Case Study: Safety and ADMET Aspects of Nanotechnology in Parenteral - - PowerPoint PPT Presentation

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Case Study: Safety and ADMET Aspects of Nanotechnology in Parenteral - - PowerPoint PPT Presentation

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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

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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

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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

Director = W. Zamboni Assoc Director = TBD Head Analytical Chemist = A. Schorzman Analytical Chemist = S. Metzger Post Doc = S. Rawal, P. Kumar

UNC GLP Bioanalytical Facility

Director = W. Zamboni 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
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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

Director = W. Zamboni Assoc Director = TBD Head Analytical Chemist = Schorzman Analytical Chemist = Metzger Post Doc = S. Rawal, P. Kumar

UNC GLP Bioanalytical Facility

Director = W. Zamboni 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
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Types of Nanoparticles and Carrier-Mediated Agents

Nanoparticles Conjugates

Monoclonal Antibodies Antibody Drug Conjugates (ADC)

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Clearance of Nanoparticles and CMAs Via the Mononuclear Phagocyte System (MPS)

Tumor

EPR MPS? PBMC Liver/Spleen

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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
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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

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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

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Name of Presentation

Pharmacologic Methods to Characterize Nanoparticles 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

These projects can be performed at:

Pharmaceutical Development Center (PDC) CRO

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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

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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

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Name of Presentation

Pharmacologic Methods to Characterize Nanoparticles 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

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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.

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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) AUC (ng/mL-h)

S-CKD602 Phase I PK: S-CKD602 Encap AUC vs Dose High Inter-patient PK Variability

CKD

  • 602
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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) AUC (ng/mL-h)

S-CKD602 Phase I PK: S-CKD602 Encap AUC vs Dose High Inter-patient PK Variability

CKD

  • 602

100x

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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) AUC (ng/mL-h)

S-CKD602 Phase I PK: S-CKD602 Encap AUC vs Dose High Inter-patient PK Variability

CKD

  • 602

100x 10-25x

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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

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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
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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 20 40 60 80 100

Encapsulated CKD-602 CL (L/h/m2) % Decrease in Monocytes

50 100 150 200 250 20 40 60 80 100 % Decrease in Monocytes Releasesd CKD602 AUC in Plasma

R2 = 0.62

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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

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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

5 10 15 20 25

Days

Number of Cells (10^9/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?

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PhenoGLOTM: UNC Study Evaluating Phenotypic Probes to Predict Doxil Efficacy & Toxicity in Patients with Ovarian Cancer

PhenoGLO Phenotypic Probes

10 20 30 40 50 60 70 80 90 100

10 20 30 40 50 60 70 80 90 100

Phenotypic Measures of RES Function S-CKD602 Clearance (L/h/m2)

PK: Clearance  Dose PD: Efficacy PD: Toxicity

Drug

Function of MPS Cells

Imaging Blood Cell Tumor Expression Genotype

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PhenoGLO Phenotypic Probes

10 20 30 40 50 60 70 80 90 100

10 20 30 40 50 60 70 80 90 100

Phenotypic Measures of RES Function S-CKD602 Clearance (L/h/m2)

PK: Clearance  Dose PD: Efficacy PD: Toxicity

Drug

Function of MPS Cells

Imaging Blood Cell Tumor Expression Genotype

PhenoGLOTM: UNC Study Evaluating Phenotypic Probes to Predict Doxil Efficacy & Toxicity in Patients with Ovarian Cancer

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PhenoGLO Phenotypic Probes

10 20 30 40 50 60 70 80 90 100

10 20 30 40 50 60 70 80 90 100

Phenotypic Measures of RES Function S-CKD602 Clearance (L/h/m2)

PK: Clearance  Dose PD: Efficacy PD: Toxicity

Drug

Function of MPS Cells

Imaging Blood Cell Tumor Expression Genotype

“High Throughput”

Screening System For Nanoparticles

PhenoGLOTM: UNC Study Evaluating Phenotypic Probes to Predict Doxil Efficacy & Toxicity in Patients with Ovarian Cancer

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SLIDE 25

Name of Presentation

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 24 48 72 96 120 144 168 192 216

Doxorubicin Conc (ng/mL) Time (hours)

Doxil Encap AUC And Response (PFS)

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Evaluation of MPS Imaging Probe (Tc99m-Sulfur Colloid; TSC) to Predict Doxil PK and PD (Efficacy & Toxicity)

TSC (<200 nm) Doxil (110 nm)

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Relationship between TSC CL in Blood and Encapsulated Doxorubicin CL in Plasma

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Patient 1 Patient 2 Patient 3

TSC Non-PEG-Lipo PEG-Lipo

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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

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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

5000 10000 15000 20000 1 2 3 4 5

r = 0.77 p-value=0.02

Equation Estimated Encapsulated Doxorubicin AUC in Hands Maximum HFS Toxicity Grade

Methods and Calculations

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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

5 10 15 20 25

Days

Number of Cells (10^9/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???
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Name of Presentation

Pharmacologic Methods to Characterize Nanoparticles 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

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Are all solid tumor conducive to nanoparticle delivery?

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Immunostaining for MPS Cells

Zamboni et al, J Lipo Res 2010

0.00 0.02 0.04 0.06 0.08 0.10 0.12

A375 Melanoma SKOV-3 Ovarian

Distribution of S-CKD602 To Tumors Release of CKD-602 in Tumors Monocytes & Dendritic Cells in Tumors Tumor Sensitivity

Relationship between Tumor Disposition of S-CKD602 and Tumor MPS (Macrophages/DC)

Relative Exposure

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Variable MPS in Orthotopic Tumors and Effects

  • n MPS in Liver

MPS in Tumor = Affects Tumor Delivery? MPS in Tumor = Affects MPS in Liver & NP Clearance?

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SLIDE 36

Name of Presentation

Pharmacologic Methods to Characterize Nanoparticles 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

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SLIDE 37

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

  • f MPS response

and activity 8 measures of NP interactions with MPS Database of results & mathematical models of NP characteristics and MPS

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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 UNC GLP Bioanalytical 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