Building Of Approved Veterinry Drug Database And Analysis Of Retrospective Enrofloxacin Pharmacokintic Data

When veterinary pharmaceuticals are used to prevent and treat food animal diseases, to promote growth and improve feed effeciency, the knowledge on drug administration amount, maximal residue level and withdrawal time are needed. When drugs were used in different animal species not according to the product labels, the pharmacokinetic parameters of the drug in this animal species are needed to estimate the extrapolated withdrawal time. The metabolites of some drugs are also pharmacoligically active, building an integrated pharmacokinetic model to describe the parent drug and its metabolite can be used to evaluate the pharamcodynamic performance and tissue disposition rates.The rapid advances in computer science make large scale data storagement and sharing and complicated mathematical model solvement possible. Application of computer science and technology on veterinary pharmacology and food animal production industry can ensure a safe and reseanable drug use. Veterinary drug informatics is a discipline covering the knowledge extraction, storage and analysis. Veterinary drug information consist of drug's physiochemical properties, drug pharmacokinetic/pharmacodynamic information, commercial formulation usage and food safety information. The aims of this paper were to build drug use database by advanced computer technology and analyse pharmacokinetic information utilizing new mathematical tools, to solve the three questions mentioned in the first paragraph.This thesis included all the work i have done in the postgraduate period, which can be divided into two sections. The first section is about data collection, including development of international approved animal drug label information database; the second section is related to data mining and data analysis, including allometric scailling of pharmacokinetic parameters using nonlinear mixed effects model; developing population pharmacokinetic model of parent drug and its metabolite, using enrofloxacin and its metabolite ciprofloxacin plasma drug concentration data in chicken and lactating goats. Data collection is the foundation of data analysis, data analysis is the objective of data collection. Data on veterinary drugs were analysed by other people, so this thesis only focuses on the pharmacokinetic data.1 Design and realization of international animal use and food animal source drug residue databaseWhen making decisions, food animal industry and animal drug products company need information of international animal drug products and residue limits, but these information come from different countries and administration departments. To meet such needs, this research suggested and designed a international animal drug information management system to serve for these decision maiking people. Several points need be considered when developing such a information system, first is the users:food animal farmers, veterinarians, animal drug developers and administration staff from governments; the second is software architecture, including the extensively used object oriented design, relational database management system and VB. NET tecchnology. The process of research followed such a route:through internet, published materials from government and acedemic publishings, collecting food animal drug labels and maximal residue limit data from US, UK, Australia and China's related authorities, then designed the database relationship diagram and make it realized in SQL Server 2000. Ordinary users visited the data from web, advanced users visited data from desk top clients. When the database was constructed, it included data from China,United States, Europian Union and Australia, among them data from United States, United Kingdom and Australia included animal drug use specification and drug residue limits, European Union (except United Kingdom) and China only have drug residue limits information. Approved animal drug information included product name, company name, active ingredients, specification, target animals, indications, amount of use, withdrawal time and residue limits. Users can browse the database through two language channels, Chinese and English. The entries of records exceeded 20,000, chemical species of each country were listed below:among the 873 aniamal drug products from United States, 193 chemicals involved; among the 1353 animal drug products from Australia,754 chemicals involved; among the 248 animal drug products from United Kingdom,220 chemicals involved. There are 110 drug residue limits for China and 116 drug residue limits for European Union. Operating platform for Database Administering System was Windows 2000 server, data administation system was Windows SQL Server 2000, Internet Server was IIS 5.0. The web client interface was developed by VB.NET language, providing the functions of data entry, upgrade, deletion and query. From the search interface, uses can do query by active ingredients, target animals and indications to get information. This database showed a unique feature, the user can gain all countries'information through only one search page. This is the first database where farmers can get oversea anmal drug information at home.2 Mixed effects modelling of the disposition of enrofloxacin across domestic animal speciesPrediction of pharmacokinetic parameters in different animal species is always the hot topic of academic debates, simple allometric scailing is one of the effective methods. To improve the prediction accuracy, this research tried to use nonlinear mixed effects model to explore allometric sacilling relationships, compare the advantages and shortcomings of traditional double logarithmic analysis and mixed effects modelling approach applied in allometric scailling of enrofloxacin pharmacokinetic parameters. Data source was serum disposition data obtained from Food Animal Residue Avoidance Databank (FARAD). Data that met a priori quality criteria was used. One method was that the serum data were computed using standard two-step method and then the gained parameters were analysed using the traditional double logarithmic analysis. The other method was that all the serum data from different animal species were fitted by the mixed effects modelling approach. The allometric exponent was either free or fixed using empirical values. Results revealed that there was not an allometric scaling relationship in enrofloxacin elimination half lives across animal species, clearance and volume of distribution showed apparent allometric scaling relationships with body weight. When the exponents were not fixed, we couldn't get reasonable results, and the performance of predictation was poor, when the exponents were fixed, the model's predicted performance was greatly improved. This study is the third one using nonlinear mixed effects model to explore allometric scailling after the studies on gentamicin and oxetetracyline allometric scailling. it broadened the scale of allometric scaling and showed some academic meannings.3 Population pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in chicken based on retrospective dataUsing pharmacokinetic model to predict the pharmacodynamics of a drug can improve the level of drug usage and decrease the occurrence of adverse effects and antimicrobial resistance, population pharmacokinetic model combined with Monre Carlo simulation can predict the efficacy of a drug in animal popultion. A population pharmacokinetic model for enrofloxacin and its metabolite ciprofloxacin in chickens based on retrospective data was developed. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin, were determined in blood samples from chickens administrated either enrofloxacin via oral and intravenous routes or ciprofloxacin via intravenous injection. The disposition of enrofloxacin and ciprofloxacin was described simultaneously by an integrated mathematic model. Two compartments were used to describe the enrofloxacin and ciprofloxacin disposition profiles. The formation of ciprofloxacin was through the central compartment of enrofloxacin. The integrated model was estimated with nonlinear mixed effects model software (NONMEM). The total clearance of enrofloxacin(CLEN) and ciprofloxacin(CLCP) was 0.613L/h and 1.15L/h, respectively. Correlation between CLEN, V2 and CLCP were estimated. After intravenous administration of enrofloxacin, the transformation rate of enrofloxacin to ciprofloxacin was 0.429L/h. The bioavailability factor after oral administration was 0.926, and 12.6% of enrofloxacin after oral administration was transformed to ciprofloxacin via first-pass effect. Pharmacodynamic evaluation was performed using area under concentration time curve of active moiety from zero to 24 hour and MIC collected from literature. The final model was evaluated by Bootstrap. Crystal ball was used to caculate target attainment rate. Enrofloxacin target attaiment rate for Escherichia.coli was 32.71% with observed data, ciprofloxacin target attaiment rate for Escherichia.coli was 37.68% with observed data. Assuming there was a additive effect of enrofloxacin and its metabolite ciprofloxacin, and the MIC of active moiety was same to enrofloxacin, active moiety target attainment rate for Escherichia.coli was 52.09% with observed data,57.80% with simulated data. This study is the first one to use population pharmacokinetic method to investigate parent drug and its metabolite disposition and pharmacodynamics using an integrated model in veterinary pharmacology. Using the introduced population pharmacokinetic and pharmacodynamic model recommended by this research can provide insights into the population dosage in food animal industry and benefit the food animal industry.4 Utilization of nonlinear mixed effects modeling approach to study the disposition of enrofloxacin and ciprofloxacin in goat breast milkClinical mastitis are the main causes of economic loss in dairy industry, the most recent published paper suggests that the mean incidence rate of clinical mastitis (CM) in the United Kingdom has increased to greater than 50 cases per 100 cows per year. Treatment with antimicrobial agents is a conventional approach. But pharmaceutical products which are administered to milk producing animals have potential to cause drug residues in the human food supply which are potentially harmful to consumers. To get reliable withdrawal time of milk, it is necessary to combine plamsa drug concentration data with milk drug concentration data to estimate drug transfer rates in milk of dairy animals, the results can be used for the further Physiologically based Pharmacokinetic modelling. The objective of this research was to estimate enrofloxacin and its metabolite ciprofloxacin milk tranfer rates in lactating goats using retrospecive data by a nonlinear mixed effects model. A nonlinear mixed effects model describing the disposition of enrofloxacin and ciprofloxacin in goat breast milk after intravenous and intramuscular administration of enrofloxacin was developed. Data source were two doctoral dissertations from a same laboratory. The effect of disease was considered in these two studies. Crossover design was applied on different administration routes. Two compartments were used to describe the enrofloxacin and ciprofloxacin disposition profiles respectively. One compartment was used to describe the enrofloxacin and ciprofloxacin disposition profiles in breast milk respectively. Enrofloxacin and ciprofloxacin were transferred into milk from central compartments. The model development process obeyed the rule "From simple to complex", first considering the single route administration and only parent drug, then combining the intravenous administration and intramuscular administration and parent drug and metabolite drug together. Clearance of enrofloxacin and ciprofloxacin were 0.559 L/h/kg,1.10 L/h/kg respectively. Enrofloxacin and ciprofloxacin entered breast milk at rates of 0.023/h,0.0403 /h. respectively; they left breast milk at rates of 1.03/h,0.246 /h respectively. Such parameters were consistent with the observation that ciprofloxacin milk concentration was larger than that of enrofloxacin in the goat breast milk.In conclusion, A web based electronic system was developed for veterinary drug informaction collected from developed coutries and our nation, via direction of rational drug usage have brought economica benefits for farmers and safe food for consumers. A nonlinear mixed effects model for enrofloxacin allometric scailing was developed in this paper, enrofloxacin and its metabolite ciprofloxacin plasma concentration data were analysed by an intergrated model for chickens, milk drug disposition profiles explored by an integrated model for milking goats. Such studies were first in veterinary medicine.