At physiological pH, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than
lipophilic media. This solubility profile is consistent with the extracellular pathogen activity typically associated
with the macrolides.1 Markedly higher tulathromycin concentrations are observed in the lung parenchyma as
compared to the plasma, and these elevated concentrations can remain in lung tissue for several days beyond
that which can be measured in the plasma. However the clinical relevance of these elevated lung concentrations is
undetermined.
As a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens.2
When acting as a cidal compound, they tend to exhibit concentration independent killing; the rate of bacterial
eradication does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory
concentration (MIC) of the targeted pathogen. Under these conditions, the time that serum concentrations remain
above the MIC becomes the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic
effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the
macrolide concentration and the exposure time, the PAE will increase to some maximal duration. 3 Tulathromycin
is eliminated from the body primarily unchanged via biliary excretion.
1
Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular
Pathogens. Clin. Infect. Dis., 27:28-32.
2
Nightingale, C.J. 1997. Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J.,
16:438-443.
3
Andes D, Anon J, Jacobs MR, Craig WA. (2004). Application of pharmacokinetics and pharmacodynamics to
antimicrobial therapy of respiratory tract infections. Clin Lab Med., 24:477-502.
Swine
Following intramuscular (IM) administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is nearly
completely absorbed, with peak plasma concentrations achieved within ~0.25 hr. The volume of distribution
exceeds 15 L/kg, which is consistent with extensive tissue binding. This large distribution volume results in a long
terminal elimination half-life (60 to 90 hours) despite a rapid systemic free drug clearance (187 mL/kg/hr). There are
no gender differences in swine tulathromycin pharmacokinetics.
Comparative Bioavailability Summary
Despite slightly lower peak concentrations with tulathromycin injection 25 mg/mL, a single IM dose of 2.5 mg
tulathromycin/kg BW of either tulathromycin injection (100 mg/mL) or tulathromycin injection (25 mg/mL)
resulted in comparable tulathromycin total systemic exposure. Therefore, tulathromycin injection 25 mg/mL is
considered to be therapeutically equivalent to tulathromycin injection 100 mg/mL when administered to swine by
IM injection at a dose of 2.5 mg tulathromycin/kg BW.
Calves
Following subcutaneous (SC) administration into the neck of feeder calves at a dosage of 2.5 mg/kg BW,
tulathromycin is nearly completely absorbed, with peak plasma concentrations achieved within ~0.25 hr. The
volume of distribution exceeds 11 L/kg4, which is consistent with extensive tissue binding. This large distribution
volume results in a long terminal elimination half-life of more than 100 hours, despite a rapid systemic free drug
clearance (170 mL/kg/hr). No pharmacokinetic differences are observed in castrated male versus female calves.
Comparative Bioavailability Summary
Despite lower peak concentrations with tulathromycin injection 25 mg/mL, a single SC dose of 2.5 mg
tulathromycin/kg BW of either tulathromycin injection (100 mg/mL) or tulathromycin injection (25 mg/mL)
resulted in comparable total systemic tulathromycin exposure. Therefore, tulathromycin injection 25 mg/mL is
considered to be therapeutically equivalent to tulathromycin injection 100 mg/mL when administered to calves by
SC injection at a dose of 2.5 mg tulathromycin/kg BW.
4 Clearance and volume estimates are based on intersubject comparisons of 2.5 mg/kg BW administered by either
subcutaneous or intravenous injection
Tulissin 25®(tulathromycin injection)Injectable Solution
At physiological pH, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than hydrophobic media. This solubility profile is consistent with the extracellular pathogen activity typically associated with the macrolides.1 Markedly higher tulathromycin concentrations are observed in the lungs as compared to the plasma. The extent to which lung concentrations represent free (active) drug was not examined. Therefore, the clinical relevance of these elevated lung concentrations is undetermined.
Although the relationship between tulathromycin and the characteristics of its antimicrobial effects has not been characterized, as a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens.2 They also tend to exhibit concentration independent killing; the rate of bacterial eradication does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of the targeted pathogen. Under these conditions, the time that serum concentrations remain above the MIC becomes the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the macrolide concentration and the exposure time, the PAE will increase to some maximal duration. Of the two variables, concentration and exposure time, drug concentration tends to be the most powerful determinant of the duration of PAE.
Tulathromycin is eliminated from the body primarily unchanged via biliary excretion.
1Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27:28-32.
2Nightingale, C.J. 1997. Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443.
Cattle
Following subcutaneous administration into the neck of feeder calves at a dosage of 2.5 mg/kg BW, tulathromycin is rapidly and nearly completely absorbed. Peak plasma concentrations generally occur within 15 minutes after dosing and product relative bioavailability exceeds 90%. Total systemic clearance is approximately 170 mL/hr/kg. Tulathromycin distributes extensively into body tissues, as evidenced by volume of distribution values of approximately 11 L/kg in healthy ruminating calves.3 This extensive volume of distribution is largely responsible for the long elimination half-life of this compound [approximately 2.75 days in the plasma (based on quantifiable terminal plasma drug concentrations) versus 8.75 days for total lung concentrations (based on data from healthy animals)]. Linear pharmacokinetics are observed with subcutaneous doses ranging from 1.27 mg/kg BW to 5.0 mg/kg BW. No pharmacokinetic differences are observed in castrated male versus female calves.
3Clearance and volume estimates are based on intersubject comparisons of 2.5 mg/kg BW administered by either subcutaneous or intravenous injection.
Swine
Following intramuscular administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is completely and rapidly absorbed (Tmax ~0.25 hour). Subsequently, the drug rapidly distributes into body tissues, achieving a volume of distribution exceeding 15 L/kg. The free drug is rapidly cleared from the systemic circulation (CLsystemic = 187 mL/hr/kg). However, it has a long terminal elimination half-life (60 to 90 hours) owing to its extensive volume of distribution. Although pulmonary tulathromycin concentrations are substantially higher than concentrations observed in the plasma, the clinical significance of these findings is undetermined. There are no gender differences in swine tulathromycin pharmacokinetics.
Tulissin 100®(tulathromycin injection)Injectable Solution
Mechanism of Action
Ketoprofen is a propionic acid derivate and nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic effects. Ketoprofen inhibits the activity of the enzymes cyclo-oxygenase I and II, resulting in a decreased formation of precursors of prostaglandins and thromboxanes. Ketoprofen also causes a decrease in the formation of thromboxane A2 synthesis, by thromboxane synthase, thereby inhibiting platelet aggregation. The principal mechanism of action of tulathromycin against bacteria involves direct inhibition of essential protein biosynthesis by selective binding to bacterial 50S ribosomal subunits. Tulathromycin acts by stimulating the dissociation of peptidyl- tRNA from the ribosome during the translocation process.
Clinical Pharmacology
In a GLP pharmacokinetic study, 60 cattle received one of 3 treatments: 2.5 mg tulathromycin/kg BW, 3 mg ketoprofen/kg BW or a combination of the two active ingredients (2.5 mg tulathromycin and 3 mg of ketoprofen/kg BW) via subcutaneous injection. Blood samples were obtained pre-dose and at 20 min, 40 min, 1, 1.5, 2, 3, 4, 6, 10, 24, 28, 32, 48, 52, 56, 72, 120, 168, 216, 264, 336, and 360 hours after dosing. The samples were analyzed using validated highperformance liquid chromatography-mass spectrometry (LC-MS/MS) methods for tulathromycin and ketoprofen concentrations. The rate of drug exposure was greater for the ketoprofen alone product.
The mean [±standard deviation (SD)] maximum plasma concentration (Cmax) and time to Cmax (tmax) was 6451 (±1342) ng/mL and 0.83 (±0.53) hr, respectively for ketoprofen alone compared to a mean (±SD) Cmax and tmax of 2322 (±1505) ng/mL and 4.0 (±2.93) hr, respectively, for ketoprofen in the combination product. However, the extent of drug exposure was slightly greater and terminal half life (t1/2) was longer for ketoprofen in the combination product. The mean (±SD) area under the drug concentration- time curve between times 0 and the last quantifiable concentration (AUC0-t(last)) was 26458 (±3605) ng*hr/mL for ketoprofen in the combination product and 23106 (±3500) for ng*hr/mL for ketoprofen alone. Similarly, the mean t 1/2 was 6.84 (±2.09) hr for ketoprofen in the combination product and 2.86 (±1.09) hr for ketoprofen alone. Although the mean (±SD) Cmax of tulathromycin in the combination group (373 (±105) ng/mL) was less than tulathromycin alone (653 (±261) ng/mL), based on mean (±SD) AUC0-t(last), the combination (13647 (±2577) ng*hr/mL) and tulathromycin alone (14088 (±4408) ng*hr/mL) groups had similar tulathromycin bioavailability.
Tulathromycin half life was also similar between the combination (93.3 (±27.9) hr) and tulathromycin alone (98.7 (±23.1) hr) groups.
Draxxin® KP
Swine
Following intramuscular (IM) administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is nearly completely absorbed, with peak plasma concentrations achieved within ~0.25 hr. The volume of distribution exceeds 15 L/kg, which is consistent with extensive tissue binding. This large distribution volume results in a long terminal elimination half-life (60 to 90 hours) despite a rapid systemic free drug clearance (187 mL/kg/hr). There are no gender differences in swine tulathromycin pharmacokinetics.
Comparative Bioavailability Summary
Despite slightly lower peak concentrations with tulathromycin injection 25 mg/mL, a single IM dose of 2.5 mg tulathromycin/kg BW of either tulathromycin injection (100 mg/mL) or tulathromycin injection (25 mg/mL) resulted in comparable tulathromycin total systemic exposure. Therefore, tulathromycin injection 25 mg/mL is considered to be therapeutically equivalent to tulathromycin injection 100 mg/mL when administered to swine by IM injection at a dose of 2.5 mg tulathromycin/kg BW.
Calves
Following subcutaneous (SC) administration into the neck of feeder calves at a dosage of 2.5 mg/kg BW, tulathromycin is nearly completely absorbed, with peak plasma concentrations achieved within ~0.25 hr. The volume of distribution exceeds 11 L/kg4, which is consistent with extensive tissue binding. This large distribution volume results in a long terminal elimination half-life of more than 100 hours, despite a rapid systemic free drug clearance (170 mL/kg/hr). No pharmacokinetic differences are observed in castrated male versus female calves.
Comparative Bioavailability Summary
Despite lower peak concentrations with tulathromycin 25 mg/mL, a single SC dose of 2.5 mg tulathromycin/kg BW of either tulathromycin injection (100 mg/mL) or tulathromycin injection (25 mg/mL) resulted in comparable total systemic tulathromycin exposure. Therefore, tulathromycin injection 25 mg/mL is considered to be therapeutically equivalent to tulathromycin injection 100 mg/mL when administered to calves by SC injection at a dose of 2.5 mg tulathromycin/kg BW.
4Clearance and volume estimates are based on inter subject comparisons of 2.5 mg/kg BW administered by either subcutaneous or intravenous injection.
VACASAN 25
At physiological pH, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than hydrophobic media. This solubility profile is consistent with the extracellular pathogen activity typically associated with the macrolides.
Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27:28-32.
Markedly higher tulathromycin concentrations are observed in the lungs as compared to the plasma. The extent to which lung concentrations represent free (active) drug was not examined. Therefore, the clinical relevance of these elevated lung concentrations is undetermined.
Although the relationship between tulathromycin and the characteristics of its antimicrobial effects has not been characterized, as a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens.
Nightingale, C.J. 1997. Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443.
They also tend to exhibit concentration independent killing; the rate of bacterial eradication does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of the targeted pathogen. Under these conditions, the time that serum concentrations remain above the MIC becomes the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the macrolide concentration and the exposure time, the PAE will increase to some maximal duration. Of the two variables, concentration and exposure time, drug concentration tends to be the most powerful determinant of the duration of PAE.
Tulathromycin is eliminated from the body primarily unchanged via biliary excretion.
1 Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27:28-32.
2 Nightingale, C.J. 1997. Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443.
Draxxin® (tulathromycin injection) Injectable Solution
CLINICAL PHARMACOLOGY
At physical pH, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than hydrophobic media. This solubility profile is consistent with the extracellular pathogen activity typically associated with the macrolides.1 Markedly higher tulathromycin concentrations are observed in the lungs as compared to plasma. The extent to which lung concentrations represent free (active) drug was not examined. Therefore, the clinical relevance of these elevated lung concentrations is undetermined.
Although the relationship between tulathromycin and the characteristics of its antimicrobial effects has not been characterized, as a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens.2 They also tend to exhibit concentration independent killing; the rate of bacterial eradication does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of the targeted pathogen. Under these conditions, the tiime that serum concentrations remain above the MIC becomes the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the macrolide concentration and the exposure time, the PAE will increase to some maximal duration. Of the two variables, concentrration and exposure time, drug concentration tends to be the most powerful determinant of the duration of PAE.
Tulathromycin is eliminated from the body primarily unchanged via biliary excretion.
1
Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27:28-32.
2
Nightingale, C.J. 1997. Pharacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443.
RESPIRmycin
Cattle
Following subcutaneous administration into the neck of feeder calves at a dosage of 2.5 mg/kg BW, tulathromycin is rapidly and nearly completely absorbed. Peak plasma concentrations generally occur within 15 minutes after dosing and product relative bioavailability exceeds 90%. Total systemic clearance is approximately 170 mL/hr/kg. Tulathromycin distributes extensively into body tissues, as evidenced by volume of distribution values of approximately 11 L/kg in healthy ruminating calves.3 This extensive volume of distribution is largely responsible for the long elimination half-life of this compound [approximately 2.75 days in the plasma (based on quantifiable terminal plasma drug concentrations) versus 8.75 days for total lung concentrations (based on data from healthy animals)]. Linear pharmacokinetics are observed with subcutaneous doses ranging from 1.27 mg/kg BW to 5.0 mg/kg BW. No pharmacokinetic differences are observed in castrated male versus female calves.
3
Clearance and volume estimates are based on intersubject comparisons of 2.5 mg/kg BW administered by either subcutaneous or intravenous injection.
Swine
Following intramuscular administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is completely and rapidly absorbed (Tmax ~0.25 hour). Subsequently, the drug rapidly distributes into body tissues, achieving a volume of distribution exceeding 15 L/kg. The free drug is rapidly cleared from the systemic circulation (CLsystemic = 187 mL/hr/kg). However, it has a long terminal elimination half-life (60 to 90 hours) owing to its extensive volume of distribution. Although pulmonary tulathromycin concentrations are substantially higher than concentrations observed in the plasma, the clinical significance of these findings is undetermined. There are no gender differences in swine tulathromycin pharmacokinetics.
RESPIRmycin
At physiological pH, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than lipophilic media. This solubility profile is consistent with the extracellular pathogen activity typically associated with the macrolides.1 Markedly higher tulathromycin concentrations are observed in the lung parenchyma as compared to the plasma, and these elevated concentrations can remain in lung tissue for several days beyond that which can be measured in the plasma. However the clinical relevance of these elevated lung concentrations is undetermined.
As a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens.2 When acting as a cidal compound, they tend to exhibit concentration independent killing; the rate of bacterial eradication does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of the targeted pathogen. Under these conditions, the time that serum concentrations remain above the MIC becomes the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the macrolide concentration and the exposure time, the PAE will increase to some maximal duration.3 Tulathromycin is eliminated from the body primarily unchanged via biliary excretion.
1 Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27:28-32.
2 Nightingale, C.J. 1997. Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443.
3 Andes D, Anon J, Jacobs MR, Craig WA. (2004). Application of pharmacokinetics and pharmacodynamics to antimicrobial therapy of respiratory tract infections. Clin Lab Med., 24:477-502.
Draxxin® 25 (tulathromycin injection) Injectable Solution
CLINICAL PHARMACOLOGY
At physical pH, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than hydrophobic media. This solubility profile is consistent with the extracellular pathogen activity typically associated with the macrolides.1 Markedly higher tulathromycin concentrations are observed in the lungs as compared to plasma. The extent to which lung concentrations represent free (active) drug was not examined. Therefore, the clinical relevance of these elevated lung concentrations is undetermined.
As a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens.2 When acting as a cidal compound, they tend to exhibit concentration independent killing; the rate of bacterial eradication does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of the targeted pathogen. Under these conditions, the tiime that serum concentrations remain above the MIC becomes the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the macrolide concentration and the exposure time, the PAE will increase to some maximal duration.3 Tulathromycin is eliminated from the body primarily unchanged via biliary excretion.
1Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27:28-32.
2Nightingale, C.J. 1997. Pharacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443.
3Andes D, Anon J, Jacobs MR, Craig, WA. (2004). Application of pharmacokinetics and pharmacodynamics to antimicrobial therapy of respiratory tract infections. Clin Lab Med., 24:477-502.
VACASAN 25