Biopharmaceutics

of the Eye

Arto Urtti

October 23, 2017

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

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

Routes of drug delivery to the eye

Others:

•Intracameral (into the

anterior chamber)

•Subretinal (between RPE

and neural retina)

•Intrascleral

•Parabulbar, retrobulbar

CHOROID

VITREOUS

subretinal

suprachoroidal

Lääkkeen anto silmän pintaanimeytyminen kornean kautta

esim. silmätipat

vain silmän etuosan kudokset saavutetaan

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

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

Jakautuminen

kudoksiin

systeeminen

imeytyminen

sidekalvon

kautta

Liuoksen

valuminen

pois

kammionesteen

virtaus

eliminaatio

uvean

verenkiertoon

kornea

EtukammioKyynel

neste

< 5 %

annoksesta

LÄÄKEAINEEN OMINAISUUDET

Sarveiskalvon permeabiliteetti

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)

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)

Non-corneal route of absorption

Number 2 in FIG

suonikalvon

veren virtaus

sidekalvo

kovakalvo

retina

RPE

Lääkkeen saattoon retinaan ?

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)

Ranta et al., J Control Rel 148: 42-48, 2010

Bioavailability

Conjunctival

blood flow

Choroidal

blood flow

Steep decrease in bioavailability

laue rby layer

bioavailability

F ≈ 0.001-0.01

Lasiaisinjektiot (intravitreal injections)

SILMÄN TAKAOSA

SAAVUTETAAN

• Kortikosteroidit

• Vasta-aineet

• Käyttö lisääntynyt

Verkkokalvon

Ikärappeuman hoito.

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

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

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

Adme

prediction

• CL

• Vss

QSPR MODEL FOR CLivt

LogCLivt = - 0.25269 - 0.53747 (LogHD) + 0.05189 (LogD7.4)

PHARMACOKINETICS AFTER INTRAVITREAL INJECTIONS

Input:Dosing rate (Jin)

Vitreous

Elimination:Jout = C x CL

Therapeutic index

Targeted C range

Toxicity

Ineffectiveness

Css = Jin / CL

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

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

Del Amo and Urtti, Drug Discov Today 2008

Drug distribution from blood

circulation to the eye

Vellonen et al., Mol Pharmaceut, 2016

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

PLASMA

Vitreous

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)

Drug permeation from plasma to the

vitreous can be predicted using free

drug concentration in plasma and

clearance between plasma and eye.

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

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

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

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

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].