Pharmacokinetic principles for

organ targeted drug deliery

Vaccation School on Systems Pharmacology – Pharmacokinetics Warwick 2014-03-20 Markus Fridén, Ulf Eriksson

Applied to targeting the lung and brain

Outline

1. Concepts of drug transport and exposure • Total drug versus unbound drug

• Mechanisms of drug transport

• Organ compartmentation

2. Organ targeting after systemic administration • PK of blood-brain barrier transport

• Other examples, liver and kidney

3. Organ targeting by local drug administration • Targeting the lung by drug inhalation

• Other examples, skin, eye, etc

4. Hands on using MaxSim2 • Simulation of local versus systemic administration

Concepts of (unbound) drug exposure

Paul Ehrlich The Lancet, 2, 1913: 445-451

"If the law is true in chemistry that corpora non agunt nisi liquida [substances are active only in solution], then for chemotherapy the principle is true that corpora non agunt nisi fixata [substances do not act unless bound]."

Corpora non fixi nisi liquida

[substances do not bind unless in solution]

Definitions used in this presentation:

”Exposure”: Unbound drug concentration (over time)

”Organ targeting”: Differential (higher or lower) exposure at an organ

target site compared to exposure in systemic blood

Systemic drug transport mechanisms

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1. Blood flow

• Arterial and venous blood

vessels

• Capillary beds

2. Bulk flow and diffusion

• In and out of fenestrated or

discontinuous (leaky) capillaries

3. Membrane transport

• Non-fenestrated (tight) capillary

beds, i.e. plasma membranes of

capillary endothelial cells

• Plasma membrane of individual

cells in any tissue

Trans-membrane transport mechanisms

Carrier-mediated transport

Organ compartmentation

- Which cells, where, in which region of the

organ are we talking about?

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Brain

Brain interstitial fluid

Liver

Hepatocyte

intracellular space

Kidney

?

Hammarlund-Udenaes et al, Pharm res 2009

PK of blood-brain barrier transport

Passive diffusion Brain

(Cu,brainISF)

Blood

(Cu,p)

Carrier-mediated

influx

Carrier-mediated efflux

Unbound brain-to-plasma ratio: Kp,uu,brain

Passive diffusion

Carrier-mediated

influx

Carrier-mediated efflux

BBB

efflux

BBB

passive

BBB

influx

BBB

passive

pu,

brainISFu,

brainuu,p,CLCL

CLCL

C

CK

Kp,uu,brain ~ 1

Kp,uu,brain > 1

Kp,uu,brain < 1

Efflux transporters at the BBB free free

bound bound

met

free free

bound bound

Structure of P-glycoprotein (Pgp, MDR1)

Pgp, BCRP, MRPs etc

Some data

in rat…

Meth

otr

exate

Lopera

mid

e

Paclita

xel

M6G

Nitro

fura

nto

in

M3G

Nelfin

avir

Moxala

cta

m

Baclo

fen

Ate

nolo

l

Norf

loxacin

Rifam

pic

in

Nadolo

l

Dela

vir

idin

e

Vera

pam

il

Saquin

avir

Zid

ovudin

e

Indom

eth

acin

Levofloxacin

Gabapentin

Morp

hin

e

Salicylic a

cid

Oxpre

nolo

l

Topir

am

ate

Alp

renolo

l

Thio

ridazin

e

Pin

dolo

l

Pro

pra

nolo

l

Meto

pro

lol

Am

itri

pty

line

Tacri

ne

Oxym

orp

hone

Lam

otr

igin

e

Codein

e

Oxycodone

Dip

henhydra

min

e

Dia

zepam

Eth

yl-

2-P

henylm

alo

nam

ide

Tra

madol

Thio

penta

l

Bupro

pio

n

0.001

0.01

0.1

1

10

100Kp,brain

Meth

otr

exate

Lopera

mid

e

Paclita

xel

M6G

Nitro

fura

nto

in

M3G

Nelfin

avir

Moxala

cta

m

Baclo

fen

Ate

nolo

l

Norf

loxacin

Rifam

pic

in

Nadolo

l

Dela

vir

idin

e

Vera

pam

il

Saquin

avir

Zid

ovudin

e

Indom

eth

acin

Levofloxacin

Gabapentin

Morp

hin

e

Salicylic a

cid

Oxpre

nolo

l

Topir

am

ate

Alp

renolo

l

Thio

ridazin

e

Pin

dolo

l

Pro

pra

nolo

l

Meto

pro

lol

Am

itri

pty

line

Tacri

ne

Oxym

orp

hone

Lam

otr

igin

e

Codein

e

Oxycodone

Dip

henhydra

min

e

Dia

zepam

Eth

yl-

2-P

henylm

alo

nam

ide

Tra

madol

Thio

penta

l

Bupro

pio

n

0.001

0.01

0.1

1

10

100Kp,uu,brain

Relationship with chemical structure

-0.6

-0.4

-0.2

-0.0

0.2

0.4

0.6 Kp,uu,brain

Kp,brain

PS

A

Acid

AC

DLogD

7.4

RotB

ond

VO

L

HB

D

MW

HB

A

Clo

gP

LogU

nio

niz

ed

AC

DLogP

Base

Neutr

al

R2

Zw

itte

rio

n

NP

SA

Rin

gC

ount

Positive correlation

Negative correlation

Targeting the lung by drug inhalation

• Introduction - Why inhalation drug delivery is beneficial - Lung targeting - definition

• Lung physiology - Key aspects for inhalation drug delivery

• Strategies for drug retention in the lung - To achieve duration of effect

• Mechanistic lung disposition model - Describe PKPD of inhaled drugs - Application shows utility of modeling

Outline

Inhalation as a route of drug administration

Why is it beneficial?

Effective delivery to target tissue

• Needle free administration

• Effective treatment of respiratory diseases

• Avoid systemic exposure/improve safety

Alternative route for drugs with poor oral bioavailability

• Rapid and complete absorption

Inhalation vs Oral Dosing Distinctive features related to local treatment

Lung ‘split’ and targeting

0 2 4 6 8 10 12

0.01

0.1

1

10

100

1000

Co

ncen

trati

on

(n

M)

Time (hrs) IT Plasma

IT Lung

IV Plasma

IV Lung

Lung targeting:

Lung IT/IV ratio

Example: salmeterol 15 ug/kg IV and IT (intratracheal) doses to Rats

Lung/Plasma ‘split’

Physiology of the lung

Key aspects for inhalation drug delivery

From Patton and Byron. Nature Reviews Drug Discovery 2007

• Differencies between airways (trachea, bronchi, bronchioles) and alveolar region

• Alveolar region has large surface area

• Biophase concentration: effective free drug concentration will vary

Pulmonary drug delivery

Absorption and Disposition in Lung

From Bäckman, Adelmann, Peterson and Jones Clinical Pharmacology & Therapeutics 2014

Lung deposited dose

The effect of particle size

18

From Patton and Byron. Nature Reviews Drug Discovery 2007

Strategies for drug retention in the lung

• Slow dissolution rate - Low solubility that is rate-limiting for absorption

• Tissue retention - High affinity to lung tissue

• Slow dissociation from target receptor

• Formulation approaches

Influence of basicity on lung duration (rat IT dosing - solutions)

5 10 15 20 250.01

0.1

1

10

% d

ose

re

ma

inin

g in

lu

ng

Time (h)

Acids/neutrals

Monobases

Dibases

Examples from

existing marketed

drugs and AZ

projects

Cooper AE, Ferguson D and Grime K. Optimisation of DMPK by the Inhaled

Route: Challenges and Approaches. Curr Drug Metab, 2012, 13, 457-473.

Background: Models of inhalation PK

Lung

Central

Tissue

Clearance

IT Dose

IV Dose

Fu1 V1

Fu4 V4

Lung

deepcompartmentFu2 V2

1

2 3

4

ClD12

ClD14

ClD23

K32

Tissue

deepcompartment

5

K54

ClD45

5-compartment model Lung-SIM (PBPK) Gastro+ lung module

Key differences • Anatomical versus cellular/sub-cellular basis • Inclusion of deposition/dissolution model • Input data in vitro/in vivo • Absorption rate limitation: Dissolution, epithelial flux versus slowness of non-

specific tissue partitioning

All models lack experimental data on absorptive/distributional

processes in the lung to justify the model structure and

substantiate simulated unbound concentrations.

Mechanistic lung disposition model

The lung compartments parameters that describe: 1. absorption of drug from the

airways into lung (kAPu) 2. extent and rate of unspecific

binding (Kp and CLd2, respectively), 3. receptor-binding kinetics in lung

tissue (Kon, Koff and Bmax) 4. flux of drug to and from the

systemic circulation (CLd1).

The lung – a closer look

Demo of Maxsim2 Lung model

25

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