4. pharmacokinetics and pharmacodynamics of gamithromycin
TRANSCRIPT
1
Presenter: Ronald K Tessman, DVM, PhD, DACVIM, DACVPM
Special thanks to:
Laura Letendre, PhD and Rose Huang, PhD
For presentation development and technical assistance
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 TulathromycinPK parameters3
Drug disposition
4
Path of a drug in‐vivo: parenteral administration
Absorption
Distribution
Metabolism
Excretion
SCIV
5
Tissues/Organs
Systemic CirculationFree Drug Bound Drug
LiverDrug & Metabolite
Drug & Metabolite
IntestineDrug &
Metabolite
Excretion in Urine
Excretion in Feces
Absorption
BiliaryExcretion
DistributionA
bsorption
Parenteral routes
Epidermis
Dermis
SubcutaneousFat tissue
Muscle
6
Fast acting
Gamithromycin pharmacokinetics
Absorption and systemic exposure
7
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
Complete absorption of Gamithromycin
PR&D0099101
9
Fast, complete absorption
Predictable Pharmacokinetic
profileTime (day)
Gam
ithrom
ycin
Concen
tration (ng/mL)
0
20
40
60
80
100
120
140
160
180
200
0 2 4 6 8 10 12
Time (hour)
Gam
ithro
myc
in
Plas
ma
Con
cent
ratio
n (n
g/m
L)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 Hrsplateau 30 min to 6 Hrs
Dose proportionality
• Dose adjustments are made with the assumption of dose proportionality
PR&D0099101
Target dose
ZACTRAN has a predictable response
11
Summary of pharmacokinetic results
• Absorption is fast– 80% of max within 15 minutes– Maximum within 1 hour
• Absorption is complete– Bioavailability is 100%
• Predictable and proportional exposure with dose from 3 to 9 mg/kg
12
Long lasting
Gamithromycin pharmacokinetics
Clearance and distribution
13
Definitions
14
Concentration gradientdriving distribution
Plasma Protein Tissue
Plasma Extracellular fluid
Membrane
15
Gamithromycin plasma protein binding = 26%
Volume of distribution:a proportionality constant
Plasma Protein Tissue
Plasma Extracellular fluid
Membrane
Amount of drug in the body (t) = Vd * plasma concentration
16
Volume distribution
17
Physical chemical properties Important to PK
• Log P: preference for water or oil?
• Solubility in water
• pKa: how much drug is ionized at each pH?
18
www.molecularstation.com
GamithromycinPhysical chemical properties
• Lipophilic– Log P = 4.69
• High H2O solubility – 50 mg/mL
• Dibasic– pKa = 9.78 and 8.88
19
O
O
Me
O
O
Me
HO OH
H
MeN Me
H
H
H
MeO O
RS
S R
R
R
S
RS
R
Me
OH
OMe
Me
OH
Me
HO
NH3C
CH3
Me1
15 14
1312
11
109
876
54
32
Ionization of Gamithromycin in plasma
Plasma pH 7.4; pKa = 9.78
20
pH = pKa ‐ 2 ~100% ionized
If pH = pKa 1:1 ratio
pH = pKa + 2 ~100% neutral
IonizedNeutral
Neutral 1 Ionized 240
Ion trapping allows lung accumulation
Membrane Membrane
Neutral 1: Ionized 380Neutral 1: Ionized 240 Neutral 1: Ionized 95000
Plasma ‐ pH 7.4 Cytosol ‐ pH 7.2Macrophage – Acidic
e.g. pH of 4.8
21
Non‐IonizedNon‐Ionized Non‐IonizedNon‐Ionized
For a pKa of 9.78
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 Gamithromycinin Plasma, PELF, Lung Tissue Homogenate, BAL Cells in Cattle using an LCMS Method throughout a Therapeutic Time Period
22
Gamithromycin tissue distribution10 days after dosing
Systemic circulation
Tissues/Organs
PR&D0198501
23
Above MIC
Ratio 487:1
Lung and plasma pharmacokinetics
PR&D0198501
24
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 Gamithromycinand PR&D0078501: Metabolite Profiles in Selected Cattle Tissue Samples from PR&D0078101
25
Elimination of Gamithromycin
PR&D0078101, PR&D0078501
26
Drug metabolism is limited
Metabolites proven
inactive and safe
Summary of GamithromycinMetabolism/distribution studies
• Protein binding is low (26%)
• Extensive tissue distribution– Lung >> plasma
– Intracellular ion trapping in the lung
• Quick systemic clearance of free drug
• Excreted primarily un‐metabolized in the bile
• Metabolites are not active
27
Effectively concentrates in the lung
Gamithromycin pharmacodynamics
28
29
Time dependence of Gamithromycinactivity
• Post‐antibiotic Effect (PAE) describes what happens to the test organism after the antibiotic is removed
• Common for macrolide class
• Gamithromycin PAE from 4.1 to 8.6 hours
• Consistent with other reported macrolides
30
Gamithromycin concentration dependence studied
31
PR&D0169301: Activity of the Gamithromycin against Histophilus somni strains associated with bovine respiratory disease: Determination of antibacterial kill kinetics.
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 Gamithromycinin Plasma, PELF, Lung Tissue Homogenate, BAL Cells in Cattle using an LCMS Method throughout a Therapeutic Time Period
Uptake kinetics in clinically relevant tissues and fluids
PR&D0198501: Disposition of Gamithromycin in plasma, pulmonary epithelial lining fluid, bronchoalveolar cells, and lung tissue in cattle
PELF (Pulmonary Epithelial Lining Fluid)
Alveolar macrophages
Capillary Wall
Interstitial Fluid
Alveolar Epithelium
Bronchoalveolar biophase
33
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
1
10
100
1000
10000
100000
0 2 4 6 8 10 12 14 16
Time, days
Ga
mit
hro
myci
n C
on
cen
tra
tio
n
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
Therapeutic lung concentrations
PR&D0198501
36
BAL and lung homogenate have high exposure (AUC).
Concentrations are reached quickly – above MIC in 30 mins.
Long lasting: above MIC for 10‐15 days.
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/mlEuropeanBRD isolates
• 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
ZACTRAN
Comparison to Tulathromycin
39
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
Pharmacokinetic K comparison
ZACTRAN Data: PR&D0198501Tulathromycin Data: Veterinary Therapeutics V5, N1, Spring 2004, p60.
41
Tulathromycin Lung
Gamithromycin Lung
Gamithromycin Plasma
Pharmacokinetic comparison
Absorption and distribution
42
Fast actingGamithromycin lung concentrations > MIC within 15 mins
Higher concentrations than Tulathromycin in lung
Pharmacokinetic comparison
Clearance
43
Fast uptake plasma to tissuePersistent activity in tissue
Efficient terminal elimination
Pharmacokinetic comparison
Distribution
44
Gamithromycin:higher lung concentrations
Conclusion
• All advantages associated with the macrolideclass
• Fast and complete absorption• Fast and extensive lung distribution• Lung concentrations > MIC
– From 15 minutes (Fast Acting)– To 10‐15 days (Long Lasting)
• Effectively concentrates in the lung tissue faster than Tulathromycin
45
Questions
1
10
100
1000
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Ga
mit
hro
my
cin
Pla
sm
a C
on
ce
ntr
ati
on
(n
g/m
L)
Time (day)
Pharmacokinetics at the Recommended dose of 6 mg/kg SC
PR&D0099101
47
Fast absorption