Pharmacokinetic principles for organ targeted drug deliery€¦ · Pharmacokinetic principles for...
Transcript of Pharmacokinetic principles for organ targeted drug deliery€¦ · Pharmacokinetic principles for...
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…
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0.01
0.1
1
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100Kp,brain
Meth
otr
exate
Lopera
mid
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Paclita
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Nitro
fura
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Nelfin
avir
Moxala
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fen
Ate
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Norf
loxacin
Rifam
pic
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Nadolo
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Dela
vir
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Vera
pam
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Zid
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Salicylic a
cid
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ridazin
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dolo
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Dia
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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
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