Transcript PK/PD - ISAP

8th ISAP Symposium
Developments in Pharmacokinetics and Pharmacodynamics (PK/PD):
optimising efficacy and prevention of resistance
Nijmegen, The Netherlands, July 4th-6th, 2001
Rational dosing:
animals versus humans
P Lees
and
F Shojaee AliAbadi
The Royal Veterinary College, UK
Rational Dosing of Antimicrobial
Drugs in Animals
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•
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General considerations
Legal guidelines for PK-PD
Aspects of pharmacokinetics in animals
PK-PD integration of danofloxacin in ruminants
(tissue cage model)
• PK-PD integration of danofloxacin in calf
pneumonia
• Rational dosing: future perspectives
Pharmacology of Antimicrobial
Therapy
Dose
Serum Conc.
Site of
action
Conc.
Application of PK/PD integration to
optimisation of antibacterial therapy
Efficacy
Recovery rate
Resistance
Residues
Toxicity
Cost
Antimicrobial Drug Treatment
Which drug ?
How much ?
How often ?
How long ?
4
3
2
1
0
0
4
8
12
16
20
24
Criteria for Setting Dose
Schedules
 Cmax > 2 x MIC90 for all bacterial species against
which activity to be claimed
 Plasma concentration > 1 x MIC90 for all bacterial
species against which activity to be claimed for
half inter-dose interval
 Dosing schedules meeting these criteria will be
effective in many patients but are unlikely to be
optimal for any antimicrobial drug group
Aspects of Pharmacokinetics in
Animals
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inter-species differences (half-life, clearance)
intra-species differences (breed)
age
depot formulations
residues in food producing species
distribution to udder (blood:milk barrier)
ruminants
chicken
fish
honey bee
Elimination Half-life of Antimicrobial
Agents : Species Differences
DRUG
ELIMINATION
MECHANISM
HALF-LIFE (h)
Man
Dog
Horse
Cow
Trimethoprim
Sulphadiazine
Sulphadimethoxine
Metronidazole
Norfloxacin
HM + RE
HM + RE
HM + RE
HM + RE
HM + RE
10.6
9.9
40.0
8.5
5.0
4.6
5.6
13.2
4.5
3.6
3.2
3.6
11.3
3.9
6.4
1.3
2.5
12.5
2.8
2.4
Benzylpenicillin
Ampicillin
Gentamicin
RE
RE + HE
RE
1.0
1.3
2.8
0.5
0.8
1.3
0.9
1.2
2.2
0.7
1.0
1.8
HM = Hepatic metabolism, HE = hepatic excretion, RE= renal excretion
Prescott, Baggot and Walker, 2000
Oral Dosing of Antimicrobial Drugs in
Ruminants
PROPERTY
Ruminal microflora
many drugs
CONSEQUENCE
metabolise Low bioavailability
Dilutional effect in rumen (120
litres in adult cow, pH = 6.5)
Drug suppression of normal flora
leading to overgrowth of pathogens
Low bioavailability and/or
slow absorption
Life threatening disease and/or
reduced fermentative digestion
Oral dosing usually restricted to pre-ruminant calves (aged <4-6 weeks)
Parenteral Dosing of Antimicrobial
Drugs in Ruminants and Pigs
Use of depot formulations giving sustained release from
intramuscular injection sites
a) aqueous suspensions e.g. Procaine benzylpenicillin,
clavulanate potentiated amoxycillin
b) oily suspensions e.g. Procaine benzylpenicillin
c) high strength solutions in organic solvents, drug
precipitating at injection site e.g. oxytetracycline
Use of Depot/Sustained Release
Formulations
CONSEQUENCES
FOR
PHARMACOKINETICS,
EFFICACY, TOXICITY AND DOSING:
• Commonly involve flip-flop pharmacokinetics
• Rising phase half-life represents elimination
• Declining phase half-life represents absorption
• Avoidance of peaks and troughs of concentration
• Maintenance of effective concentrations for 1-4 days
• Useful for time-dependent drugs (maintenance of T>MIC)
• Problem of injection site residue in muscle
Residues of Antimicrobial Drugs in
Food Producing Species
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Muscle, fat, liver, kidney, eggs, milk
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In EU maximum residue limits (MRLs) set by CVMP
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MRLs set on basis of residue concentration and
a) No Observable Effect Level (NOEL) in animal toxicity
studies
b) No microbiological effect level (NMEL)
•
Acceptable daily intake (ADI) determined using
safety factor (SF) of 100 to 1000 (NOEL) or 10
(NMEL)
Drug Pharmacokinetics in Mastitis
Therapy in Cattle
PASSAGE OF BLOOD : MILK BARRIER
Good
1) Lipid soluble neutral molecules
2) Lipid soluble weak organic bases
Poor
1) Ionised molecules (strong acids and bases)
2) Lipid soluble weak organic acids
3) Lipid insoluble weak organic bases
Blood pH = 7.35 – 7.40
Milk pH = 6.50 – 6.80
1 + 10 (pHm – pKa)
Rm/p = --------------------------- Weak acid
1 + 10 (pHp - pKa)
Milk : Plasma Concentration Ratios in
Cattle
DRUG
LIPID
SOLUBILITY
PKa
Milk ultrafiltrate : Plasma
Ultrafiltrate
Theoretical
Experimental
ACIDS*
Benzylpenicillin
Sulphadimethoxine
Sulphamethazine
Low
Moderate
Moderate
2.7
6.0
7.4
0.25
0.20
0.58
0.13-0.26
0.23
0.59
BASES**
Trimethoprim
Spiramycin
Streptomycin
Polymyxin B
High
High
Low
Very low
7.3
8.2
7.8
10.0
2.32
3.57
3.13
3.97
2.90
4.60
0.50
0.30
* Improved penetration in mastitis
** Improved/reduced penetration in mastitis
Prescott, Baggot and Walker, 2000
Drug Pharmacokinetics in Mastitis
Therapy in Cattle
Intramammary Dosing of
Antimicrobial Drugs in Ruminants
Use of intramammary infusion tubes for
treatment of mastitis in cattle
a) lactation therapy
b) dry cow therapy
PHARMACOKINETIC (and Efficacy ?)
Variability of Antimicrobial Drugs in
Poultry
• MEDICATION
- Continuous dosing in water
- Pulse dosing in water
- In feed medication (pelletted food)
• VARIABILITY
- Inherent inter-animal variation in A, D, M, E
- Inter-animal variation in intake
Metabolites
Excretion
Distribution
Tissue bound
Metabolism
Poultry
Unique Anatomical
Considerations
Poultry
Unique Anatomical Considerations
1) Haematology / immunology
2) Respiratory / Pulmonary system
3) Musculoskeletal system
4) Reproductive system
5) Integument
6) Gastrointestinal
7) Excretory / urinary systems
Excretory / urinary systems
1) Bilateral tri-lobed elongated kidneys, “resting” in
synsacrum / retroperitoneal fossae
2) No bladder (ureters traverse to cloaca)
3) Histologically
“chaotic”,
medullary / cortical regions
without
specific
4) Urine produced is rich in uric acid. Uric acid /
urates are a “white cap” on darker GI excreta
5) Renal portal system supplies peritubular capillary
network
Enrofloxacin
Absorption:
Oral
Rapidly absorbed in monogastric species,
preruminant calves and chicken.
Absorption in adult ruminants is variable
and has ranged from 10 to 50%.
Enrofloxacin
Distribution:
Rapidly and widely distributed into all
measured body tissues and fluids in many
species, including cats, cattle, chickens, dogs,
horses, and rabbits.
Enrofloxacin Concentration in chicken tissues (mg/ml or g) 1
h post treatment (O.S. 10mg/kg)
Brain 1.1
Kidney 1
Skin 1.1
Liver 4.6
Lung 2.4
Muscle 2
Heart 2.8
Spleen 2.5
Serum 1.4
Enrofloxacin
Enrofloxacin is metabolised to
ciprofloxacin
in chickens.
Enrofloxacin
Preparation of dosage form:
1) The stock solutions should be prepared fresh daily.
2) Protect stock solution or medicated water from:
1) Freezing
2) Direct sunlight.
3) Use water with low hardness.
4) Galvanized metal watering systems or containers should
not be used to carry or store this product (possible
chelation with metal ions)
5) Chlorinators should not be operated while administering
this medication.
Enrofloxacin serum concentrations after continuous
dosage at a dose rate of 50 ppm
Concentration ( mg/ml)
1.2
1.0
0.8
0.6
0.4
0.2
0
0
24
48
Time (h)
72
96
PK/PD integration for enrofloxacin in chickens following continuous
OS administration at a dose rate of 50 ppm (10 mg/kg)
PK/PD
Integration
Mycoplasma
spp
Staphylococcus
spp
E.coli
Salmonella
spp
MIC 50
0.25
0.12
0.06
0.03
Cmax/MIC
4.40
9.17
18.33
36.67
AUC24h/MIC
82.80
172.50
345.00
690.00
MIC 90 (100?)
1.00
1.00
0.50
0.50
Cmax/MIC
1.10
1.10
2.20
2.20
AUC24h/MIC
20.70
20.70
41.40
41.40
I Need Some
Fresh Air
PHARMACOKINETIC (and Efficacy ?)
Variability of Antimicrobial Drugs in Fish
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MEDICATION e.g. FURUNCULOSIS
Baths:
Short-term baths
Long-term baths
Topical treatments
Injection
MEDICATED FOOD
•
VARIABILITY
- Inherent inter-animal variation in A, D, M, E
- Inter-animal variation in intake
- Temperature dependency of pharmacokinetics
- Temperature dependency of residues
Salmon Farming
Elimination Half-life of Antimicrobial
Agents in Fish : Species and
Temperature Differences
DRUG
SPECIES
TEMPERATURE
(C)
HALF-LIFE
(h)
Sulphadimidine
Carp
Carp
Rainbow trout
Rainbow trout
10
20
10
20
50
26
21
15
Trimethoprim
Carp
Carp
10
24
41
20
Oxytetracycline
Rainbow trout
African catfish
12
25
90
80
Antibacterial Therapy in Fish
Antibacterials
Dose
Species
(mg /kg/day - in feed)
Withdrawal time
(Degree days)
Amoxycillin
40-80 for 10 days
Salmon
Atlantic Salmon
Oxolinic acid
10 for 10 days
Salmon, trout
500
Oxytetracycline
75 for 4-10 days
Salmon, trout
400 - 500
Florfenicol
10 for 10 days
Atlantic Salmon
150
Sarafloxacin
10 for 5 days
Atlantic Salmon
150
Major indications: Furunculosis
50 or 80
40
Bacterial Disease in Bees
AMERICAN FOULBROOD
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Spore forming bacterium: Paenibacillus larvae
Brood disease
High contagious
Treatment: burning hives and contaminated equipment
EUROPEAN FOULBROOD
• Non-spore forming bacterium: Melissococcus pluton
• “Stress” disease, most prevalent in spring/early summer
• Treatment: oxytetracycline, ampicillin, mirosamicin
European Foulbrood
• Objective is to deliver drug to young larvae
• Drug must have good bioavailability after oral intake in
adult bee
• Secreted from the jelly glands to jelly which is acidic
(pH~4)
• Lipophilic and/or basic drugs are likely to achieve high
concentrations in jelly by ion-trapping
• Drug should be stable in jelly
eggs are laid
by the queen
3rd day
the eggs hatch
into worm-like larvae
Only Royal Jelly
7th day
Fully grown larvae
Cells sealed off
by workers
Royal Jelly (Queen)
Royal Jelly + Pollen and Honey (Worker)
Worker
Pollen / Syrup
Honey Crop
Stomach
absorption
Jelly glands
Body nutrients
Royal Jelly
Larva
Ventricle
Ventricle
Nakajima C, Sakogawa T, Okayama A, et al. Disposition of mirosamicin in honeybee hives. J Vet Pharmacol Ther
(England), Aug 1998, 21(4) p269-73
Disposition profile of Ampicillin (ABPC) in larvae after single
dose of 30 mg/hives in syrup or paste.
--- Syrup
Paste
Nakajima C, Okayama A, Sakogawa T, et al. Disposition of ampicillin in honeybees and hives. J Vet
Med Sci (Japan), Sep 1997, 59(9) p765-7
Disposition profile of mirosamicin (MRM) in honey bees after
continuous administration for a week at a dosage of 200
mg/hive/week in pollen-substitute paste (hive 1-6).
Days after termination of dosing
Nakajima C, Sakogawa T, Okayama A, et al. Disposition of mirosamicin in honeybee hives. J Vet
Pharmacol Ther (England), Aug 1998, 21(4) p269-73
Disposition profile of mirosamicin (MRM) in honey bees after
continuous administration for a week at a dosage of 200
mg/hive/week in pollen-substitute paste (hive 1-6).
Days after termination of dosing
Nakajima C, Sakogawa T, Okayama A, et al. Disposition of mirosamicin in honeybee hives. J Vet
Pharmacol Ther (England), Aug 1998, 21(4) p269-73
Tissue Cage Model of Acute Sterile
Inflammation
• Implantation of perforated tissue cages at subcutaneous
sites (4 per animal)
• Internal volume
= 35 ml (calf, camel, horse)
= 15 ml (pig)
= 10 ml (sheep, goat)
• After >30 days, stimulation of granulation tissue by
intracaveal injection 0.5 ml 1% carrageenan solution
• Withdrawal at pre-determined times of inflammed fluid
(exudate)
• Withdrawal of non-inflammed fluid from control tissue
cages (transudate)
PK/PD Integration of
Fluoroquinolones
Tissue Cage Model of Sterile Inflammation
 IV or IM administration (ruminant species)
 Measurement of serum, exudate and transudate drug
concentration-time relationships
 Calculation of PK parameters
 Measurement of ex vivo antibacterial activity in serum,
exudate and transudate against e.g. M. haemolytica
(PD)
 Integration of PK/PD data (sigmoidal E-max equation)
Mean ex vivo antibacterial activity of danofloxacin
against M.haemolytica WOO251 in goat serum following
IM administration at a dose rate of 1.25mg/kg
1.E+09
Log cfu/ml
Con.
1h
1.E+06
3h
6h
9h
1.E+03
12 h
24 h
48 h
1.E+00
0
6
12
18
Incubation time (h)
24
Ex vivo time killing curve and PK/PD
integration in serum of goat 5, 9 h
sample
1.00E+08
Css = 0.065 mg/ml
Log cfu/ml
1.00E+07
Ex vivo AUC24h = 0.065 x 24 = 1.56 mg.h/ml
Ex vivo AUC24h/MIC = 1.56 / 0.030 = 52
1.00E+06
1.00E+05
1.00E+04
Sample Conc.
1.00E+03
Bacterial Count
1.00E+02
1.00E+01
1.00E+00
0
6
12
18
Incubation time (h)
24
Danofloxacin concentration (mg/ml)
In vivo PK/PD integration in serum of goat 5
after single IM injection at a dose rate of 1.25
mg/kg
1.000
Cmax / MIC = 12
AUC24h = 2.32 mg.h/ml
AUC24h/MIC = 2.32 / 0.030 = 77
0.100
T>MIC =13.5 h
Serum Conc.
0.010
0.001
0
6
12
Time (h)
18
24
Danofloxacin concentration (mg/ml)
In vivo and ex vivo PK/PD integration in
serum of goat 5 after single IM injection at a
dose rate of 1.25 mg/kg
1.000
Cmax / MIC = 12
AUC24h = 2.32 mg.h/ml
AUC24h/MIC = 2.32 / 0.030 = 77
0.100
Serum Conc.
T>MIC =13.5 h
Bacterial Count
0.010
0.001
0
6
12
Time (h)
18
24
Sigmoidal Emax relationship for bacterial count
versus ex vivo AUC24h / MIC in goat 1 serum
Bacteriostatic
AUC24h / MIC= 18
Log cfu/ml difference
1
0
Observed
-1
Predicted
Bactericidal
AUC24h / MIC = 39
Elimination
AUC24h / MIC = 90
-2
-3
-4
-5
-6
-7
0
50
100
150
AUC24h / MIC
200
250
300
AUC24h / MIC Values and Hill Constants
for Danofloxacin Determined Ex Vivo in
the Goat
AUC24h / MIC
SERUM
EXUDATE
TRANSUDATE
Bacteriostatic
22.61.7
18.3±1.6
23.4±4.0
Bactericidal
29.62.5
28.2±2.4
36.7±1.6
Elimination
52.48.1
55.1±4.4
55.5±2.0
Slope*
15.5±2.9
11.±3.9
13.4±3.9
*Hill Constant
Values are mean  standard error of the mean (n=6)
Ex Vivo AUC24h/MIC Values for Danofloxacin
in Serum from Ruminant Species
AUC24h / MIC
SPECIES
Calf
Sheep
Goat
Camel
Bacteriostatic
15.92.0
17.81.7
22.61.7
17.23.6
Bactericidal
18.11.9
20.21.7
29.62.5
21.23.7
Elimination
33.53.5
28.71.8
52.48.1
68.715.6
Values are mean  standard error of the mean (n=6)
Preliminary Study of Danofloxacin
AUC/MIC in Calf Model of Pneumonia
• M.haemolytica model of calf pneumonia (MIC = 0.03 mg/ml)
• 18 calves allocated randomly to 3 groups of 6
- no treatment
- AUC / MIC = 15*
(0.29 mg/kg danofloxacin)
- AUC / MIC = 120 **
(2.30 mg/kg danofloxacin)
* Prediction of poor response
** Prediction of bacterial
and clinical cure
) from in vivo pharmacokinetic
) and ex vivo
) pharmacodynamic data
Median in vivo antibacterial activity of a fluoroquinolone
against M.haemolytica in bronchial secretions
Controls
Change in bacterial count (cfu/ml)
6
AUC / MIC = 15
4
AUC / MIC = 120
2
0
0
-2
-4
-6
6
12
18
24
Proposal for Future Studies
Clinical Disease e.g. Calf Pneumonia
 Measurement of population pharmacokinetics
 Determination of distribution of MICs
Distribution of MIC
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•
•
•
Normal
Lognormal
Bimodal
Other
Concentration (mg/ml)
Simulated plasma concentration-time curves
and their mean in a small population
3
2.5
Possible toxicity
2
Optimal efficacy
Possible resistance
1.5
1
0.5
0
0
6
12
Time (h)
18
24
PK/PD Integration of
Antimicrobial Drugs in Clinical
Trials
Drug treatment of disease in given
population
Population PK measurements
Determination of disease outcome
Integration of PK/PD data using sigmoidal
E-max equation combined with appropriate
mathematical modelling and statistical
evaluation
Acknowledgments
• Pfizer Animal Health (Collaboration in and support of calf
studies)
– Tim Rowan
– Simon Sunderland
– Patxi Sarasola
• Moredun Research Institute (Collaboration in study of
calf model of pneumonia)
– Quintin McKellar
– Willie Donachie
Rational Dosing of Antimicrobial Drugs
Animal
•Anatomy
•Physiology
•Biochemistry
Disease
•Microbiology
•Clinical
Drug PD
•Spectrum
•Type of activity
•Potency
•Resistance
•Host toxicity
Drug PK
•Dissolution
•Absorption
•Distribution
•Metabolism
•Excretion
•Residue