.M administration. A total of 124 Streptococcus suis from most cities of China were isolated to determine the minimum inhibitory concentration (MIC) of florfenicol. The MIC50 and MIC90 were calculated as 1 and 2 μg/ml. A serotype 2 Streptococcus suis (WH-2), with MIC value similar to MIC90, was selected as a representative for an in vitro and ex vivo pharmacodynamics study. The MIC values of WH-2 in TSB and plasma were 2 μg/ml, and the MBC/MIC ratios were 2 in TSB and plasma. The MPC was detected to be 3.2 μg/ml. According to inhibitory sigmoid Emax model, plasma AUC0-24h/MIC values of florfenicol versus Streptococcus suis were 37.89, 44.02, and 46.42 h for the bactericidal, bacteriostatic, and elimination activity, respectively. Monte Carlo simulations the optimal doses for bactericidal, bacteriostatic, and elimination effects were calculated as 16.5, 19.17, and 20.14 mg/kg b.w. for 50% target attainment rates (TAR), and 21.55, 25.02, and 26.85 mg/kg b.w. for 90% TAR, respectively. The PK-PD cutoff value (COPD) analyzed from MCS for florfenicol against Streptococcus suis was 1 μg/ml which could provide a sensitivity cutoff value. These results contributed an optimized alternative to clinical veterinary medicine and showed that the dose of 25.02 mg/kg florfenicol for 24 h could have a bactericidal action against Streptococcus suis after I.M administration. However, it should be validated in clinical practice in the future investigations.

Pharmacokinetic-pharmacodynamic integration of enrofloxacin and its metabolite ciprofloxacin in buffalo calves.

The present study was planned with an objective to test the pharmacokinetics of a new formulation of enrofloxacin (Flobac® SA) in buffalo calves. The drug was administered at the dose rate of 7.5 mg kg−1 body weight through the intravenous (i.v.) and intramuscular (i.m.) route followed by plasma collection and analysis at different time intervals. After analysis, using High Performance Liquid Chromatography – Ultraviolet, various pharmacokinetic parameters were calculated using visual fit for compartmental analysis, followed by integration with pharmacodynamic parameters against Escherichia coli and Pasteurella multocida. Although total area under plasma drug concentration time curve was higher through the i.v. route, mean residence time and metabolic conversion ratio was higher following administration by the i.m. route indicating longer persistence of the drug in body. Overall i.m. bioavailability of the parent compound with its metabolite was found to be 91%. Upon, Pharmacokinetic–Pharmacodynamic integration, all the parameters indicated significant antibacterial activity. It can be concluded that the dose of enrofloxacin used in the present study can be administered to contain infections caused by P. multocida and E. coli in buffalo calves.

Mutant prevention concentration, pharmacokinetic-pharmacodynamic integration, and modeling of enrofloxacin data established in diseased buffalo calves.

The pharmacokinetic-pharmacodynamic (PK/PD) modeling of enrofloxacin data using mutant prevention concentration (MPC) of enrofloxacin was conducted in febrile buffalo calves to optimize dosage regimen and to prevent the emergence of antimicrobial resistance. The serum peak concentration (Cmax ), terminal half-life (t1/2 K10) , apparent volume of distribution (Vd(area) /F), and mean residence time (MRT) of enrofloxacin were 1.40±0.27μg/mL, 7.96±0.86h, 7.74±1.26L/kg, and 11.57±1.01h, respectively, following drug administration at dosage 12mg/kg by intramuscular route. The minimum inhibitory concentration (MIC), minimum bactericidal concentration, and MPC of enrofloxacin against Pasteurella multocida were 0.055, 0.060, and 1.45μg/mL, respectively. Modeling of exvivo growth inhibition data to the sigmoid Emax equation provided AUC24h /MIC values to produce effects of bacteriostatic (33h), bactericidal (39h), and bacterial eradication (41h). The estimated daily dosage of enrofloxacin in febrile buffalo calves was 3.5 and 8.4mg/kg against P.multocida/pathogens having MIC90 ≤0.125 and 0.30μg/mL, respectively, based on the determined AUC24h /MIC values by modeling PK/PD data. The lipopolysaccharide-induced fever had no direct effect on the antibacterial activity of the enrofloxacin and alterations in PK of the drug, and its metabolite will be beneficial for its use to treat infectious diseases caused by sensitive pathogens in buffalo species. In addition, invitro MPC data in conjunction with invivo PK data indicated that clinically it would be easier to eradicate less susceptible strains of P.multocida in diseased calves.

Pharmacology should be at the centre of all preclinical and clinical studies on new psychoactive substances (recreational drugs)

Despite the publication of a substantial body of preclinical and clinical information on recent recreational drugs such as 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and cathinone compounds such as mephedrone there remains a disturbing lack of consensus as to how dangerous these compounds are to the health of the individual and to society in general. This perspective proposes that use of good pharmacological practice should be mandatory in all preclinical and clinical studies. Its use will assist both translation and reverse translation of information produced in animals and clinical subjects. We propose several basic rules to be followed in all future studies. Preclinical studies should employ pharmacokinetic-pharmacodynamic integration thereby exposing animals to known or calculable drug concentrations. This will provide results relevant to pharmacology rather than toxicology and, crucially, data relevant to human drug use. Full experimental detail should be routinely provided, to allow comparison with other similar work. In clinical studies evidence should be provided that the drug under investigation has been ingested by the subjects being examined, and details given of all other drugs being ingested. Drug-drug interactions are an unavoidable confound but studies of a size that allows reliable statistical evaluation and preferably allows sub-group analysis, particularly by using meta-analysis, should help with this problem. This may require greater collaboration between investigative groups, as routinely occurs during pharmaceutical clinical trials. Other proposals include greater integration of preclinical and clinical scientists in both preclinical and clinical studies and changes in the law regarding Good Manufacturing Process (GMP) sourcing of drug for human studies.

Pharmacokinetic–pharmacodynamic integration and modelling of florfenicol in calves

Florfenicol was administered subcutaneously to 10 calves at a dose of 40mg/kg. Pharmacokinetic-pharmacodynamic (PK-PD) integration and modelling of the data were undertaken using a tissue cage model, which allowed comparison of microbial growth inhibition profiles in three fluids, serum, exudate and transudate. Terminal half-lives were relatively long, so that florfenicol concentrations were well maintained in all three fluids. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration were determined in vitro for six strains each of the calf pneumonia pathogens, Mannhemia haemolytica and Pasteurella multocida. An PK-PD integration for three serum indices provided mean values for P.multocida and M.haemolytica, respectively, of 12.6 and 10.4 for Cmax /MIC, 183 and 152h for AUC0-24h /MIC and 78 and 76h for T>MIC. Average florfenicol concentrations in serum exceeded 4×MIC and 1.5×MIC for the periods 0-24 and 48-72h, respectively. Ex vivo growth inhibition curves for M.haemolytica and P.multocida demonstrated a rapid (with 8h of exposure) and marked (6 log10 reduction in bacterial count or greater) killing response, suggesting a concentration-dependent killing action. During 24-h incubation periods, inhibition of growth to a bacteriostatic level or greater was maintained in serum samples collected up to 96h and in transudate and exudate samples harvested up to 120h. Based on the sigmoidal Emax relationship, PK-PD modelling of the ex vivo time-kill data provided AUC0-24h /MIC serum values for three levels of growth inhibition, bacteriostatic, bactericidal and 4 log10 decrease in bacterial count; mean values were, respectively, 8.2, 26.6 and 39.0h for M.haemolytica and 7.6, 18.1 and 25.0h for P.multocida. Similar values were obtained for transudate and exudate. Based on pharmacokinetic and PK-PD modelled data obtained in this study and scientific literature values for MIC distributions, Monte Carlo simulations over 100000 trials were undertaken to predict once daily dosages of florfenicol required to provide 50% and 90% target attainment rates for three levels of growth inhibition, namely, bacteriostasis, bactericidal action and 4 log10 reduction in bacterial count.

Pharmacokinetic–pharmacodynamic integration and modelling of oxytetracycline administered alone and in combination with carprofen in calves

The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of oxytetracycline were investigated, when administered both alone and in the presence of carprofen, in healthy calves. The study comprised a four treatment, four sequences, and four period cross-over design and used a tissue cage model, which permitted the collection of serum, inflamed tissue cage fluid (exudate) and non-inflamed tissue cage fluid (transudate). There were no clinically relevant differences in the PK profile of oxytetracycline when administered alone and when administered with carprofen. PK–PD integration was undertaken for a pathogenic strain of Mannheimia haemolytic (A1 76/1), by correlating in vitro minimum inhibitory concentration (MIC) and time-kill data with in vivo PK data obtained in the cross-over study. Based on in vitro susceptibility in cation adjusted Mueller Hinton Broth (CAMHB) and in vivo determined PK variables, ratios of maximum concentration (Cmax) and area under curve (AUC) to MIC and time for which concentration exceeded MIC (T>MIC) were determined. The CAMHB MIC data satisfied integrated PK/PD relationships predicted to achieve efficacy for approximately 48h after dosing; mean values for serum were 5.13 (Cmax/MIC), 49.3h (T>MIC) and 126.6h (AUC96h/MIC). Similar findings were obtained when oxytetracycline was administered in the presence of carprofen, with PK–PD indices based on MIC determined in CAMHB. However, PK–PD integration of data, based on oxytetracycline MICs determined in the biological fluids, serum, exudate and transudate, suggest that it possesses, at most, limited direct killing activity against the M. haemolytica strain A1 76/1; mean values for serum were 0.277 (Cmax/MIC), 0h (T>MIC) and 6.84h (AUC96h/MIC). The data suggest that the beneficial therapeutic effects of oxytetracycline may depend, at least in part, on actions other than direct inhibition of bacterial growth.

An agenda for UK clinical pharmacology: From basic to clinical neuropharmacology: targetophilia or pharmacodynamics?

Historically, much drug discovery and development in psychopharmacology tended to be empirical. However, over the last 20 years it has primarily been target oriented, with synthesis and selection of compounds designed to act at a specific neurochemical site. Such compounds are then examined in functional animal models of disease. There is little evidence that this approach (which we call 'targetophilia') has enhanced the discovery process and some indications that it may have retarded it. A major problem is the weakness of many animal models in mimicking the disease and the lack of appropriate biochemical markers of drug action in animals and patients. In this review we argue that preclinical studies should be conducted as if they were clinical studies in design, analysis, and reporting, and that clinical pharmacologists should be involved at the earliest stages, to help ensure that animal models reflect as closely as possible the clinical disease. In addition, their familiarity with pharmacokinetic-pharmacodynamic integration (PK-PD) would help ensure that appropriate dosing and drug measurement techniques are applied to the discovery process, thereby producing results with relevance to therapeutics. Better integration of experimental and clinical pharmacologists early in the discovery process would allow observations in animals and patients to be quickly exchanged between the two disciplines. This non-linear approach to discovery used to be the way research proceeded, and it resulted in productivity that has never been bettered. It also follows that occasionally 'look-see' studies, a proven technique for drug discovery, deserve to be reintroduced.

PK–PD integration and PK–PD modelling of nonsteroidal anti‐inflammatory drugs: principles and applications in veterinary pharmacology

Much useful information relevant to elucidation of mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) at the molecular level can be obtained from integrating pharmacokinetic (PK) and pharmacodynamic (PD) data, such data being obtained usually, although not necessarily, in separate studies. Integrating PK and PD data can also provide a basis for selecting clinically relevant dosing schedules for subsequent evaluation in disease models and clinical trials. The principles underlying and uses of PK-PD integration are illustrated in this review for phenylbutazone in the horse and cow, carprofen and meloxicam in the horse, carprofen and meloxicam in the cat and nimesulide in the dog. In the PK-PD modelling approach for NSAIDs, the PK and PD data are generated (usually though not necessarily) in vivo in the same investigation and then modelled in silico, usually using the integrated effect compartment or indirect response models. Drug effect is classically modelled with the sigmoidal E(max) (Hill) equation to derive PD parameters which define efficacy, potency and sensitivity. The PK-PD modelling approach for NSAIDs can be undertaken at the molecular level using surrogates of inhibition of cyclooxygenase (COX) isoforms (or indeed other enzymes e.g. 5-lipoxygenase). Examples are provided of the generation of PD parameters for several NSAIDs (carprofen, ketoprofen, vedaprofen, flunixin and tolfenamic acid) in species of veterinary interest (horse, calf, sheep and goat), which indicate that all drugs investigated except vedaprofen were non-selective for COX-1 and COX-2 in the four species investigated under the experimental conditions used, vedaprofen being a COX-1 selective NSAID. In these studies, plasma concentration was linked to COX inhibitory action in the biophase using an effect compartment model. Data for S-(+)-ketoprofen have been additionally subjected to inter-species modelling and allometric scaling of both PK and PD parameters. For several species values of four PK parameters were highly correlated with body weight, whilst values for PD parameters based on COX inhibition lacked allometric relationship with body weight. PK-PD modelling of NSAIDs has also been undertaken using clinical end-points and surrogates for clinical end-points in disease models. By measurement of clinically relevant indices in clinically relevant models, data generated for PD parameters have been used to set dosages and dose intervals for evaluation and confirmation in clinical trials. PK-PD modelling of NSAIDs is likely to prove superior to conventional dose titration studies for dosage schedule determination, as it sweeps the whole of the concentration-effect relationship for all animals and therefore permits determination of genuine PD parameters. It also introduces time as a second independent variable thus allowing prediction of dosage interval. Using indirect response models and clinically relevant indices, PD data have been determined for flunixin, phenylbutazone and meloxicam in the horse, nimesulide in the dog and meloxicam in the cat.