2. Special thanks to:
Laura Letendre, PhD and Rose Huang, PhD
For presentation development and technical assistance
3. Outline
• Principles of drug disposition
– ADME properties of drugs
– Routes of administration
• Pharmacokinetics (PK) of Gamithromycin
– Absorption
– Distribution
– Clearance
• Pharmacodynamics (PD) Gamithromycin in
lungs
– Comparison of Gamithromycin and Tulathromycin
PK parameters3
8. Pharmacokinetics study
• Treatment groups
– 3 mg/kg IV dose; n =12
– 3, 6, or 9 mg/kg SC; n = 4/group
• Cattle characteristics
– 12 male castrate and 12 female angus cattle
– Less than 1 year old
– Weight = 182 to 260 kg
• Analysis
– Gamithromycin plasma concentration
– Pharmacokinetics
PR&D0099101:Evaluation of the pharmacokinetic profile of Gamithromycin in plasma from cattle treated
with a single intravenous dose (3mg/kg) or a single subcutaneous dose at 3, 6, or 9 mg/kg of Gamithromycin.
8
10. 0
20
40
60
80
100
120
140
160
180
200
0 2 4 6 8 10 12
Time (hour)
Gamithromycin
PlasmaConcentration(ng/mL)
Prolonged absorption phase of
Gamithromycin
PR&D0099101
Absorption rate = Elimination rate
10
Fast absorption
•80% of max
within 15 mins
•Max within 1 Hr
High concentrations
maintained for 6 Hrs
plateau 30 min to 6
Hrs
22. Pulmonary distribution study
• Treatment groups
– 6 mg/kg SC; n = 33
• Cattle characteristics
– 18 male and 15 female, crossbred beef calves
– Aged 7‐8 months
– Weight 100‐300 kg
• Gamithromycin analysis
• Plasma
• Lung tissue homogenate
• Other biofluids
PR&D0198501 : Evaluation of the Duration of the Concentration of Gamithromycin
in Plasma, PELF, Lung Tissue Homogenate, BAL Cells in Cattle using an LCMS Method throughout a Therapeutic Time Period
22
25. Metabolism study
• Treatment groups
– 6 mg/kg SC; n = 14
• Cattle characteristics
– 7 steers and 7 heifers, healthy beef calves
– Aged 6‐7 months
– Weight 190‐240 kg
• Gamithromycin analysis
– Plasma
– Feces and urine
– Tissues and organs
• Liver, kidneys, lungs, muscle, abdominal fat and injection site
– Total radioactive residues of Gamithromycin
– Metabolite profiles
PR&D0078101 : Distribution and Excretion of Total Residues after the Subcutaneous Dosing in Cattle with Gamithromycin
and PR&D0078501: Metabolite Profiles in Selected Cattle Tissue Samples from PR&D0078101
25
32. Bronchoalveolar lavage study
• Treatment groups
– 6 mg/kg SC in the neck; n = 33
• Cattle characteristics
– Crossbred beef calves
– 7‐8 months old
– 100‐300 kg
• Analysis
– Gamithromycin concentrations in the
• Plasma
• Pulmonary Epithelial Lining Fluid (PELF)
• Lung tissue homogenate
• Bronchoalveolar lavage (BAL) cells
– Pharmacokinetics
32
PR&D0198501 : Evaluation of the Duration of the Concentration of Gamithromycin
in Plasma, PELF, Lung Tissue Homogenate, BAL Cells in Cattle using an LCMS Method throughout a Therapeutic Time Period
34. Bronchoalveolar lavage
• Use
– Quantification of Gamithromycin in the BAL fluid
– BAL fluid
• Pulmonary epithelial lining fluid & cell content
(predominately alveolar macrophages)
• First line of defense against commensals and invading
pathogens
– Strong support for fast acting and long lasting
34
35. 1
10
100
1000
10000
100000
0 2 4 6 8 10 12 14 16
Time, days
GamithromycinConcentration
Lung (ng/g)
BAL cells (ng/mL)
PELF (ng/mL)
MIC of 1 ug/mL
Therapeutic lung concentrations
PR&D0198501
Peak lung concentration (12 hrs)
35
Fast
bacteria kill
Rapid
therapeutic
efficacy
37. Time above MIC
PR&D0198501
37
Above MIC in
BAL cells for 15
days
Figure 1. Time over which concentrations of
gamithromycin in lung tissues exceed MIC90
0 5 10 15 20
M. haemolytica
P. multocida
H. somni
Time in days
BAL cells Whole lung PELF
1.0H. somni
1.0P. multocida
0.5M. haemolytica
MIC90 µg/mlEuropean
BRD isolates
38. • Conclusions and clinical relevance
– Fast absorption
– Preferential concentrates in PELF, BAL cells and lung tissue
– Concentrations in excess of the MIC90 for the common
bacterial pathogens:
• Mannheimia haemolytica
• Pasteurella multocida
• Histophilus somni
– Present in specific biophases within 30 minutes of
administration
– Persists for 7 days (PELF) to greater than 15 days (BAL cells
and lung tissue) following administration of a single dose
Summary
PR&D0198501
38
40. Tulathromycin references
• Nowakowski, M.A., et al., "Pharmacokinetics and
Lung Tissue Concentrations of Tulathromycin a
New Triamilide Antibiotic Cattle"
Veterinary Therapeutics. 5. 1. 2004. Print.
• Evans, N. "Tulathromycin: An Overview of a New
Triamilide Antimicrobial for Livestock Respiratory
Disease"
Veterinary Therapeutics. 6. 2. 2005. Print.
40
