MINOR USE ANIMAL DRUG

• Sponsoring Institution: National Institute of Food and Agriculture
• Project Status: COMPLETE
• Funding Source: SPECIAL GRANT
• Reporting Frequency: Annual
• Accession No.: 0221409
• Grant No.: 2010-34143-21138
• Proposal No.: 2010-01477
• Project Start Date: Sep 1, 2010
• Project End Date: Aug 31, 2012
• Grant Year: 2010
• Program Code: [SS]- Minor Use Animal Drugs

Recipient Organization
UNIVERSITY OF CALIFORNIA, OAKLAND
1111 FRANKLIN, 6TH FLOOR
OAKLAND,CA 94607

Performing Department
Administration

Non Technical Summary
Federal regulations require extensive experimental data on efficacy, safety, and residue levels before any drug can be used in a food animal species. Data must be obtained for each animal species for which drug use is intended. At present, most minor species of food animals do not have the benefit of safe and effective drugs, such as are available for cattle, swine, and poultry. This situation has the potential for adverse effects upon both the producers and consumers of animal products. The purpose is to conduct a national program to obtain minor and specialty animal drug clearances (tolerances, exemptions, and registrations) in cooperation with state, federal and industry personnel.

Animal Health Component

100%

Research Effort Categories

Basic

(N/A)

Applied

100%

Developmental

(N/A)

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
711	3299	2000	50%
311	3820	1180	25%
307	3610	1180	25%

Knowledge Area
311 - Animal Diseases; 711 - Ensure Food Products Free of Harmful Chemicals, Including Residues from Agricultural and Other Sources; 307 - Animal Management Systems;

Subject Of Investigation
3610 - Sheep, live animal; 3299 - Poultry, general/other; 3820 - Goats, meat, and mohair;

Field Of Science
1180 - Pharmacology; 2000 - Chemistry;

Keywords

animal drug

minor use

clearance

registration

Goals / Objectives
Identify the animal drug needs for minor species and minor uses in major species. Generate and disseminate data for the safe, effective, and legal use of drugs used primarily in therapy or reproductive management of minor animal species. Facilitate FDA/CVM approvals of drugs for minor species and minor uses.

Project Methods
A system has been developed to review, evaluate, and recommend the feasibility of each animal drug clearance project submitted and to implement the collection of research data needed to establish a labelled registration for the use in question. When a project is accepted, field and laboratory data will be obtained and submitted to the Minor Use Animal Drug Program office for submission of a petition to FDA/CVM for registration.

Progress 09/01/10 to 08/31/12

Outputs
Target Audience: Veterinarians and commodity groups Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? Erythromycin/salmonids (ADR135): Environmental assessment (EA) report was sent to FDA/CVM for review. Chronic toxicity study with Daphnia magna completed. Physiochemical properties study performed. Because the physical characteristics of ERTT, an empirical pKa could not be established. Final EA report was submitted 05/2010. Results support the safe use of erythromycin thiocyanate in freshwater-reared salmonids at a dose of 100 mg/kg bodyweight/day for 21-28 days. FDA/CVM submitted notification that the Final Report for the pivotal Daphnia magna chronic toxicity study was complete (1/12/2011). CIDRg/sheep(ADR258): FDA/CVM accepted the data and was summarized in a Public Master File. All required studies were published in the Federal Register 11/17/2009. Romet/gamebirds (ADR272): Collaborative project with Northeast region and part of a PhD project on avian species grouping. Samples were analyzed in our laboratory. Fenbendazole/game birds(ADR 280): Samples were analyzed in our laboratory 2011. Analytical portion of the Human Food Safety (HFS) report was submitted to ISU. Lincomycin soluble powder/honeybees (ADR311): All studies are complete. Availability of the data for control of American foulbrood in honey bees is on the FDA/CVM website 07/1/2011. Progesterone CIDRs/goats(ADR324): Target animal safety (TAS), milk residue study and Quality Assurance (QA) are complete. Final technical report was accepted by FDA/CVM. Efficacy study began at UCD and Iowa State University (ISU) 2009. Quality assurance (QA) was performed. All raw data from UCD was submitted to ISU 08/2010. Study started 09/2010. FDA/CVM stated (8/12/2011) that HFS safety requirements for the use of CIDR-G in goats were satisfied for toxicology, residue chemistry, and microbial food safety. HFS technical section was complete 8/12/2011. Withdrawal period was established as zero and a milk discard time of zero. Florfenicol (Nuflor Injectable Solution)/sheep(ADR325): Data for the old formulation was published. HFS report was submitted to FDA/CVM. FDA/CVM (2/11/2011) concluded that the tissue residue depletion study was acceptable and assigned a 42-day withdrawal period. FDA/CVM commented that microbial food safety issues still need to be addressed for the impact of florfenicol on antimicrobial resistance among bacteria of public health concern in or on treated sheep as well as human intestinal flora. Tulathromycin/goats(ADR340) (collaborative/ NC region). Tissue LC/MS method for sample analysis was validated. Validation of analytical methods for liver, muscle, kidney and fat samples is complete. Plasma/tissue samples for TAS and HFS were analyzed and data generated. Freezer stability samples from ISU were analyzed. Currently this report is being finalized. Florfenicol (Nuflor Gold)/sheep(ADR350): Pilot study evaluating administration route (IM vs SC) and doses of 20 (IM) or 40 (SC) mg/kg was performed and samples analyzed. Another dose range finding study using the SC route is required. Once the proposed label dose is determined, the TAS study will be performed. Study is pending until CVM provides further guidance.

Publications

• Type: Journal Articles Status: Published Year Published: 2012 Citation: Tulathromycin assay validation and tissue residues after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus).
• Type: Journal Articles Status: Published Year Published: 2011 Citation: Pharmacokinetics of tulathromycin after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus).
• Type: Journal Articles Status: Published Year Published: 2012 Citation: Pharmacokinetics of ceftiofur crystalline free acid after single and multiple subcutaneous administrations in healthy alpacas (Vicugna pacos).
• Type: Journal Articles Status: Published Year Published: 2012 Citation: Development of a physiologically based pharmacokinetic model to predict tulathromycin distribution in goats.
• Type: Journal Articles Status: Awaiting Publication Year Published: 2011 Citation: Pharmacokinetics and tissue elimination of tulathromycin following subcutaneous administration in meat goats.
• Type: Journal Articles Status: Published Year Published: 2012 Citation: Pharmacokinetics of a single intramuscular injection of ceftiofur crystalline-free acid in American black ducks (Anas rubripes).
• Type: Journal Articles Status: Published Year Published: 2011 Citation: Antimicrobial susceptibility of Arcanobacterium pyogenes isolated from the lungs of white-tailed deer (Odocoileus virginianus) with pneumonia.

Progress 09/01/11 to 08/31/12

Outputs
OUTPUTS: Erythromycin/salmonids (ADR135): Environmental assessment (EA) report was sent to FDA/CVM for review. Chronic toxicity study with Daphnia magna completed. Physiochemical properties study performed. Because the physical characteristics of ERTT, an empirical pKa could not be established. Final EA report was submitted 05/2010. Results support the safe use of erythromycin thiocyanate in freshwater-reared salmonids at a dose of 100 mg/kg bodyweight/day for 21-28 days. FDA/CVM submitted notification that the Final Report for the pivotal Daphnia magna chronic toxicity study was complete (1/12/2011). CIDRg/sheep(ADR258): FDA/CVM accepted the data and was summarized in a Public Master File. All required studies were published in the Federal Register 11/17/2009. Romet/gamebirds (ADR272): Collaborative project with Northeast region and part of a PhD project on avian species grouping. Samples were analyzed in our laboratory. Fenbendazole/game birds(ADR 280): Samples were analyzed in our laboratory 2011. Analytical portion of the Human Food Safety (HFS) report was submitted to ISU. Lincomycin soluble powder/honeybees (ADR311): All studies are complete. Availability of the data for control of American foulbrood in honey bees is on the FDA/CVM website 07/1/2011. Progesterone CIDRs/goats(ADR324): Target animal safety (TAS), milk residue study and Quality Assurance (QA) are complete. Final technical report was accepted by FDA/CVM. Efficacy study began at UCD and Iowa State University (ISU) 2009. Quality assurance (QA) was performed. All raw data from UCD was submitted to ISU 08/2010. Study started 09/2010. FDA/CVM stated (8/12/2011) that HFS safety requirements for the use of CIDR-G in goats were satisfied for toxicology, residue chemistry, and microbial food safety. HFS technical section was complete 8/12/2011. Withdrawal period was established as zero and a milk discard time of zero. Florfenicol (Nuflor Injectable Solution)/sheep(ADR325): Data for the old formulation was published. HFS report was submitted to FDA/CVM. FDA/CVM (2/11/2011) concluded that the tissue residue depletion study was acceptable and assigned a 42-day withdrawal period. FDA/CVM commented that microbial food safety issues still need to be addressed for the impact of florfenicol on antimicrobial resistance among bacteria of public health concern in or on treated sheep as well as human intestinal flora. Tulathromycin/goats(ADR340) (collaborative/ NC region). Tissue LC/MS method for sample analysis was validated. Validation of analytical methods for liver, muscle, kidney and fat samples is complete. Plasma/tissue samples for TAS and HFS were analyzed and data generated. Freezer stability samples from ISU were analyzed. Currently this report is being finalized. Florfenicol (Nuflor Gold)/sheep(ADR350): Pilot study evaluating administration route (IM vs SC) and doses of 20 (IM) or 40 (SC) mg/kg was performed and samples analyzed. Another dose range finding study using the SC route is required. Once the proposed label dose is determined, the TAS study will be performed. Study is pending until CVM provides further guidance. PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Veterinarians and commodity groups PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
Pharmacokinetics, human food safety, and target animal safety studies are required by FDA/CVM to obtain minor and specialty animal drug clearances in minor species for drug registration. Data must be obtained for each animal species for which drug use is intended. These minor use animal drug registrations will impact the farmers and ranchers of the Western Region with the potential beneficiaries of this research being the consumers in the Western Region and the rest of the United States.

Publications

• Clothier KA, Leavens T, Griffith RW, Wetzlich SE, Baynes RE, Riviere JE, Tell LA. Pharmacokinetics of tulathromycin after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus). J Vet Pharmacol Ther., 34(5):448-454, 2011.
• Dechant, JE, Rowe, JD, Byrne, BA, Wetzlich, SE, Kieu, HT, Tell, LA. Pharmacokinetics of ceftiofur crystalline free acid after single and multiple subcutaneous administrations in healthy alpacas (Vicugna pacos). J Vet Pharmacol Therap (first published online April 5, 2012).
• Leavens TL, Tell LA, Clothier KA, Griffith RW, Baynes RE, Riviere JE. Development of a physiologically based pharmacokinetic model to predict tulathromycin distribution in goats. J Vet Pharmacol Therap (first published online 2011), 35(2):121-131, 2012.
• Romanet J, Smith GW, Leavens TL, Baynes RE, Wetzlich SE, Riviere JE, Tell LA. Pharmacokinetics and tissue elimination of tulathromycin following subcutaneous administration in meat goats. Am J Vet Res., In Press 2011.
• Hope KL, Tell LA, Byrne BA, Murray S, Wetzlich SE, Ware LH, Lynch W, Padilla LR, Boedeker NC. Pharmacokinetics of a single intramuscular injection of ceftiofur crystalline-free acid in American black ducks (Anas rubripes). Am J Vet Res, 73(5):620-627, 2012.
• Tell LA, Brooks JW, Lintner V, Matthews T, Kariyawasam S. Antimicrobial susceptibility of Arcanobacterium pyogenes isolated from the lungs of white-tailed deer (Odocoileus virginianus) with pneumonia. Vet Diagn Invest., 23(5):1009-1013, 2011.
• Clothier KA, Leavens T, Griffith RW, Wetzlich SE, Baynes RE, Riviere JE, Tell LA. Tulathromycin assay validation and tissue residues after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus). J Vet Pharmacol Ther., 35(2):113-120, 2012.

Progress 09/01/10 to 08/31/11

Outputs
OUTPUTS: Erythromycin/salmonids (ADR135): Environmental assessment (EA) report was sent to FDA/CVM for review and a request a chronic toxicity study with Daphnia magna be performed and was completed. Physiochemical properties study was performed. Because of the physical characteristics of ERTT, an empirical pKa could not be established. Final EA report was completed in 05/2010 and submitted. Results support the safe use of erythromycin thiocyanate in all freshwater-reared salmonids at a dose of 100 mg/kg bodyweight/day for 21-28 days. On 1/12/2011, FDA/CVM submitted notification that the Final Study Report for the pivotal Daphnia magna chronic toxicity study is considered complete. CIDRg/sheep(ADR258): FDA/CVM accepted the data and summarized this in a Public Master File. All required studies are published in the Federal Register 74(220)59073-59074, 11/17/2009. Romet/gamebirds (ADR272): Collaborative project with Northeast (NE) region and part of a PhD thesis project on avian species grouping. Numerous samples were analyzed in our NRSP laboratory. Lincomycin soluble powder/honeybees (ADR311): All required studies are complete. Announcement of the Availability of Data for the use of lincomycin hydrochloride water soluble powder for the control of American foulbrood (Paenibacillus larvae) in honey bees, is posted on the FDA/CVM website 07/1/2011. Progesterone CIDRs/goats(ADR324): Target animal safety (TAS), milk residue study and quality assurance are complete. Final technical report was accepted by FDA/CVM. Efficacy protocol was accepted by FDA/CVM. Efficacy study began at UCD and Iowa State University (ISU) 2009. Quality assurance (QA) was performed. All raw data from UCD was submitted to ISU 08/2010. Study initiated 09/2010.Florfenicol (Nuflor Injectable Solution)/sheep(ADR325): All data for the old formulation for this project was published. HFS technical report was submitted to FDA/CVM. On 02/11/2011, FDA/CVM concluded that the tissue residue depletion study was acceptable for supporting a withdrawal determination, and assigned a 42-day withdrawal period. Other comments from FDA/VM were that microbial food safety issues still need to be addressed which include the impact of florfenicol on antimicrobial resistance among bacteria of public health concern in or on treated sheep as well as human intestinal flora.Tulathromycin/goats(ADR340) (collaborative/ NC region). Tissue LC/MS method for sample analysis was validated. Validation of analytical methods for liver, muscle, kidney and fat samples is complete. Plasma/tissue samples for TAS were analyzed and QA was performed. Plasma/tissue samples for Human Food Safety study (HFS) were analyzed and data generated. Method validation report was submitted to the NC Region for QA review. Florfenicol (Nuflor Gold)/sheep(ADR350): Pilot study evaluating administration route (IM vs SC) and doses of 20 (IM) or 40 (SC) mg/kg was performed and all samples analyzed. Another dose range finding study using the SC route of administration is required. Once the proposed label dose is determined, the TAS study will be performed. Study is pending until CVM provides further guidance. PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Veterinarians and commodity groups. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
Pharmacokinetics, human food safety, and target animal safety studies are required by FDA/CVM to obtain minor and specialty animal drug clearances in minor species for drug registration. Data must be obtained for each animal species for which drug use is intended. These minor use animal drug registrations will impact the farmers and ranchers of the Western Region with the potential beneficiaries of this research being the consumers in the Western Region and the rest of the United States.

Publications

• Young G, Smith GW, Leavens TL, Wetzlich SE, Baynes RE, Mason SE, Riviere JE, Tell LA. 2011, Pharmacokinetics of tulathromycin following subcutaneous administration in meat goats. Res Vet Sci, 90(3): 477-479. Clothier KA, Leavens T, Griffith RW, Wetzlich SE, Baynes RE, Riviere JE, Tell LA. 2011, Pharmacokinetics of tulathromycin after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus). J Vet Pharmacol Therap (published online).
• Clothier KA, Leavens T, Griffith RW, Wetzlich SE, Baynes RE, Riviere JE, Tell LA. 2011, Tulathromycin assay validation and tissue residues after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus). J Vet Pharmacol Therap (Published online).
• Leavens T, Tell LA, Clothier KA, Griffith RW, Baynes RE, Riviere JE. 2011, Development of a physiologically based pharmacokinetic model to predict tulathromycin distribution in goats. J Vet Pharmacol Ther, 500-12.
• Dore E, Angelos JA, Rowe JD, Carlson JL, Wetzlich SE, Kieu HT, Tell LA. 2011, Pharmacokinetics of ceftiofur crystalline free acid after single subcutaneous administration in lactating and nonlactating domestic goats (Capra aegagrus hircus). J Vet Pharmacol Ther, 34(1): 25-30.