Biopharmaceutics of the Eye. Arto Urtti October 23, 2017

Transkriptio

1 Biopharmaceutics of the Eye Arto Urtti October 23, 2017

2 STRUCTURE OF EYE Tear production Eyelid Optic nerve Vitreous body Sclera Eyelash Retina Lens Ciliary process Cornea Aqueous humor Iris Conjunctival sac Choroid Eyelid Drainage duct for removal of tears Kaisa Mari Hämäläinen

3 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. EPITHELIAL BARRIER TISSUE BOUNDARY SOLID PHASE BLOOD VESSEL strong weak continuous porous low high fenestrated Diffusion resistance complete tight MUSCLE TARGET SITE CIRCULATING FLUID FLUID FLOW ACTIVE TRANSPORT TEAR FLUID CILIARY BODY POSTERIOR CHAMBER IRIS CORNEA ANTERIOR CHAMBER SCLERA LENS VITREOUS BODY

4 Routes of drug delivery to the eye Others: Intracameral (into the anterior chamber) Subretinal (between RPE and neural retina) Intrascleral Parabulbar, retrobulbar

5 VITREOUS subretinal CHOROID suprachoroidal

6 Lääkkeen anto silmän pintaan imeytyminen kornean kautta esim. silmätipat vain silmän etuosan kudokset saavutetaan

7 < 5 % annoksesta Jakautuminen kudoksiin systeeminen imeytyminen sidekalvon kautta Kyynel neste Etukammio eliminaatio uvean verenkiertoo n kornea Liuoksen valuminen nenään ja nieluun systeemiimeytyminen kammionesteen virtaus Biologinen hyötyosuus silmään < 5% Tippoja annostellaan 1-8x päivittäin Systeemi-imeytyminen nopeaa ja usein yli 70% annoksesta

8 Pharmacokinetics after topical instillation of an eyedrop Corneal permeation Cl co µl/min Depends on MW, logp Tissues V d ml V d depends on drug binding and partitioning to cells/tissues Systemic absorption through conjunctiva CL cj 10 µl/min TEAR FLUID V = 7 µl cornea Aqueous humour V AH 300 µl Uveal blood flow; CL UBF 0-20 µl/min Depends on MW, logp?? Systemic absorption is fast and extensive. Solution drainage and tear turnover CL tt 1 µl/min (normal tear turnover) Initial drainage depends on the instilled volume, ph, tonicity. Aqueous humor outflow CL AH 3 µl/min Relatively independent of drug properties

9 LÄÄKEAINEEN OMINAISUUDET Sarveiskalvon permeabiliteetti Jakautuminen kudoksiin < 5 % annoksesta systeeminen imeytyminen sidekalvon kautta Kyynel neste Etukammio eliminaatio uvean verenkiertoon Liuoksen valuminen pois kornea kammionesteen virtaus

10 Kornean permeabiliteetti Epiteeli on rasvapitoinen Solukko; strooma on vesipitoinen kudos sarveiskalvo Epiteeli Stroma Epiteeli on este ja varasto Rasvaliukoisuus (logp) - optimi logp noin 2-3 Kornean permeabiliteetin ennustaminen logp app = Hbtot logd7.4 (Kidron et al., Pharm Res 27: , 2010)

11 Topical formulations Formulations: suspensions, gels, viscous eyedrops Maximal ocular bioavailability F = CL co / (CL conj + CL tf ) Lacrimation, tear fluid Lacrimation, tear fluid Delivery system Drug solution Epithelium Aqueous humor Dissolution Corneal permeation Lacrimation, tear fluid Lacrimation, tear fluid, conjunctival clearance Elimination Sink of blood circulation Cornea CL conj = systemic clearance through conjunctiva (dissolved drug) CL tf = clearance via normal tear turnover (dissolved drug)

12 Non-corneal route of absorption Number 2 in FIG

13 kovakalvo RPE retina sidekalvo suonikalvon veren virtaus Lääkkeen saattoon retinaan?

14 Sidekalvon alainen injektio (sub-conjunctival injection) kovakalvo RPE retina sidekalvo suonikalvon veren virtaus Drug delivery to the anterior chamber (e.g. local anesthesia) * Bioavailability 10% Drug delivery to the posterior chamber?

15 Bioavailability Conjunctival blood flow Choroidal blood flow Ranta et al., J Control Rel 148: 42-48, 2010

16 Steep decrease in bioavailability laue rby layer bioavailability F

17 Lasiaisinjektiot (intravitreal injections) Kortikosteroidit Vasta-aineet Käyttö lisääntynyt Verkkokalvon Ikärappeuman hoito. SILMÄN TAKAOSA SAAVUTETAAN

18 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

19 Eliminaatio lasiaisinjektion jälkeen V d lähes vakio (anatominen tilavuus) t 1/2 lasiaisessa * Pienet molekyylit 1-10 h posteriorinen ja anteriorinen puhdistuma * Proteiinit 5-10 vrk posteriorinen puhdistuma

20 Rabbit intravitreal pharmacokinetics Anterior + posterior CL Anterior CL Relation to flow factors: CL ivt << Q ocular * low extraction ratio (E) permeability controlled clearance: CL ivt = P ocular x S ocular

21 Adme prediction CL V ss

22 QSPR MODEL FOR CL ivt LogCL ivt = (LogHD) (LogD 7.4 )

23 PHARMACOKINETICS AFTER INTRAVITREAL INJECTIONS Toxicity Vitreous Input: Dosing rate (J in ) Therapeutic index Targeted C range Elimination: J out = C x CL Ineffectiveness C ss = J in / CL

24 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

25 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

26 Del Amo and Urtti, Drug Discov Today 2008

27 Vellonen et al., Mol Pharmaceut, 2016 Drug distribution from blood circulation to the eye

28 Approach Distribution clearance (CL BV ): blood ocular barrier permeability x surface area (P X S) from QSPR model Protein binding Assumed to be zero in the vitreous f u and C in plasma C u

29 PLASMA Vitreous

30 Prediction of vitreal drug distribution from plasma Rabbit Humans AUC 0-12h (µg h/ml) Dose (g) Experiment al Simulated 1 Simulated

31 Drug permeation from plasma to the vitreous can be predicted using free drug concentration in plasma and clearance between plasma and eye.

32 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

33 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

34 Drug target site Drug target 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 Drug Drug release DRUG melanin Melanosomal membrane plasma membrane

35 Membrane permeability and melanin binding * significant interplay IC-50 Like chloroquine Like timolol IC-50 High binding affinity and low membrane permeability prolonged retention Drug activity prolonged or decreased depending on the drug potency (e.g. IC-50) Rimpelä et al., 2017

36 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].