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 (TOND 2 I) Lab
Source of Drugs or Studies: UNC Investigators, NCI, NIH, & Pharmaceutical Co. NCCH Clinical Trials Unit & Sample Processing Steering Committee UNC LCCC & UNC ESOP Lab Dr. Dees, LCCC Analytical Chemistry & Dr. Sharpless, LCCC MP1U Pharmacology Labs Dr. Frye, CICBDD Director = C. Walko Dr. DeSimone, CCCNE C-CCNE Analytical and PK Core Dr. Jay, ESOP Dr. Brouwer, ESOP Industry Rep = TBD Director = W. Zamboni UNC GLP Bioanalytical --------------------------------------- Facility Consultants Director = W. Zamboni Dr. Madden, MD Anderson CC Assoc Director = J. Kagel Dr. Baxter, PhD, OpAns Analytical Chemist = B. Braun QAU = S. Newman Translational Oncology and Nanoparticle Drug Development Initiative (TOND 2 I) Lab Director = W. Zamboni Assoc Director = TBD Head Analytical Chemist = A. Schorzman Analytical Chemist = S. Metzger Post Doc = S. Rawal, P. Kumar
Source of Drugs or Studies: UNC Investigators, NCI, NIH, & Pharmaceutical Co. NCCH Clinical Trials Unit & Sample Processing Steering Committee UNC LCCC & UNC ESOP Lab Dr. Dees, LCCC Analytical Chemistry & Dr. Sharpless, LCCC MP1U Pharmacology Labs Dr. Frye, CICBDD Director = C. Walko Dr. DeSimone, CCCNE C-CCNE Analytical and PK Core Dr. Jay, ESOP Dr. Brouwer, ESOP Industry Rep = TBD Director = W. Zamboni UNC GLP Bioanalytical Facility --------------------------------------- Director = W. Zamboni Consultants Assoc Director = J. Kagel Dr. Madden, MD Anderson CC Analytical Chemist = B. Braun Dr. Baxter, PhD, OpAns QAU = S. Newman Translational Oncology and Nanoparticle Drug Development Initiative (TOND 2 I) Lab Director = W. Zamboni Assoc Director = TBD Head Analytical Chemist = Schorzman Analytical Chemist = Metzger Post Doc = S. Rawal, P. Kumar
Types of Nanoparticles and Carrier-Mediated Agents Monoclonal Antibodies Nanoparticles Conjugates Antibody Drug Conjugates (ADC)
Clearance of Nanoparticles and CMAs Via the Mononuclear Phagocyte System (MPS) PBMC Liver/Spleen Tumor EPR MPS?
Pharmacologic Issues of Nanoparticle/Liposomal Agents: Characterize Encapsulated/Released Drug & PK Variability S-CKD602 Carrier Warhead Active Lactone Form Encapsulated / Conjugated Released Goal in Tumor: Goal in Plasma: Sum Total = Encapsulated + Released - Release drug from - Remain within or carrier Attached to carrier - Decrease toxicity - Decrease toxicity
Pharmacologic Methods to Characterize CMAs In Vitro and In Vivo Analytical and PK Studies of Phenotypic Interaction Nanoparticle Agents between Nanoparticles and RES/MPS New PK/PD Metrics for NPs Name of Presentation
Pharmacologic Methods to Characterize CMAs In Vitro and In Vivo Analytical and PK Studies of Phenotypic Interaction Nanoparticle Agents between Nanoparticles and RES/MPS New PK/PD Metrics for NPs Name of Presentation
Pharmacologic Methods to Characterize Nanoparticles In Vitro and In Vivo Analytical and PK Studies of Phenotypic Interaction Nanoparticle Agents between Nanoparticles and RES/MPS These projects can be performed at: New PK/PD Metrics for NPs Pharmaceutical Development Center (PDC) CRO Name of Presentation
Active Research Programs Evaluating Nanoparticle Pharmacology and the MPS Brain Muscle and Fat Heart Lung IV/PO Pancreas Kidney Tumor Liver Plasma and Blood Cells Spleen
Active Research Programs Evaluating Nanoparticle Pharmacology and the MPS Brain Muscle and Fat Heart Lung IV/PO Pancreas Kidney Tumor Liver Plasma and Blood Cells Spleen
Pharmacologic Methods to Characterize Nanoparticles In Vitro and In Vivo Analytical and PK Studies of Phenotypic Interaction Nanoparticle Agents between Nanoparticles and RES/MPS New PK/PD Metrics for NPs Name of Presentation
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.
S-CKD602 Phase I PK: S-CKD602 Encap AUC vs Dose High Inter-patient PK Variability 100,000 10,000 AUC (ng/mL-h) 1,000 CKD -602 100 10 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/m 2 )
S-CKD602 Phase I PK: S-CKD602 Encap AUC vs Dose High Inter-patient PK Variability 100,000 10,000 AUC (ng/mL-h) 1,000 CKD -602 100 100x 10 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/m 2 )
S-CKD602 Phase I PK: S-CKD602 Encap AUC vs Dose High Inter-patient PK Variability 100,000 10,000 AUC (ng/mL-h) 10-25x 1,000 CKD -602 100 100x 10 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/m 2 )
Increased PK Variability in Liposomal Formulations Compared to Non-Liposomal Formulations of Anticancer Agents PK Variability for Individual Agents Relationship of Clearance Rate and PK Variability P<0.001
Bi-directional Interaction between Monocytes and Liposomal Agents: Phase I and PK Study of S-CKD602 in Patients with Refractory Solid Tumors CKD -602 Zamboni WC, Maruca L, Friedland DM, Ramalingam S, Edwards RP, Stoller RG, Belani CP, Strychor S, Ou YC, Tonda ME, Ramanathan RK.
Relationship between Clearance of Encapsulated Drug and Release of Drug from Carrier and % Decrease in Monocytes Drug Drug 0.50 250 Encapsulated CKD-602 CL (L/h/m 2 ) Releasesd CKD602 AUC in Plasma R² = 0.57 0.40 200 R 2 = 0.62 0.30 150 0.20 100 0.10 50 0.00 0 0 20 40 60 80 100 0 20 40 60 80 100 % Decrease in Monocytes % Decrease in Monocytes
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
Relationship Between Nanoparticles/Liposomes and MPS Acidic pH HCl.H-N HCl.H-N HCl.H-N N O N N O N N O OH N O H 3 C OH O O O H H 3 C H 3 C O O O H O H Active Lactone Form Age Related Effect on Released CKD-602: < 60 yo = Greater Release? Reduction in Monocytes in Blood 1.0 0.8 Number of Cells (10^9/L) 0.6 0.4 0.2 0.0 0 5 10 15 20 25 Days Age Related Effect on Monocytes: < 60 yo = Greater Decrease
PhenoGLO TM : UNC Study Evaluating Phenotypic Probes to Predict Doxil Efficacy & Toxicity in Patients with Ovarian Cancer PK: Clearance Dose PhenoGLO Phenotypic Probes 100 90 S-CKD602 Clearance (L/h/m2) 80 70 Drug 60 50 Function of 40 Imaging 30 MPS Cells 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Phenotypic Measures of RES Function PD: Efficacy Blood Cell Tumor Expression PD: Toxicity Genotype
PhenoGLO TM : UNC Study Evaluating Phenotypic Probes to Predict Doxil Efficacy & Toxicity in Patients with Ovarian Cancer PK: Clearance Dose PhenoGLO Phenotypic Probes 100 90 Function of S-CKD602 Clearance (L/h/m2) 80 70 MPS Cells Drug 60 50 40 Imaging 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Phenotypic Measures of RES Function PD: Efficacy Blood Cell Tumor Expression PD: Toxicity Genotype
PhenoGLO TM : UNC Study Evaluating Phenotypic Probes to Predict Doxil Efficacy & Toxicity in Patients with Ovarian Cancer PK: Clearance Dose “ High Throughput” PhenoGLO Phenotypic Probes 100 90 Screening System S-CKD602 Clearance (L/h/m2) 80 70 For Nanoparticles Drug 60 50 40 Imaging 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Phenotypic Measures of RES Function Function of PD: Efficacy MPS Cells Blood Cell Tumor Expression PD: Toxicity Genotype
PhenoGLO-IT TM /PhenoGLO-PP TM : UNC Study Evaluating Phenotypic Probes to Predict Doxil Efficacy & Toxicity in Patients with Platinum Refractory Ovarian Cancer Doxil PK Interaction Phenotypic Probes of Doxil Encap AUC (Encap and Released between MPS Predict And Doxorubicin) Nanoparticles Doxil Encap AUC Response (PFS) and MPS 100000 Doxorubicin Conc (ng/mL) 10000 1000 100 10 0 24 48 72 96 120 144 168 192 216 Time (hours) Results Days 1 to 7 Days -7 to -1 Name of Presentation
Evaluation of MPS Imaging Probe (Tc99m-Sulfur Colloid; TSC) to Predict Doxil PK and PD (Efficacy & Toxicity) Doxil (110 nm) TSC (<200 nm)
Relationship between TSC CL in Blood and Encapsulated Doxorubicin CL in Plasma
TSC Non-PEG-Lipo PEG-Lipo Patient 1 Patient 2 Patient 3
Can TSC PK in hands can be used to predict the development of hand-foot syndrome (HFS) toxicity ? TSC Image in Hands PPE in Hands after Doxil Treatment http://upload.wikimedia.org/wikipedia/commons/thumb/2/22/Hand-foot_Syndrome.jpg/230px-Hand-foot_Syndrome.jpg
PD Results – TSC Predicts HFS: NP issue PK follows MPS Cells Methods and Calculations Maximum HFS Toxicity Grade vs. Equation Estimated Encapsulated Doxorubicin AUC in Hands for All Patients Maximum HFS Toxicity Grade 5 r = 0.77 p-value=0.02 4 3 2 1 0 0 5000 10000 15000 20000 Equation Estimated Encapsulated Doxorubicin AUC in Hands
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