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Transcript of 8th ISAP Symposium Developments in Pharmacokinetics and Pharmacodynamics (PK/PD): optimising...
8th ISAP Symposium
Developments in Pharmacokinetics and Pharmacodynamics (PK/PD):
optimising efficacy and prevention of resistance
Nijmegen, The Netherlands, July 4th-6th, 2001
P Leesand
F Shojaee AliAbadiThe Royal Veterinary College, UK
Rational dosing: animals versus humans
Rational Dosing of Antimicrobial Drugs in Animals
• 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
Application of PK/PD integration to optimisation of antibacterial therapy
EfficacyEfficacyRecovery rateRecovery rate
ResistanceResistanceResiduesResiduesToxicityToxicity
CostCost
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
• 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
HM = Hepatic metabolism, HE = hepatic excretion, RE= renal excretion Prescott, Baggot and Walker, 2000
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
RERE + 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
Oral Dosing of Antimicrobial Drugs in Ruminants
PROPERTY CONSEQUENCE
Ruminal microflora metabolise many drugs
Low bioavailability
Dilutional effect in rumen (120 litres in adult cow, pH = 6.5)
Low bioavailability and/or slow absorption
Drug suppression of normal flora leading to overgrowth of pathogens
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
• Muscle, fat, liver, kidney, eggs, milk
• In EU maximum residue limits (MRLs) set by CVMP
• MRLs set on basis of residue concentration anda) No Observable Effect Level (NOEL) in animal toxicity studiesb) 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
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
PASSAGE OF BLOOD : MILK BARRIER
Blood pH = 7.35 – 7.40Milk pH = 6.50 – 6.80 1 + 10 (pHm – pKa)
Rm/p = --------------------------- Weak acid1 + 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
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
Poultry Unique Anatomical Considerations
1) Haematology / immunology
2) Respiratory / Pulmonary system
3) Musculoskeletal system
4) Reproductive system
5) Integument
6) Gastrointestinal
7)7) Excretory / urinary systemsExcretory / urinary systems
Excretory / urinary systems
1)1) Bilateral tri-lobed elongated kidneys, “resting” in Bilateral tri-lobed elongated kidneys, “resting” in synsacrum / retroperitoneal fossae synsacrum / retroperitoneal fossae
2)2) No bladder (ureters traverse to cloaca) No bladder (ureters traverse to cloaca)
3)3) Histologically “chaotic”, without specific medullary / Histologically “chaotic”, without specific medullary / cortical regions cortical regions
4)4) Urine produced is rich in uric acid. Uric acid / urates Urine produced is rich in uric acid. Uric acid / urates are a “white cap” on darker GI excretaare a “white cap” on darker GI excreta
5)5) Renal portal system supplies peritubular capillary Renal portal system supplies peritubular capillary network network
Enrofloxacin
Absorption:Absorption:
OralOral
Rapidly absorbed in monogastric species, Rapidly absorbed in monogastric species, preruminant calves and chicken. preruminant calves and chicken.
Absorption in adult ruminants is variable Absorption in adult ruminants is variable and has ranged from 10 to 50%. and has ranged from 10 to 50%.
Enrofloxacin
Distribution:Distribution:
Rapidly and widely distributed into all Rapidly and widely distributed into all measured body tissues and fluids in many measured body tissues and fluids in many species, including cats, cattle, chickens, dogs, species, including cats, cattle, chickens, dogs, horses, and rabbits. horses, and rabbits.
Enrofloxacin Concentration in chicken tissues (Enrofloxacin Concentration in chicken tissues (g/ml or g) g/ml or g) 1 h post treatment (O.S. 10mg/kg)1 h post treatment (O.S. 10mg/kg)
Brain 1.1
Lung 2.4
Heart 2.8
Spleen 2.5
Kidney 1
Liver 4.6
Muscle 2
Skin 1.1
Serum 1.4
EnrofloxacinPreparation of dosage form:
1) The stock solutions should be prepared fresh daily.
2) Protect stock solution or medicated water from:1) Freezing2) 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.
Time (h)
Co
nce
ntr
atio
n (
g/m
l)Enrofloxacin serum concentrations after continuous
dosage at a dose rate of 50 ppm
0
0.2
0.4
0.6
0.8
1.0
1.2
0 24 48 72 96
PK/PD integration for enrofloxacin in chickens following continuous PK/PD integration for enrofloxacin in chickens following continuous OS administration at a dose rate of 50 ppm (10 mg/kg)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
PHARMACOKINETIC (and Efficacy ?) Variability of Antimicrobial Drugs in Fish
• MEDICATION e.g. FURUNCULOSISBaths:
Short-term baths Long-term baths
Topical treatmentsInjectionMEDICATED FOOD
• VARIABILITY- Inherent inter-animal variation in A, D, M, E- Inter-animal variation in intake- Temperature dependency of pharmacokinetics- Temperature dependency of residues
Elimination Half-life of Antimicrobial Agents in Fish : Species and
Temperature DifferencesDRUG 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(mg /kg/day - in feed)
Species Withdrawal time(Degree days)
Amoxycillin 40-80 for 10 days Salmon
Atlantic Salmon
50 or 80
40
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
Bacterial Disease in Bees
AMERICAN FOULBROOD• 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 laidby the queen
3rd daythe eggs hatch
into worm-like larvae
7th dayFully grown larvae
Cells sealed offby workers
Only Royal Jelly Royal Jelly (Queen)
Royal Jelly + Pollen and Honey (Worker)
Honey Crop Stomach
absorptionJelly glands
Pollen / Syrup
Royal Jelly
Ventricle
Larva
Worker
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
Ventricle
Body nutrients
Disposition profile of Ampicillin (ABPC) in larvae after single dose of 30 mg/hives in syrup or 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
--- Syrup
Paste
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).
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
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
Days after termination of dosing
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).
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+00
1.E+03
1.E+06
1.E+09
0 6 12 18 24
Incubation time (h)
Lo
g c
fu/m
l
Con.
1 h
3 h
6 h
9 h
12 h
24 h
48 h
Ex vivo time killing curve and PK/PD integration in serum of goat 5, 9 h
sampleCss = 0.065 g/ml
1.00E+00
1.00E+01
1.00E+02
1.00E+03
1.00E+04
1.00E+05
1.00E+06
1.00E+07
1.00E+08
0 6 12 18 24
Incubation time (h)
Lo
g c
fu/m
l
Ex vivo AUC24h = 0.065 x 24 = 1.56 g.h/mlEx vivo AUC24h/MIC = 1.56 / 0.030 = 52
Sample Conc.
Bacterial Count
In vivo PK/PD integration in serum of goat 5 after single IM injection at a dose rate of 1.25
mg/kg Cmax / MIC = 12
T>MIC =13.5 h
0.001
0.010
0.100
1.000
0 6 12 18 24
Time (h)
Dan
ofl
oxa
cin
co
nce
ntr
atio
n (g
/ml)
Serum Conc.
AUC24h = 2.32 g.h/mlAUC24h/MIC = 2.32 / 0.030 = 77
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 D
ano
flo
xaci
n c
on
cen
trat
ion
(g
/ml)
Cmax / MIC = 12
T>MIC =13.5 h
0.001
0.010
0.100
1.000
0 6 12 18 24
Time (h)
Serum Conc.
Bacterial Count
AUC24h = 2.32 g.h/mlAUC24h/MIC = 2.32 / 0.030 = 77
-7
-6
-5
-4
-3
-2
-1
0
1
0 50 100 150 200 250 300
AUC24h / MIC
Observed
Predicted
Bacteriostatic AUC24h / MIC= 18
Bactericidal AUC24h / MIC = 39
Elimination AUC24h / MIC = 90L
og
cfu
/ml
dif
fere
nce
Sigmoidal Emax relationship for bacterial count versus ex vivo AUC24h / MIC in goat 1 serum
AUC24h / MIC Values and Hill Constants for Danofloxacin Determined Ex Vivo in
the Goat
AUC24h / MIC SERUM
EXUDATE TRANSUDATE
Bacteriostatic 22.61.7 18.3±1.6 23.4±4.0
Bactericidal 29.62.5 28.2±2.4 36.7±1.6
Elimination 52.48.1 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 SPECIESCalf Sheep Goat Camel
Bacteriostatic 15.92.0
17.81.7 22.61.7 17.23.6
Bactericidal 18.11.9
20.21.7 29.62.5 21.23.7
Elimination 33.53.5 28.71.8 52.48.1 68.715.6Values 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 g/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 ) from in vivo pharmacokinetic
** Prediction of bacterial ) and ex vivo
and clinical cure ) pharmacodynamic data
Median in vivo antibacterial activity of a fluoroquinolone against M.haemolytica in bronchial secretions
-6
-4
-2
0
2
4
6
0 6 12 18 24
Controls
AUC / MIC = 15
AUC / MIC = 120
Ch
ang
e in
bac
teri
al c
ou
nt
(cfu
/ml)
Proposal for Future Studies
Clinical Disease e.g. Calf Pneumonia
Measurement of population pharmacokinetics
Determination of distribution of MICs
0
0.5
1
1.5
2
2.5
3
0 6 12 18 24
Time (h)
Co
nce
ntr
atio
n (
g/m
l)
Possible toxicity
Optimal efficacyPossible resistance
Simulated plasma concentration-time curves and their mean in a small population
PK/PD Integration of Antimicrobial Drugs in Clinical
TrialsDrug treatment of disease in given
populationPopulation PK measurementsDetermination of disease outcomeIntegration 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