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Biopharmaceutics
of the Eye
Arto Urtti
October 23, 2017
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Kaisa Mari Hämäläinen
STRUCTURE OF EYESTRUCTURE OF EYE
Optic nerveVitreous body
Retina
Lens
Ciliary
process
Tear production
Eyelid
Sclera
Eyelash
Cornea
Aqueous humor
Iris
Conjunctival sac
Drainage duct for
removal of tears
EyelidChoroid
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Ocular anatomy and its impact on pharmacokinetics
… that make up the eye, showing the barriers and diffusion resistances and the transport and flow
systems that regulate drug movement.
strong
weak
EPITHELIAL BARRIER TISSUE BOUNDARY SOLID PHASE BLOOD VESSEL
continuous
porous
low high fenestrated
complete
tightDiffusion resistance
CIRCULATING FLUID
FLUID FLOW
ACTIVE TRANSPORT
MUSCLE TARGET SITE
TEAR FLUID
CORNEA
ANTERIOR
CHAMBER
POSTERIOR
CHAMBER
IRIS
LENS VITREOUS BODY
SCLERA
CILIARY
BODY
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Routes of drug delivery to the eye
Others:
•Intracameral (into the
anterior chamber)
•Subretinal (between RPE
and neural retina)
•Intrascleral
•Parabulbar, retrobulbar
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CHOROID
VITREOUS
subretinal
suprachoroidal
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Lääkkeen anto silmän pintaanimeytyminen kornean kautta
esim. silmätipat
vain silmän etuosan kudokset saavutetaan
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Jakautuminen
kudoksiin
systeeminen
imeytyminen
sidekalvon
kautta
Liuoksen
valuminen nenään ja
nieluun systeemi-
imeytyminen
kammionesteen
virtaus
eliminaatio
uvean
verenkiertoo
n
kornea
EtukammioKyynel
neste
< 5 %
annoksesta
Biologinen hyötyosuus silmään < 5%
Tippoja annostellaan 1-8x päivittäin
Systeemi-imeytyminen nopeaa ja usein
yli 70% annoksesta
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Tissues
Vd ≈ 0.3–1.5 ml
Systemic
absorption
through
conjunctiva
CLcj ≈ 10 µl/min
Systemic
absorption
is fast and extensive.Solution drainage
and tear turnover
CLtt ≈ 1 µl/min
(normal tear turnover)
Initial drainage depends
on the instilled volume,
pH, tonicity.
Aqueous humor outflow
CLAH ≈ 3 µl/min
Relatively independent of
drug properties
Uveal blood
flow; CLUBF ≈
0-20 µl/min
Depends on
MW, logP ??cornea
Aqueous
humour
VAH ≈ 300 µl
TEAR
FLUID
V = 7 µl
Pharmacokinetics after
topical instillation
of an eyedrop Corneal
permeation
Clco ≈ 0.1-1 µl/min
Depends on MW, logP
Vd depends
on drug binding
and partitioning
to cells/tissues
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Jakautuminen
kudoksiin
systeeminen
imeytyminen
sidekalvon
kautta
Liuoksen
valuminen
pois
kammionesteen
virtaus
eliminaatio
uvean
verenkiertoon
kornea
EtukammioKyynel
neste
< 5 %
annoksesta
LÄÄKEAINEEN OMINAISUUDET
Sarveiskalvon permeabiliteetti
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Kornean permeabiliteetti
Epiteeli
Stromasarveiskalvo
Rasvaliukoisuus (logP)
- optimi logP noin 2-3
Epiteeli on rasvapitoinen
Solukko; strooma on vesi-
pitoinen kudos
Epiteeli on este ja varasto
Kornean permeabiliteetin ennustaminen
logPapp = - 3.885 - 0.183 Hbtot + 0.277 logD7.4
(Kidron et al., Pharm Res 27: 1398-1407, 2010)
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Delivery system Drug solution Aqueous humorEpithelium
Dissolution
Cornea
Lacrimation,
tear fluid
Lacrimation,
tear fluid
Lacrimation,
tear fluid
Lacrimation,
tear fluid,
conjunctival
clearance
Corneal
permeation
Elimination
Sink of blood circulation
Topical formulations• Formulations: suspensions, gels, viscous eyedrops
• Maximal ocular bioavailability F = CLco / (CLconj + CLtf)
CLconj = systemic clearance through conjunctiva (dissolved drug)
CLtf = clearance via normal tear turnover (dissolved drug)
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Non-corneal route of absorption
Number 2 in FIG
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suonikalvon
veren virtaus
sidekalvo
kovakalvo
retina
RPE
Lääkkeen saattoon retinaan ?
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suonikalvon
veren virtaus
sidekalvo
kovakalvo
retina
RPE
Drug delivery to the anterior chamber (e.g. local anesthesia)
* Bioavailability ≈ 10%
Drug delivery to the posterior chamber ?
Sidekalvon alainen injektio
(sub-conjunctival injection)
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Ranta et al., J Control Rel 148: 42-48, 2010
Bioavailability
Conjunctival
blood flow
Choroidal
blood flow
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Steep decrease in bioavailability
laue rby layer
bioavailability
F ≈ 0.001-0.01
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Lasiaisinjektiot (intravitreal injections)
SILMÄN TAKAOSA
SAAVUTETAAN
• Kortikosteroidit
• Vasta-aineet
• Käyttö lisääntynyt
Verkkokalvon
Ikärappeuman hoito.
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Blood ocular barriers
Retinal pigment epithelium
Retinal capillary endothelia
Ciliary capillary endothelia
Iris capillary endothelia
• DRUG DISTRIBUTION
BLOOD EYE
• DRUG ELIMINATION
EYE BLOOD
Active transporters
Passive diffusion
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Eliminaatio
lasiaisinjektion
jälkeen
Vd lähes vakio (anatominen
tilavuus)
t1/2 lasiaisessa
* Pienet molekyylit
•1-10 h
• posteriorinen ja
anteriorinen puhdistuma
* Proteiinit
•5-10 vrk
• posteriorinen puhdistuma
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Rabbit intravitreal pharmacokinetics
Relation to flow factors:
CLivt << Qocular
* low extraction ratio (E)
permeability controlled clearance: CLivt = Pocular x S ocular
Anterior CL
Anterior +
posterior CL
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Adme
prediction
• CL
• Vss
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QSPR MODEL FOR CLivt
LogCLivt = - 0.25269 - 0.53747 (LogHD) + 0.05189 (LogD7.4)
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PHARMACOKINETICS AFTER INTRAVITREAL INJECTIONS
Input:Dosing rate (Jin)
Vitreous
Elimination:Jout = C x CL
Therapeutic index
Targeted C range
Toxicity
Ineffectiveness
Css = Jin / CL
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Combining drug delivery rate with
IVT clearance predictions
Estimation of drug dose for
prolonged dosing
Impact of release rate, drug potency,
and clearance on dose per injection.
Del Amo et al., EJPB 2015
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Intravitreaalinen
• Lääkeaineen vaikutusajan pidentäminen
lasiaisessa / retinassa
• Lääkkeen kohdennus retinan soluihin
• Injektiot liuos vs suspensio
• Implantit
• Ozurdex
• Solukapselit
• Geneettisesti muokatut solut
• Jatkuva proteiinin tuotto (esim. CNTF)
* Geenihoito
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Del Amo and Urtti, Drug Discov Today 2008
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Drug distribution from blood
circulation to the eye
Vellonen et al., Mol Pharmaceut, 2016
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Approach
Distribution clearance (CLBV):
• blood ocular barrier permeability x surface area (P X S)
• from QSPR model
Protein binding
• Assumed to be zero in the vitreous
• fu and C in plasma Cu
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PLASMA
Vitreous
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Prediction of vitreal drug distribution from plasma
Rabbit
Humans
Dose (g) Experiment
al
Simulated 1 Simulated 2
1.0 14 28 15
2.0 22 60 32
AUC0-12h (µg h/ml)
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Drug permeation from plasma to the
vitreous can be predicted using free
drug concentration in plasma and
clearance between plasma and eye.
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Pigmenttiin sitoutuminen
• Melaniini, melanosomi
• Iiris, sädekehä, retinan pigmenttiepiteeli,
suonikalvo
• Monet lääkeaineet sitoutuvat melaniiniin
• Lääkeaineen rakenteen vaikutus sitoutumiseen
epäselvä
• Seuraukset:
– Vaikutusajan pidentyminen
– Huippuvaikutuksen heikkeneminen
– Lääkkeen kertyminen pigmentoituihin soluihin
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Pigment
• Melanin
• Pigmentation in tissues– Eye
• Iris, ciliary body, RPE, choroid, sclera
• Melanosomes– melanin in the vesicle
• Drug binding– Conc: pigmented tissue >> albino tissue
– Longer retention
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Drug
Drug target
Drug
release
Drug target site
DRUG
melanin
Melanosomal
membrane
plasma
membrane
Exposure of the cell interior to free
drug may be affected by:• melanin binding of the drug
• Interplay of melanin binding and permeation in
• melanosome membrane
• plasma membrane
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Membrane permeability and melanin binding
* significant interplay
Like chloroquine
Like timolol
Rimpelä et al., 2017
High binding affinity and low membrane permeability
prolonged retention
Drug activity prolonged or decreased depending on the
drug potency (e.g. IC-50)
IC-50
IC-50
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Schematic presentation of the ocular structure with the routes of drug kinetics illustrated. The numbers refer to following processes:
(1) trans-corneal permeation from the lacrimal fluid into the anterior chamber, (2) non-corneal drug permeation across the
conjunctiva and sclera into the anterior uvea, (3) drug distribution from the blood stream via blood–aqueous barrier into the anterior
chamber, (4) elimination of drug from the anterior chamber by the aqueous humor turnover to the trabecular meshwork and
Sclemm's canal, (5) drug elimination from the aqueous humor into the systemic uveoscleral circulation, (6) drug distribution from the
blood into the posterior eye across the blood–retina barrier, (7) intravitreal drug administration, (8) drug elimination from the vitreous
via posterior route across the blood retina barrier, and (9) drug elimination from the vitreous via anterior route to the posterior
chamber [1].