pk/pd considerations for corticosteroids
TRANSCRIPT
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PK/PD considerations for corticosteroids
P L Toutain,
National Veterinary School, Toulouse, France
Wuhan October 2015
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Anti-inflammatory drugs
Corticosteroids NSAIDs
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Glucocorticoids: main properties
• Glucocorticosteroids (GCS) are broad and potent anti-inflammatory drugs.
• They are extensively used to mitigate or suppress inflammation associated with a variety of conditions especially joint and respiratory system inflammation.
• GCs are not curative:
• GCs are only palliative symptomatic treatments and chronic use of GCs can be, in fine , detrimental
• GCs possess many other pharmacological properties (not reviewed in this presentation)
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The cortisol or hydrocortisone
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Cortisol : An endogenous hormone and a
surrogate endpoint of the duration of the GCS effects; it physiology should be understood to use properly GCS
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Cortisol synthesis • All GCs used in therapeutics are synthetic
derivatives of cortisol.
• Cortisol (hydrocortisone) is synthesized in the adrenal cortex and it is the main corticosteroid hormone in most species.
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Steroids synthesis by the adrenal gland
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Aldosterone
Cortisol
Androgens
Epinephrine (adrenalin)
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Cortisol ou Hydrocortisone structure – activity relationship
Three structural properties are required for a GC activity (i.e. for cortisol to bind to GC receptor)
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Cortisol (hydrocortisone)
• Minimal information on cortisol physiology (secretion, distribution & elimination ) needs to be known to understand the clinical pharmacology of GCS
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Plasma cortisol
• Cortisol levels are very different in domestic species
• Pattern of secretion – Circadian rhythm (h)
– Pulsatilty (minute)
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Plasma cortisol level
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0
100
200
300
400
500
600
1 2 3 4 5
Series1
Plasma concentration (ng/mL)
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Plasma cortisol levels: circadian rhythm & pulsatility
Toutain et al. Domestic.Anim.Endocrinol. 1988, 5:55 12
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All dogs Rest dogs
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Plasma cortisol levels: circadian rhythm & pulsatility
• The cortisol secretion is pulsatile with minute-to-minute variations in the plasma cortisol concentrations making the interpretation of snapshot plasma samples difficult.
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Modeling of circadian cortisol
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Binding of cortisol to plasma proteins
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• In mammalian plasma, cortisol binds to a specific alpha-glycoprotein: corticosteroid-binding globulin (CBG).
• Binding to CBG is saturable (Bmax)
FreeNSFreeKd
FreeBFreeTotal
max
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Binding of synthetic GCS to plasma protein
• Prednisolone also binds to transcortin
• Other synthetic GS only bind to albumin
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Prednisolone cannot be used for an adrenal suppression test
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Prednisolone
(600µg/kg)
Immediate decrease of cortisol due to the displacement of cortisol from the CBG by prednidsolone
Adrenal suppression test Prednisolone vs. Dexamethasone (IV)
0 0
20
40
60
80
0.16 0.5 1 2 3 4 6 24 48 72 96
Toutain et al., Am.J.Vet.Res 1985, 9: 1750
Cortisol concentration (ng / ml)
0 0
40
60
80
100
0.25 0.5 1 2 4 8 12 24 48
20
Cortisol concentration (ng / ml)
Hours Hours
Dexamethasone (50µg/kg)
Delayed decrease due to the suppression of ACTH secretion
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Urine cortisol
• The advantage of urine cortisol is due to the fact, that unlike plasma sample, a snapshot urine sample is representative of the total cortisol secretion over the entire preceding period of time separating two micturitions, i.e. it is not subjected to time-to-time variation like plasma cortisol.
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Cortic 00.21
Urine cortisol • Diagnostic of Cushing syndrom
Urine Cortisol : cushing : 118 ± 15 ng/mL;
Sensitivity of the test 100%. Spécificity= 22% (confusion
with dogs having a poluuric/polydipsic syndrom
Feldman, JAVMA 1992, 200 : 1637
healthy
dog
dogs with
hyperadrenocorticism
dogs with
polyuria/polydipsia
0.3
1
3
10
30
100
300
1000
3000
Ra
pp
ort
:
co
rtis
ol/cré
atin
ine
(x1
0-6
)
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Urine cortisol (doping control)
• International threshold: 1µg/ml or 1000ng/mL
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Urine cortisol Population investigations (n=254)
Average (geometric)
48ng/mL
maximum 388
Probability exceeding
Urine concentration ng/ml
10-3 611
10-4 1025
10-5 1606
Popot & al EVJ 1997 29 220-229 23
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Regulation of cortisol secretion to be understood to predict the
suppressive effect of GCS
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Cortic 00A.26
Suppressive effect of corticosteroids on the hypothalamic pituitary adrenal axis (HPA)
• Stimulation of cortisol synthesis (no storage)
• Trophic action on the zona fasciculata and reticularis
ACTH
SNC
CRF
ACTH
CORTISOL
ACTH
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Cortic 00A.27
Control Short term Long term
SNC SNC SNC
- - ACTH ACTH ACTH
COR
CS
CRF CRF CRF
COR
t t
Suppressive effect of synthetic GC
ACTH ACTH ACTH
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Cortisol bind to specific receptor
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Inactive glucocorticoid receptors (GR) are located in the cytoplam; after binding to cortisol, the GR is activated and translocated into nucleus; then, GR bind the
glucocorticoid response element (GRE) in the DNA and regulate the responsive gene (activation). The GR can also inhibit transcription by a direct protein/protein interaction
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Cortic 00A.29
Corticosteroid Mechanism of action
Lipocortin Corticoids
PLA2
Plasma membrane Inhibition of phospholipase A2
(PLA2)
Arachidonic acid
PG, TXA2 Leucotrienes
+
Ferguson In: Adams, 1995
cyclooxygenases lipoxygenase
NSAIDs
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20 et 20ß dihydrocortisone
O CH3
C = O
CH2 O H
...... OH
O
CH3
Cortisone
O CH3
O
HO
CH3
H
11-Ketoetiocholanolone
O
HO
CH3
C = O
CH2 O H
...... OH
CH3
CORTISOL
HO CH3
HOCH
CH2 O H
...... OH
O
CH3
20ß dihydrocortisol
6ß hydroxycortisol
11ß - hydroxy etiocholanolone
HO CH3
O
HO
CH3
H
HO CH3
C = O
CH2 O H
...... OH
O
CH3
OH
11 ß - deshydrogénase
Métabolisme du cortisol
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Cortisol metabolism is used as a biomarker of drug metabolism
(polymorphism associated to CYP3A)
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Corticosterioids - Filiation -
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Synthetic glucocorticosteroids (GCs)
• Chemical modification of cortisol have generated derivatives with: – Greater separation of glucocorticoid and
mineralocorticoid activity(selectivity)
– Higher potency
– Longer duration of action
• Chemical modification of cortisol do not have generated derivatives with: – Separation of AI effect from effect on carbohydrates, lipids
and proteins metabolism or without adrenal suppression
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Cortic 00A.36
The main CS used in veterinary medicine for systemic administration
• Prednisolone
• Méthylprednisolone
• Dexaméthasone
• Triamcinolone acétonide
• Fluméthasone
• Isoflupredone
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Cortic 00A.37
The main CS used for systemic inhalation
Fluticasone propionate Beclométhasone 17 monopropinate Budesonide
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The two main group of CS
Cortisol
Non halogenated -derivatives
Prednisolone
Methylprednisolone
budenoside
Halogeneted-derivatives
With mineralocorticoid
activity
Isoflupredone
No mineralocorticoid activity
Dexmethasone, betamethasone
triamcinolone acetonide
betamethasone
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Synthetic derivatives of cortisol
• All therapeutic GCs have a 21-carbon cortisol skeleton
• A variety of GCs have been developed to increase the potency of the anti-inflammatory effect and to decrease or even suppress the mineralocorticoid effects of cortisol
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Cortisone Prednisone
Fluoro-
prednisolone
(Predef 2X)
C9 C16
C16
C6 CH3
C11
OOH
Methylprednisone
Methylprednisolone
C11
OOH
C6
C9 CH3 - Flumethasone
OH - TRIAMCINOLONE
CH3 - Dexamethasone - Betamethasone
C11
OOH
PROPERTY
ANTI-INFLAMMATORY - GLUCOCORTICOID
MINERALOCORTICOID
Prednisolone F Cortisol
C16 & C17 Triamcinolone acetonide
Δ
Δ
C6 CH3
40
GC filiation
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The 2 main PD parameters:
Emax ED50/EC50
EC502
Emax 1
Efficacy Potency
Emax 2
1
2
1 2
EC501
Issue for vets Issue for analysts
Potent drug=low LOQ
ECVPT Toulouse 2009 - 44
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Relative potency of corticosteroids
Substances glucocorticoïd
action
Minéralocorticoïd
action Duration action
Cortisol 1 1 12h
Prednisolone 5 0.8 24h
Méthylprednisolone 5 0.8 24h
Isoflupredone 25 25 48-72h
Triamcinolone 5 0 24h
Triamcinolone
acétonide 30 0 48-72h
Dexamethasone 25 0 48-72h
betamethasone 25 0 48-72h
Flumethasone 120 0 48-72h
Order of potency of the different corticoids is now internationally accepted and
cannot be reconsidered even if there are some discrepancies in the literature 47
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Relative anti-inflammatory (AI) potency of topical GC used for inhalation (1=dexamethasone)
Substances AI Potency
(1=dexamethasone)
Comments
Beclomethasone
dipropionate
0.5 A prodrug of
beclomathasone
monopropionate
Beclomethasone 17-
monopropionate
13 Active moiety of
beclomethasone
dipropionate
Beclomethasone 0.5 Metabolite of
beclomethasone
monopropionate
Fluticasone propionate 18 Active substance
Budesonide 9
Triamcinolone acetonide 50
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Corticoïds : esters & Formulations
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Corticoïdes : Substance active vs. esters
Substances
(principes actifs)
alcohol Esters
(prodrogues)
Hydrosolubles Non
hydrosolubles
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Most GCs are administered as esters
substance
Hydrosoluble
(IV)
Phosphate
Succinate
……….
Non hydrosoluble
(depot)
Acetate
Butyrate
………
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Most GCs are administered as esters
• Most GC are administered as esters,
• Esterification considerably alters the disposition and duration of the GC action. – Esterification with a monoacid (like acetic acid) at C-
21 gives non-hydrosoluble drugs that can be used as long-acting formulations when administered by the intramuscular, subcutaneous or IA routes.
– Esterification of the same parental drug by a diacid (such as succinic acid) can give a hydrosoluble ester enabling a salt to be formed (e.g. a sodium succinate). Phosphate esters are also hydrosoluble.
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Formulations of corticoïds Méthylprednisolone (medrol)
Methylprednisolone
sodium succinate
(Solumedrol®)
Methylprednisolone
acetate
(Dépomedrol®)
HO CH
C = O
CH O - CO - CH3
...... OH
O
CH 3
3
2
CH3
C23H30O6 = 402,5 H H
H
HO CH
C = O
CH OH
...... OH
O
CH 3
3
2
CH3
C22H30O5= 374,5
HO CH
C = O
CH2 - O - CO - (CH2)2 - COONa
...... OH
O
CH 3
3
CH3
C26H33O8Na = 396,5
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Cortic 00A.55
Esters Esterification en C21 et/ou C17 des OH Par des monoacides : formes insolubles - acetate ( 21-acétate) - dimethylbutyrate (21) - phenylpropionate - dipropionate ( C17 , C21) - valerate, pyvalate - benzoate ( C17 )
Corticoids
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Esters are prodrugs
• Practically all esters except beclomethasone 17-monoprpionate and fluticasone propionate are inactive prodrugs and have to be hydrolyzed to release their active moiety because an OH radical at C-21 is necessary for the binding of corticoids to their cellular receptors.
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Near all ester are prodrugs Prednisolone & prednisolone acetate
Prednisolone Prednisolone acetate A prodrug
Hydrolysis
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Hydrolysis by esterases
• Hydrolysis by esterases may occur either in different body fluids such as blood or synovial fluid (as for methylprednisolone acetate for which the half-life is about 1h in synovial fluid) or mainly in liver (as for succinate), meaning that for a local administration, the judicious selection of an appropriate ester is in order
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Fluticasone propionate & beclomethasone monopropionate are not prodrugs
• Fluticasone propionate Active drug
Beclomethasone 17,21 dipropionate A prodrug
Beclomethasone 17-monopropionate Active drug
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Corticoïds :
Route of administration
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Route of administration
systemic
IV, PO, IM…..
Local
GCS also use for systemic administration
Intra-articular
Intramammary
GC specifically developed for local administration
Percutaneous inhalation
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PK of corticoids
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Cortic 00A.63
Disposition of méthylprednisolone
• Méthylprednisolone succinate (MPS) vs. méthylprednisolone acetate (MPA)
Plasma Concentration (ng / ml)
30 20
10
5
0
0 40 80 120 160 200 240 280
Toutain et al. J.Pharm.Sci 1986., 75,251
480 min 0 60 120 240 360
102
103
105
104
10
Plasma Concentration (ng / ml)
MP
MPS
hours
MPA
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Prednisolone succinate vs. prednisolone acetate
• illustrates the differences between the disposition of prednisolone after administration of prednisolone succinate by the IV and IM routes and after prednisolone acetate administration by the IM route.
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Cortic 00A.65
2
6
10 15 20
0 24 48 72 96 144
104
2 4
103
10 10
0
102
6 8
IM
IV
Co
nce
ntr
atio
n (
ng
/ m
l)
Prednisolone
sodium succinate
Prednisolone acetate
Heures
Toutain et al. Am.J.Vet.Res 1985, 46:719-725
Disposition of prednisolone: hydrosuble vs. Unsoluble formulation (0.6 mg/kg)
IM
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Pharmacokinetic parameters of GCs
Substances CL
(mL/kg/min)
Vd
(mL/Kg)
HL
(h)
F%
Hydrocortisone
(tritiated cortisol)
2.28
229 1.55
Hydrocortisone
(after HC
succinate,1g)
2.56 600 10.1
Prednisolone 3.91 561 1.65 IM:92
Methylprednisolone 15 3600 2.85
Dexamethasone 7.33 2060 10.7
Triamcinolone
acetonide
8.1 5300 12
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DXM disposition: rest vs. exercise
Clearance: -25% VSS:-17% Half-life: no change
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Adrenal suppression: Plasma cortisol levels and
synthetic corticoid treatment
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Adrenal suppression of cortisol secretion by synthetic GCs
• Synthetic GC are able to inhibit the production of cortisol – negative feedback on ACTH
secretion.
• The duration of the AI effect of a synthetic GC for a systemic administration is generally similar to the duration of suppression of endogenous cortisol
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Synthetic GC Cortisol
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Adrenal suppression of cortisol secretion by synthetic GCs
• It should be stressed that adrenal suppression is not only associated with a given substance but also with a particular ester of that substance and for a particular ester, the route of administration and the administered dose.
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Prednisolone (600µg/kg) Short action
Adrenal suppression Prednisolone vs. Dexamethasone (IV)
0 0
20
40
60
80
0.16 0.5 1 2 3 4 6 24 48 72 96
Toutain et al., Am.J.Vet.Res 1985, 9: 1750
Cortisol concentration (ng / ml)
0 0
40
60
80
100
0.25 0.5 1 2 4 8 12 24 48
20
Cortisol concentration (ng / ml)
Hours Hours
Dexamethasone (50µg/kg)
Longer duration of action
71
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Succinate (IM)
Short action
Adrenal suppression of prednisolone (600µg/kg) succinate vs. Acetate (IM)
Toutain et al., Am.J.Vet.Res 1985, 9: 1750
0 0
40
60
80
100
0.25 0.5 1 2 4 8 12 24 48
20
Cortisol concentration (ng / ml)
Hours
Acetate (IM)
long action
days
72
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Duration of adrenal suppression (IV route)
Substances Anti-inflammatory
potency
Mineralocorticoid
potency
Adrenal suppression
(h, days)
hydrocortisone 1 1 About 24h
Hydrocortisone
hemisuccinate
0 0 A prodrug of cortisol
Prednisolone 5 1 About 24h
Methylprednisolone 5 1 About 24h
isoflupredone 25 25 No data
Triamcinolone 5 0 No data
Triamcinolone
acetonide
30-50 0 24h
Dexamethasone 25 0 72-96h
Betamethasone 25 0 Likely similar to DXM
Flumethasone 120 0 Likely longer than for
DXM 73
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Adrenal suppression of cortisol secretion by synthetic GCs
• For local administrations, the fraction that gains access to the blood can be too low to impact on the adrenal gland function.
74
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Adrenal suppression for an intra-articular methylprednisolone acetate administration
75
Autefage et al., Equine Vet J 1986
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IC50 for cortisol suppression
• (Mager et al., 2003)
Substances IC50 (ng/mL)
Cortisol 8
Prednisolone 1.2
Methylprednisolone 0.52
Dexamethasone 0.17
78
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Corticosteroid esters and local routes of administration
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Cortic 00A.80
Intra-articular administration
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Intra-articular administration
• Two technical issues:
– Selection of a joint;
– Technic of administration:
• Blind or not?,
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Pro: mostly of non scientific nature
– To help the horses perform the job they were bred for and to prolong their careers and lives
– Postoperative administration may be beneficial in protecting the cartilage and improving the cosmetic appearance of the joint
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Heathrow EHLSC 2008
CONS: mostly of scientific nature and rather well documented
– Lack of curative effect
– joint flare
– Risk for further injury
– Articular cartilage degenerative/steroid chondropathy
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Musculoskeletal injury following local corticosteroid injection in Thoroughbred racehorses
• Veterinary records for 1911 thoroughbred
• Thoroughbred racehorses receiving local corticosteroid injection (LCI) suffer musculoskeletal injury MSIs at approximately 4.5 times the rate of horses not receiving treatment, and for horses receiving multiple LCI the rate is approximately twice that of horses receiving single LCIs.
84
Whitton, C., et al 2012Faculty of Veterinary Science, University of Melbourne, Victoria, 3030, Australia.
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Accuracy of IA administration: blind vs. ultrasound-guided injection
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Disposition of methylprednisolone in the synovial fluid
86
• Disappearance of MPA within 6 days but a persistence of its active moiety for 5 to 39 days depending on the horse. The terminal half-life of MP was between 81 and 261h:
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Origin of the sustained release of MP after a MPA administration
• the reason for the persistence of MP was most likely due to a precipitation of MPA that adhers to the synovial membrane and most likely acts as a foreign body.
• This likely explains why MPA is not well tolerated in horses (McIlwraith, 2010) and that other GC are now preferred for IA administration, namely betamethasone esters and triamcinolone acetonide
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IA disposition of methylprednisolone (MP) in synovial fluid after an methylprednisolone actate administration (MPA, Dépomédrol® )
(200 mg in toto)
10
MP
syn
ovi
al f
luid
co
nce
ntr
atio
n (
ng
/ m
l)
10
10
10
10
2
3
4
5
6
20 40 60 80 100 (Days) 10
30
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Cortic 00A.89
40
20
Contrôle 0.14 1 2 4 6 12
HY
DR
OC
OR
TISO
NE
pla
smat
iqu
e (n
g /
ml)
8 10
60
0
Semaines
Adrenal suppression following a methylprednisolone actate (200mg in toto) IA administration in cattle assesssed by a series
of ACTH tests
Return to control value needs 3 months
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Triamcinolone acetonide
(redrawn from raw data of Kay et al. (Kay et al., 2008)
Data were fitted with a biexponential equation to give the terminal half-life of TA in synovial fluid as 20.2h with an overall mean residence time of 13.8h.
Mean synovial Triamcinolone acetonide (TA) concentration (ng/mL) vs. time (h) in the metacarpophalangeal joint after an administration of TA at a dose of 9mg in toto (16µg/kg
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Inhalation
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Inhaled Corticosteroids : indications
1. Airways inflammation
2. Recurrent airways obstruction ou RAO or heaves) • (formally named COPD)
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Why inhalation?
• To ensure selectivity (no other effect)
– Long-lasting treatments
• Specific GCS were developped for this application
– Highly potent (small volume)
– Slow eliminated from the airways
– High systemic clearance for the absorbed fraction
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Inhaled Corticosteroids (ICS)
• Inhaled corticosteroids (ICS) are now considered the first-line therapy in treating asthma and are approved for chronic use in children as young as 12 months of age.
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Cortic 00A.97
Many devices: are they equivalent?
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Relative anti-inflammatory (AI) potency of topical GC used for inhalation (1=dexamethasone)
Substances AI Potency
(1=dexamethasone)
Comments
Beclomethasone
dipropionate
0.5 A prodrug of
beclomathasone
monopropionate
Beclomethasone 17-
monopropionate
13 Active moiety of
beclomethasone
dipropionate
Beclomethasone 0.5 Metabolite of
beclomethasone
monopropionate
Fluticasone propionate 18 Active substance
Budesonide 9
Triamcinolone acetonide 50
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Disposition of GG after inhalation
Inhalation
Atmosphere
User safety
Swallowing Digestive tract
Possible Adrenal suppression
Lung disposition
Possible Adrenal suppression
100
Yes for beclomethasone No for fluticasone
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Inhalation treatment: an user safety issue?
• During exhalation, some degree of air pollution of the drug was evident and user safety was accounted for by ventilating the room sufficiently during administration
• Q: Do we have a part of liability if releasing DT for inhalation while no marketing authorization exist in case of difficulties for staff who are at high risk of adverse effects from exposure (e.g, pregnant women or those with demonstrated sensitivity to the specific agent).
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Systemic disposition of inhaled GS
• Drug deposited in the oropharynx, in up to 80% of horses and does not contribute to the therapeutic effect but is swallowed and contributes to the systemic exposure with possible systemic side effects.
• Inhaled GC are well absorbed by the lung parenchyma but have a rather low or very low bioavailability when ingested.
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Pharmacodynamic of inhaled GS
• Such a progressive establishment of clinical effects and return to pretreatment status makes it difficult or even impossible to establish any PK/PD relationship useful for drug monitoring.
• In addition, the dose-effect relationship is flat and difficult to establish.
108