decision making on nanomedicines: preclinical in vivo studies · i.m. prompt from aqueous slow and...
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Decision Making on Nanomedicines: Preclinical in vivo Studies
http://lifesci.boun.edu.tr
http://sanyalgroup.boun.edu.tr
Prof. Rana Sanyal Prof. Rana Sanyal
http://rsresearch.net
www.boun.edu.tr
www.lifesci.boun.edu.tr
www.rsresearch.net
Why are we here?
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Boğaziçi UniversityCenter for Life Sciences & Technologies
BIOMEDICAL
PHARMACEUTICAL
BIOTECHNOLOGY
TEST‐ANALYSIS
VIVARIUM
CLEAN ROOM
Sustainability:
Research Labs 43
Personnel 22
Drug Loaded Surface Applications
Soluble Drug Delivery Systems
Metal (Magnetic) Nanoparticles
Hedeflendirilmiş Polimer ‐ İlaç
Functional Surfaces
Polymer Brushes
Targeted Polymer‐drug conjugates
Cardiovascular stent
Oncology & Neurology Applications
Hydrogels
Nanofibers
Micelles / nanoparticles
Orthopedic İmplants
Bioconjugate Chemistry (2017), 28(9), 2420‐2428.ACS Macro Letters (2016), 5(6), 676‐681.
ACS Applıed Materıals & Interfaces (2018) 10(17), 14399‐14409.ACS Omega, 2017, 2(10), 6658–6667.Journal of Colloid and Interface Science (2017), 507, 360‐369.Chemical Communications (2017), 53(63), 8894‐8897.Bioconjugate Chemistry (2017), 28, 1443–1451.Journal of Controlled Release (2017) 246, 164‐173.RSC Advances (2016), 6(78), 74757‐74764.J P l S i P l Ch (2016) 54(7) 926 934
Biomacromolecules(2017), 18, 490‐497.ACS Applied Materials & Interfaces (2016), 8(30), 19813‐19826.
Bioconj Chem (2018), 29(6), 1885‐1896.Bioconj Chem (2017) 28(12), 2962‐2975.Biomacromolecules (2017) 18(12), 3963‐3970. ACS Appl Mater & Interfaces (2017) 9(39), 34194‐34203.Biomacromolecules (2017), 18(8), 2463‐2477.Mol Pharm (2017), 14, 1373‐1383.Mol Pharm (2016) 13, 1482‐1490.J Pharm Pharmacol (2016), 68, 1010–1020.
Polymer‐drug conjugates
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RS RESEARCH: Development of New Generation Nanomedicines
RS nanomedicines are highly tunable:
fast‐forward development of targeted nanomedicines
with superior performance
Novel Drug Delivery Platform
Products in pipeline
2010
2015
2017
Therapies target only
cancer cells
Biopharmaceutical company
Headquarters in Istanbul, Turkey
RS Researchestablished
Research started
First VC Investment
Pipeline
Candidate Research PreclinicalIND
ApprovalClinical Platform Indication
RS-0139 I
NSCLC
Breast CA
Prostate CA
RS-0337 II Breast CA
RS-0461 II Ovarian CA
RS-0625 I Ovarian CA
RS-0583 I Pancreas CA
We target multiple cancer indications with plug&play approach
We optimize drug-linker-targeting moiety combination
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2010Research startedBogazici University
2015Company FoundedTeknopark Istanbul
Seed fund received2.0 M Euro – ACT
(Netherlands based VC)2017
Phase-I Trial RS-01392018
2018-2019Non-dilutiveor Series-AQ2 2018
Switzerland Office More clinical trials -
Global presence -
Pipeline depth -
RS Research can Collaborate on
EXPERIMENTS
DRUG SYNTHESIS CARRIER
ANALYSIS
IN VITRO TESTS
IN VIVO EXPERIMENTS
PURIFICATION
RS RESEARCH Analysis (Characterizations): Impurity identificationBiosimilar / Bionovel physical Nanoparticle / micelle Polymer / hydrogel
In Vivo Experiments:PharmacokineticsAnimal disease models (Xenograft etc) Toxicity (Acute, chronic)
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How Does an Molecule Become a “Drug”?
Organic synthesis Enzyme analysis Cell analysis
Structure determination
In vivodisease models
PharmacokineticRat (IV, PO)
Metabolism (RLM, HLM) Drug – drug interactions (3A4/2D6)
Caco‐2, protein binding
NovascreenHERGAmes
14/28‐d toxicology Preclinical Candidate
How Does an Organic Molecule Become a “Drug”?
Phase IPreclinical Candidate
Phase III
Phase II
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Polymer – drug conjugate
Targeted PDC
Cytotoxic drug
Log [drug] concentration (M)
Establishing Activity
Enzymatic Release
Plasma Release
Drug Release (%)
Enzyme Cleavable
Drug Release
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What is Pharmacokinetics?
• Study of the time course of the drug absorption, distribution, metabolism and excretion in body (ADME)
• Follow time course by measuring drug concntration in some reference tissue: usually blood or plasma and urine
Aministration Sites
• Intravascular – placement of drug directly into blood
No absorption step is required
• Extravascular‐ placement of drug in a tissue outside the blood
To enter blood, an absorption step must take place.
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Common Administration Routes
IntravenousI.V.
Absorbtion AvoidedRapid Onset
Emergency UseDosage Titration
For high MW drugsBest for large
volumes
Increased RiskSlow injection
Must be soluble
Sub-cutaneous
S.C.
Prompt from aqueous
Slow and sustained from other preps
Insoluble suspensions
Implants
Small volumePain (necrosis)
Irritation
Intramuscular
I.M.
Prompt from aqueous
Slow and sustained from other preps
Moderate volumesOily substances
Interfere with diagnosticsNot with
anticoagulantsP.O. Variable Most convenient
Most cost-effectiveSafest
Patient cooperation
Availability???Liver/Gut
RouteAbsorption
PatternSpecial Utility Limitation &
Precautions
Absorption & Distribution
• Absorption is defined as process by which a drug proceeds from site of administration to site of measurement.
• Once absorbed a drug is distributed to various tissues in the body by the blood.
• Any drug leaving the site of measurement which does not return has undergone elimination.
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Elimination
• Two principle organs of Elimination:
• Kidney: Primary site for excretion of chemically unaltered or unchanged drug.
• Liver: Usual organ for matebolism
Interpretation of Concentration‐ Time Profile
Concentration
time
Cmax
tmax
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Pharmacokinetic ModelMathematically describes the change in the amount of drug(“pharmaco”) in the body with time (“kinetic”)One‐Compartment Model
Drug input...by I.V. Infusion,absorption, etc.
THE BODY
Drug Removal...by metabolism,renal excretion, etc.
distribution
Change in Plasma Concentration as a Function of Time
Plas
ma
Conc
entra
tion
(Cp)
time
0.1
1
10
Plas
ma
Conc
entra
tion
time
0
0.5
1
1.5
2
2.5
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Change in Plasma Concentration as a Function of Time
Plas
ma
Conc
entra
tion
(Cp)
time
Cp = Cpoe-kt
0.1
1
10
Slope = -k/2.303
k= elimination rate constant
Cpo
The elimination half life t1/2 is the time required to reduce the plasma concentration fromCp to 1/2Cp
t1/2 = 0.693/k
Volume of Distribution (Vd or Vss)
Plas
ma
Conc
entra
tion
(Cp)
time
Cp = Cpoe-kt
0.1
1
10
Cpo
Vss = Dose i.v./ Cpo
Ak
Vss = A / Cp
Volume of distribution is a proportionality constant that relates the amount of drug in the body (A) to the plasma concentration (Cp).
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Benchmarks
• Assuming a body mass of 70kg• Total body water = 42 L (0.60 L/kg)
• Blood volume = 5 L (0.07 L/kg)
• Plasma volume = 3 L (0.04 L/kg)
• Extracellular fluıd volume = 16 L (0.23 L/kg)
Clearance
Clearance (CL) is a propotionality constant relating the rate of elimination (metabolism, excretion), to the plasmaconcentration.
dXe/dt
Cp= CL
Xe
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Clearance Graphical Analysis
Plas
ma
Conc
entra
tion
(Cp)
time
Cp = Cpoe-kt
0.1
1
10
Slope = -k/2.303
k= elimination rate constant
Cpo
Vss = Dose i.v./ Cpo
CL / Vss = k
Types of Clearance
• Major:• Renal Clearance: Excretion of unmetabolized parent drug in the urine
• Hepatic Clearance: Removal of Parent derug by conversion to metabolites
• Minor: Excretion in sweat, exhalation
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Hepatic Clearance: Well Stirred Model
• Q = blood flow (mL/min)
• C = drug concentration (g/mL)
• CLint = intrinsic clearance (mL/min)
• E = Extraction ratio
Q
Cin
Q
Cout
CLint
LIVERE =
Cin – Cout
Cin
Extremes of Hepatic Clearance
• High Clearance • Rapid metabolism
• Poor oral bioavailability
• Low Clearance• Slow metabolism
• Potantially good bioavailability
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High Extraction Ratio (Clearance)
• Metabolism is rapid compared to blood flow CLint >> Q
• Total clearance is limited to blood flow rate, so CL= Q
Q
slow
Q
CLint
LIVER slow
fast
Low Extraction Ratio
• Metabolism is slow compared to blood flow CLint << Q
• Total clearance is limited by matabolic capacity,
so CL= CLint x fu (protein binding)
Q
fast
Q
CLint
LIVER fast
slow
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Clearance and Volume
• Clearance and Volume of distribution are the most important pharmacokinetic parameters
• CL and Vss are considered primary PK parameters because they are directly related to physiological processes.
• Half‐life and elimination rate constant are secondary PK parameters because they cannot be directly related to physiological processes.
Example: Increase in CL
Plas
ma
Conc
entra
tion
(Cp)
time
0.1
1
10
Cpo t1/2 = 0.693 x V
CL
No change in Cpo, because V was not changed
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Example: Increase in VPl
asm
aCo
ncen
tratio
n(C
p)
time
0.1
1
10
Cpo t1/2 = 0.693 x V
CL
Change in Cpo, and a change in half-life
V = Dose i.v. / Cpo
But everyone asks for long half‐life...
• What will the chemical modification do to clearance?
• What will the chemical modification do to the volume of distribution?
Then you can decide whether the modification will change the half‐life in desired manner.
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Oral Absorption
Concentration
time
Cmax
tmax
Elimination“terminal”phaseAbsorption
phase
Oral Bioavailability
• Physiologically: F = fa x fg x fh
• Pharmacokinetically: Is the fraction of the dose reaching systemic circulation
• Mathematically: The “area under the plasma concentration vs. Time curve” (AUC) is used to measure the extent of absorption.
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Oral Absorption
Concentration
time
AUCoinf
0
inf
= Cp dt
Calculating Bioavailability
• For absolute bioavailability the reference is the i.v. Dose
F absolute = AUCinf
o,PO
AUCinf o,IV
Dose IV
Dose POx
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Extent of Absorption: Influence of Bioavailability
Concentration
time
(MEC)MinimumEffective
Concentration
Thank you