case study: safety and admet aspects of nanotechnology...

Case Study: Safety and ADMET Aspects of

Nanotechnology in Parenteral Drug Products

Bidirectional Interaction between Nanoparticles

and the Mononuclear Phagocyte System (MPS)

William C. Zamboni, PharmD, PhD Associate Professor

Director of GLP Bioanalytical Facility

Director of Translational Oncology and Nanoparticle Drug Development Initiative (TOND2I) Lab

UNC LCCC & UNC ESOP

Analytical Chemistry &

Pharmacology Labs

C-CCNE Analytical and PK Core

Director = W. Zamboni

Translational Oncology and

Nanoparticle Drug Development

Initiative (TOND2I) Lab


Assoc Director = TBD

Head Analytical Chemist = A. Schorzman

Analytical Chemist = S. Metzger

Post Doc = S. Rawal, P. Kumar

UNC GLP Bioanalytical

Facility


Assoc Director = J. Kagel

Analytical Chemist = B. Braun

QAU = S. Newman

Source of Drugs or Studies:

UNC Investigators, NCI, NIH, & Pharmaceutical Co.

NCCH

Clinical Trials Unit &

Sample Processing

Lab

Director = C. Walko

Steering Committee Dr. Dees, LCCC

Dr. Sharpless, LCCC MP1U

Dr. Frye, CICBDD

Dr. DeSimone, CCCNE

Dr. Jay, ESOP

Dr. Brouwer, ESOP

Industry Rep = TBD

---------------------------------------

Consultants Dr. Madden, MD Anderson CC

Dr. Baxter, PhD, OpAns

UNC LCCC & UNC ESOP

Analytical Chemistry &

Pharmacology Labs

C-CCNE Analytical and PK Core


Translational Oncology and

Nanoparticle Drug Development

Initiative (TOND2I) Lab


Assoc Director = TBD

Head Analytical Chemist = Schorzman

Analytical Chemist = Metzger

Post Doc = S. Rawal, P. Kumar


Facility


Assoc Director = J. Kagel

Analytical Chemist = B. Braun

QAU = S. Newman

Source of Drugs or Studies:

UNC Investigators, NCI, NIH, & Pharmaceutical Co.

NCCH

Clinical Trials Unit &

Sample Processing

Lab

Director = C. Walko

Steering Committee Dr. Dees, LCCC

Dr. Sharpless, LCCC MP1U

Dr. Frye, CICBDD

Dr. DeSimone, CCCNE

Dr. Jay, ESOP

Dr. Brouwer, ESOP

Industry Rep = TBD

---------------------------------------

Consultants Dr. Madden, MD Anderson CC

Dr. Baxter, PhD, OpAns

Types of Nanoparticles and Carrier-Mediated Agents

Nanoparticles

Conjugates

Monoclonal Antibodies

Antibody Drug Conjugates

(ADC)

Clearance of Nanoparticles and CMAs Via the

Mononuclear Phagocyte System (MPS)

Tumor EPR

MPS?

PBMC

Liver/Spleen

Encapsulated / Conjugated Released

Sum Total = Encapsulated + Released

Active Lactone Form

Pharmacologic Issues of Nanoparticle/Liposomal Agents:

Characterize Encapsulated/Released Drug & PK Variability

S-CKD602

Warhead

Carrier

Goal in Plasma:

- Remain within or

Attached to carrier

- Decrease toxicity

Goal in Tumor:

-Release drug from

carrier

- Decrease toxicity

Name of Presentation

Pharmacologic Methods to Characterize

CMAs In Vitro and In Vivo

Phenotypic Interaction

between Nanoparticles and

RES/MPS

New PK/PD Metrics for NPs

Analytical and PK Studies of

Nanoparticle Agents



Nanoparticles In Vitro and In Vivo



RES/MPS



Nanoparticle Agents

These projects can be performed at:

Pharmaceutical Development Center (PDC)

CRO

Active Research Programs Evaluating Nanoparticle

Pharmacology and the MPS

Brain

Heart

Lung

Tumor

Plasma and

Blood Cells

Liver

Kidney

Pancreas

IV/PO

Spleen

Muscle and Fat






RES/MPS



Nanoparticle Agents

Phase I and PK Study of S-CKD602 in

Patients with Refractory Solid Tumors:

Factors Affecting the PK Disposition

WC Zamboni, S Ramalingam, DM Friedland, CP Belani, RG Stoller, S Strychor, NB Modi, RP Nath, ME Tonda, RK Ramanathan.

10

100

1,000

10,000

100,000

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6

Dose (mg/m2)

AU

C (

ng

/mL

-h)

S-CKD602 Phase I PK: S-CKD602 Encap AUC vs Dose

High Inter-patient PK Variability

CKD

-602

10

100

1,000

10,000

100,000

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6

Dose (mg/m2)

AU

C (

ng

/mL

-h)



CKD

-602

100x

10

100

1,000

10,000

100,000

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6

Dose (mg/m2)

AU

C (

ng

/mL

-h)



CKD

-602

100x

10-25x

Increased PK Variability in Liposomal Formulations Compared

to Non-Liposomal Formulations of Anticancer Agents

PK Variability for Individual Agents

P<0.001

Relationship of Clearance Rate and PK

Variability

Bi-directional Interaction between Monocytes and

Liposomal Agents:

Phase I and PK Study of S-CKD602 in Patients

with Refractory Solid Tumors

Zamboni WC, Maruca L, Friedland DM, Ramalingam S, Edwards RP, Stoller RG, Belani CP, Strychor S, Ou YC, Tonda

ME, Ramanathan RK.

CKD

-602

Relationship between Clearance of Encapsulated Drug

and Release of Drug from Carrier

and % Decrease in Monocytes

Drug Drug

R² = 0.57

0.00

0.10

0.20

0.30

0.40

0.50

0 20 40 60 80 100

En

cap

su

lated

C

KD

-602 C

L (L

/h

/m

2)

% Decrease in Monocytes

0

50

100

150

200

250

0 20 40 60 80 100% Decrease in Monocytes

Rele

asesd

CK

D602 A

UC

in

Pla

sm

a

R2 = 0.62

Reduction in Doxil Clearance Associated with

Reduction in Precycle Monocyte Count

Decrease Doxil CL C1 to C3 Decrease Pre-Monocytes

Gabizon, CCP 2008 Irene La-Beck, CCP 2011

Active Lactone

Form

Acidic pH

O H

N N O

O O H3C

HCl.H-N

O H

N N

O

O O H3C

HCl.H-N

O H

N N

O

OH O H3C

OH

HCl.H-N

Relationship Between Nanoparticles/Liposomes

and MPS

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25

Days

Nu

mb

er

of

Ce

lls

(1

0^

9/L

)

Reduction in Monocytes in Blood

Age Related Effect on Monocytes:

< 60 yo = Greater Decrease

Age Related Effect on

Released CKD-602:

< 60 yo = Greater Release?

PhenoGLOTM: UNC Study Evaluating Phenotypic Probes to Predict

Doxil Efficacy & Toxicity in Patients with Ovarian Cancer

PhenoGLO Phenotypic Probes

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

Phenotypic Measures of RES Function

S-C

KD

602

Cle

aran

ce (L

/h/m

2)

PK: Clearance Dose

PD: Efficacy

PD: Toxicity

Drug

Function of

MPS Cells Imaging

Blood Cell

Tumor

Expression

Genotype

http://www.innerbody.com/image/lympov.html



0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100


S-C

KD

602

Cle

aran

ce (L

/h/m

2)

PK: Clearance Dose

PD: Efficacy

PD: Toxicity

Drug

Function of

MPS Cells

Imaging

Blood Cell

Tumor

Expression

Genotype






0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100


S-C

KD

602

Cle

aran

ce (L

/h/m

2)

PK: Clearance Dose

PD: Efficacy

PD: Toxicity

Drug

Function of

MPS Cells

Imaging

Blood Cell

Tumor

Expression

Genotype

“High Throughput”

Screening System

For Nanoparticles






Doxil PK

(Encap and Released

Doxorubicin)

Phenotypic Probes of

MPS Predict

Doxil Encap AUC

Interaction

between

Nanoparticles

and MPS

PhenoGLO-ITTM/PhenoGLO-PPTM: UNC Study Evaluating

Phenotypic Probes to Predict Doxil Efficacy & Toxicity in

Patients with Platinum Refractory Ovarian Cancer

Days -7 to -1 Days 1 to 7 Results

10

100

1000

10000

100000

0 24 48 72 96 120 144 168 192 216

Do

xo

ru

bicin

C

on

c (n

g/m

L)

Time (hours)

Doxil Encap AUC

And

Response (PFS)

Evaluation of MPS Imaging Probe (Tc99m-Sulfur Colloid;

TSC) to Predict Doxil PK and PD (Efficacy & Toxicity)

TSC (<200 nm)

Doxil (110 nm)

Relationship between TSC CL in Blood and

Encapsulated Doxorubicin CL in Plasma

Patient 1 Patient 2 Patient 3

TSC

Non-PEG-Lipo

PEG-Lipo

Can TSC PK in hands can be used to predict the

development of hand-foot syndrome (HFS) toxicity?

http://upload.wikimedia.org/wikipedia/commons/thumb/2/22/Hand-foot_Syndrome.jpg/230px-Hand-foot_Syndrome.jpg

TSC Image in Hands PPE in Hands after Doxil Treatment

PD Results – TSC Predicts HFS: NP issue PK follows MPS Cells

Maximum HFS Toxicity Grade vs. Equation Estimated Encapsulated Doxorubicin AUC in Hands for All Patients

0 5000 10000 15000 200000

1

2

3

4

5

r=0.77

p-value=0.02

Equation Estimated Encapsulated Doxorubicin AUC in Hands

Maxim

um

HF

S T

oxic

ity G

rade

Methods and Calculations

Active Lactone

Form

Acidic pH

O H

N N O

O O H3C

HCl.H-N

O H N N O

O O H3C

HCl.H-N

O H N N O

OH O H3C OH

HCl.H-N

Bi-Directional Interaction Between Nanoparticles and MPS

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25

Days

Num

ber o

f Cel

ls (1

0^9/

L)

Reduction in Monocytes in Blood

Feedback

Loop?

Patient Characteristics: - Age

- Gender

- Body Composition

- Race

- Type of Cancer***

- Comorbidities

- Others???

Cofactors: - Hormones

- Chemokines

- Complement

- Others???

Treatment: - Chemotherapy

- Radiation

- Other drugs

- Steroids

- Others???






RES/MPS



Nanoparticle Agents

Are all solid tumor conducive to

nanoparticle delivery?

Immunostaining for MPS Cells

Zamboni et al, J Lipo Res 2010

0.00

0.02

0.04

0.06

0.08

0.10

0.12A375 Melanoma

SKOV-3 Ovarian

Distribution of

S-CKD602To Tumors

Release of

CKD-602 in Tumors

Monocytes

& DendriticCells in

Tumors

Tumor

Sensitivity

Relationship between Tumor Disposition of

S-CKD602 and Tumor MPS (Macrophages/DC)

Re

lative

E

xp

osu

re

Variable MPS in Orthotopic Tumors and Effects

on MPS in Liver

MPS in Tumor

= Affects Tumor Delivery?

MPS in Tumor

= Affects MPS in Liver & NP Clearance?






RES/MPS



Nanoparticle Agents

Profile interaction

between NP and MPS

in animal and human

samples

PhenoGLO-HTSTM: Profiling the Interaction between

Nanoparticle Agents and MPS System

> 300 NP

anticancer agents

in development

Flow cytometry

screening platform

of MPS response

and activity

8 measures of

NP interactions

with MPS

Database of results &

mathematical models of

NP characteristics

and MPS

Acknowledgements

Lab Group:

TONDI Lab:

Whitney Caron

Gina Song

Sumit Rawal

Parag Kumar

Allison Schorzman

Sara Metzger

Chris Walko

Charlene Santos

Anthony Chhay

Hugh Giovinazzo

Amanda Keeler

Andrew Lucas

Shane Moore

Katie Sandison

Ryan Schell

Taylor White

Jennifer Coleman


Facility:

John Kagel

Suzanne Newman

Brenda Braun

Clinical Study Group:

Paola A. Gehrig

Arif Sheikh

Marija Ivanovic

Linda Van Le

Vicki Bae-Jump

Howard McLeod

Larry Arnold

Leigh Thorne

Terri Tarrant

Alan Fong

Bahjat Qaqish

Preclinical Study Group:

Leaf Huang

Joe DeSimone

Mary Napier

Russ Mumper

David LaLush

Mike Jay

Jim Bear

Ned Sharpless

Chuck Perou

David Darr

Carey Anders

Ryan Miller

Janiel Shields

Tim Wiltshire

Andrew Dudley

Resouces:

TONDI Lab

- Sample Processing

- Analytical

- HPLC

- LC-MS/MS

- Exactive

- Orbitrap

Funding:

NIH C-CCNE Grant 2010

NIH / NCI (1 U54 CA151652-01)

NIH CCCNE Pilot Grant 2009

NIH/NCI CA119343

UNC UCRF Grant 2009

NCTracs Grant 2010 - Caron

NCTracs Grant 2011 - Song

UNC ESOP

UNC LCCC

case study: safety and admet aspects of nanotechnology...

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