PBPK modeling for dosimetry of nonclinical and pediatric radioimmunotherapy

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1 PBPK modeling for dosimetry of nonclinical and pediatric radioimmunotherapy Kalevi J.A. Kairemo, MD, PhD, MSc(Eng) Professor, Consultant in Nuclear Medicine, Clinical Pharmacology & Chemistry Head, Department of Clinical Physiology & Nuclear Medicine, South Karelia Central Hospital Department of Oncology, Institute of Clinical Medicine, University of Helsinki, Finland

2 Summary 1) Clinical RIT (example) Quantification, radiopharmacokinetics, -dynamics 2) Animal RIT Biodistribution 3) PKPB modeling Quantification, radiopharmacokinetics, -dynamics, constants 4) Dosimetry 3D, MIRD, OLINDA, mouse, human 5) Future aspects

3 Clinical RIT In-111 and Y-90 monoclonal antibody against targeting secretory alfa-fetoprotein (AFP) in hepatic tissue was used. These antibodies were tested for radiotherapy and radioimmunotherapy dose planning of hepatoblastoma, a rare childhood malignancy Radiopharmacokinetic parameters after serial quantitative whole body scannings based on geometric mean and transmission images were determined Biodistribution data and organ level kinetic parameters were calculated and were compared those with nonclinical data in mice A 3-D dose planning programme was used to calculate tumor doses for In-111 and Y-90, delineated on PET/CT, using a dose point kernel approach The 3-D results with MIRD doses were obtained for organs in SPECT imaging field, i.e. bone marrow, heart, kidneys, liver, spleen, lungs.

4 Methods Antibody Conjugate The humanized hafp31 IgG was conjugated with the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate, for radiolabeling with either In-111 or Y-90 radioisotopes. The conjugation was carried out to yield a substitution of approximately three to six DOTA chelates per antibody molecule. Subsequent ELISA analyses demonstrated that hafp3l IgG-DOTA showed no loss in immunoreactivity at those levels of substitution. Preparation of the Radiolabeled DOTA-hAFP31 IgG The radiolabeled DOTA-hAFP3l IgG study drug was prepared at the Radiopharmacy laboratory at the Hospital (HUCH) using DOTA-conjugated hafp3l IgG supplied by Immunomedics, Inc. (Morris Plains, NJ) and radiopharmaceutical/radiochemical (sterile, pyrogen-free) grade Y-90 and/or In-111 isotopes purchased from CIS Bio international (Gif-sur-Yvette, France). The radionuclide (mci): antibody (mg) ratio was 5: 1 for Y-90 and 2: 1 for In-111 during the radiolabeling procedure. Quality control of the radiolabeled Y-90 - or In-111 -DOTA-IgG conjugate was performed by instant thin layer chromatography (ITLC). Once prepared, the radiolabeled DOTA-hAFP3l IgG study drug was used within 2 hours. Antibody infusion For purposes of specific tumor targeting, biodistribution, dosimetry estimation and pharmacokinetics, the patient received In hafp31 seven days prior to the Y-90 -hafp31 infusion. Vital signs were assessed at prescribed time points prior to, during and following completion of the infusions. Following establishment of a patent intravenous line equipped with a 0.2 micron in-line filter, the prescribed amount of unconjugated hafp3l IgG was added to saline in an infusion container. The unconjugated hafp31 IgG was infused at a rate that aliowed approximately 10% of the product to be infused over 10 minutes and the remainder of the unconjugated antibody was infused over a 30 minute period. Approvals for Ethical Committees and Institutional Review Boards, National Agency of Medicines for both Dx and Tx phases separately

5 Methods: Imagings At hours whole body planar images in AP and PA directions were acquired with a Toshiba GCA 7200A/UI gamma camera using a cm/min scanning speed. The gamma energies of 177 kev and 245 kev of In-111 were registered using 20% windows. Additionally a whole body transmission scan was performed using a cobalt-57 flood source. The patient was imaged at 2 and 7 days after therapeutic infusion using Brehmsstrahlung scintigraphy, energy range of kev, whole body scans, AP and PA, 7.5 cm/min. The SPECT acquisition, 30 sec frames, 3 degree angles, a MEGP parallel hole collimator optimal up to 300 kev gamma-rays; SPECT reconstruction FBP, and a Metz-filter. The matrix size was 128 x 128 pixels, the slice reconstruction volume 4.3 mm. Attenuation correction was performed using short and long axis fitted elliptical estimate of the body outline. The slice thickness was 9.3 mm. PET and CT images of the abdominal area were acquired using the GE Discovery STE PET/CT scanner with Advance 5.1software. The slice thickness was 3.3 mm. An automatic mutual information image registration method to register the SPECT, PET and CT images was used. The registration algorithm was implemented using the National Library of Medicine Insight Image Segmentation and Registration Toolkit open-source software system. Anatomical landmarks such as the kidneys, the liver and the patient outline were used to verify the registration of the images. Cumulative activity The cumulative activity for the abdominal area was determined from the whole body scans, normalized by counts from a standard In-111 source. The counts from whole body AP and PA scans were combined using a geometric mean. The activity curves for liver, whole body and the abdominal area to determine the cumulative activity in the liver (tumor) and the abdominal area of the SPECT study. We assigned the infused activity as the total activity for the whole body at 1hr. The physical decay constant was used to calculate the cumulative activity in the patient abdominal area and liver with the biological clearance data. The method includes the varying biological clearance between the liver and rest of the abdominal area.

Whole body imaging (quantification) Transmission Emission 57 Co, µ

(calculated), uncorrected 111 In GM image and

6 Whole body imaging (quantification) Transmission Emission 57 Co, µ = cm In, µ = 0.11 cm -1, d/2 Geometric mean GM, attenuation-corrected From left to right: 57 Co attenuation (measured), 111 In attenuation (calculated), uncorrected 111 In GM image and attenuation-corrected 111 In GM image. N N 0 N=N 0 e -µ(co)l L= -1/µ Co ln(c/c 0 ) Planar transmission source Kairemo et al., WFNMB 2002

7 PBPK Model for Mabs in Mice & Humans System flow chart Heiskanen T, Heiskanen T, Kairemo K, Curr Pharm Design 2009; 15:

8 Radiopharmacokinetics, diagnostic dose, pediatric liver cancer, 1/1 Tx MoAb dose Kairemo et al., WJNM 2008:

9 PBPK Model for Mabs in Mice & Humans Two compartment model of liver circulation Three compartment model of tissue/organ Heiskanen T, Heiskanen T, Kairemo K, Curr Pharm Design 2009; 15:

10 FDG-PET Imagings during RIT -12 d +25 d +57 d +79 d Day 0= onset of RIT

11 Percentage ( %) of injected Mab molecules FDG-PET- CT images of the patient tumor region 40 Data 1 30 Liver Liver tumor Whole abdomen Heart hour after injection

12 . Methods: Absorbed dose calculations The internal doses were estimated using OLINDA code (Organ Level Internal Dose Assessment code, Vanderbilt University 2003) with the standard anatomy of a 5-years old child (body mass 19.4 kg) and the measured In-111 time-activity data of liver, heart, spleen, lungs and rest of the body. The mean organ dose of liver, cardiac wall, spleen, and red bone marrow, as well as effective dose, (msv/mbq) were calculated both for In-111 and Y-90. The absorbed dose calculations were performed using a software package developed by us. The software was modified for this work to be compatible with the Varian Medical Systems Eclipse treatment planning system and Inspiration software platform (Varian Medical Systems, Palo Alto, CA, USA). New additional functionality utilized in this study was the ability to calculate dose volume histograms (DVH) and the ability to apply a mutual information based image registration technique. The software calculates the absorbed dose distribution by a convolution of a point source kernel with an activity map. The point source kernel is a spherically symmetric dose distribution of point source of unit cumulative activity. The kernels used in this study were obtained with Monte Carlo methods. We calculated the photon component of the absorbed dose using the Fast Fourier Transform convolution and the non-penetrating (low energy beta particles) component was calculated by locally depositing the dose in each voxel. The activity map used in the dose calculation was the first SPECT image acquired at 2 days after infusion. The calculated cumulative activity of the abdominal area and assign that to be the total activity of the counts in the SPECT image outside the liver, for the liver the total activity was derived from the liver specific activity clearance curve. The size activity map and dose calculation matrix was 64 x 64 x 64 voxels and the voxel size was 0.86 cm in all three dimensions. Both the In-111 and Y-90 treatments are calculated using the same activity maps and cumulative activity data. The organs and the tumor were outlined in the CT study and DVH was computed for the organs and the tumor. The total dose received by the patient was obtained by summing the dose distribution of the In-111 and Y-90 treatment. We used the photon S-factors for In-111 together with the calculated cumulative activity in the Liver in determination of doses in various target organs.

13 Actual 3-D dosimetry, hepatoblastoma, diagnostic In-111 anti-afp MoAb dose, tumor delineation by PET/CT

14 Actual 3-D dosimetry, hepatoblastoma, therapeutic Y-90 anti-afp MoAb dose, tumor delineation by PET/CT

15 Actual 3-D dosimetry in dose-volume histograms, hepatoblastoma, diagnostic In-111 and therapeutic Y-90 anti-afp MoAb doses Bone Bone marrow Bone Bone marrow Heart Liver Spleen Tumor Volume [%] Heart Liver Spleen Tumor Dose [Gy] Dose [Gy] A. Dose volume histogram of the In-111 therapy B. Dose volume histogram of the Y-90 therapy

16 PBPK Model for Mabs in Mice & Humans Simulated and experimental biodistribution of 111In-DOTA-hAFP31 IgG in a human. Heiskanen T, Heiskanen T, Kairemo K, Curr Pharm Design 2009; 15:

17 PBPK Model for Mabs in Mice & Humans Simulated accumulation of MAB in tumor for different values of concentration of antigen in tumor AGM (mg/l). Heiskanen T, Heiskanen T, Kairemo K, Curr Pharm Design 2009; 15:

18 Calculated Absorbed Radiation doses, MIRD formalism In-111 (mgy/mbq) Y-90 (mgy/mbq) Y-90 (Gy/43 MBq) OLINDA Y-90 (Gy/43 MBq) 3-D programme CARDIAC WALL LIVER SPLEEN RED BONE MARROW Sic! Blood kinetics 0.30 EFFECTIVE DOSE

19 Animal experiments In-111 and Y-90 monoclonal antibody against targeting secretory alfa-fetoprotein (AFP) was used Biodistribution experiments were carried out in normal mice, and data was recorded at 4hrs, 1 day, 2 days, 3 days, 4 days, 5 days, 7 days and 10 days. From the biodistribution data from 5 animals half-lives were calculated based on organ uptakes presented as % per gram of injected activity. The half-lives were obtained by fitting a monoexponential function. From the biodistribution data organ level kinetic parameters were calculated and compared those with clinical data A mouse MIRD dose planning programme* to calculate organ doses for In-111 and Y-90 was used *Hui TE, Fisher DR, Kuhn JA, Williams LE, Nourigat C, Badger CC, Beatty BG, Beatty JD. A mouse model for calculating cross-organ beta doses from 90 Y-labeled immunoconjugates. Cancer 1994; 73(3suppl):

20 Biodistribution in Mice (mean, n=35) %i.d./g Time 4 h 24 h 48 h 72 h 120 h 168 h 240 h Liver 10,2 7,2 6,9 6,5 6,1 5 5,5 Spleen 11,5 8,7 8,6 8,7 9,1 8,6 8,3 Kidney 9,2 6,6 6 5,9 5,7 5,5 5 Lungs 8,5 7,9 8,2 6,6 6,1 5,9 5,9 Blood 36,7 27,2 24,3 22,7 20,7 20,5 17,7 Stomach 2,1 1,4 1,7 1,9 1,4 1 1,6 S.I. 3,5 2,7 2,6 2,6 2,3 2 2,4 L.I. 1,8 1,8 1,7 1,9 1,8 1,2 1,5 Bone 4 3,7 3,3 3,1 3 2,9 3,4 W.B. 2,1 1,8 1,6 1,5 1,5 1,4 1,2

21 PBPK Model for Mabs in Mice Simulated biodistribution (continuous curves) of 111In-DOTA-hAFP31 IgG in a mouse Heiskanen T, Heiskanen T, Kairemo K, Curr Pharm Design 2009; 15:

22 Calculated In-111-DOTA-hAFP half-lives in the child and in balb/c mice injected with In-111-DOTA-hAFP T1/2B (h) patient T1/2B (h) mouse Spleen Kidney Lungs Blood Bone Rest of the body 490 N.D.

23 Calculated Y-90-DOTA-hAFP doses in balb/c mice injected with In-111-DOTA-hAFP Gy/MBq mouse Spleen* 2.11 Kidney 2.10 Lungs 2.94 Whole body 0.84 *Calculated Y-90-DOTA-hAFP dose in patient was 0.012Gy in patient

24 Summary of the results: From quantitative serial imaging based on 8 whole body images at hrs human In-111-anti-AFP- MoAb, the half-lives of spleen, lungs, kidneys and whole body could be calculated. The measured blood half-life was in concordance with PKPB modeling data. The calculated MIRD Y-90 doses were for cardiac wall 0.75 Gy, liver 0.62 Gy, spleen 0.51Gy and bone marrow Gy, and the effective whole body dose was 0.18 Gy, i.e mgy/mbq. The 3-D program demonstrated the mean doses in normal tissues as follows: heart 0.58 Gy, liver 0.48 Gy, spleen 0.37 Gy and bone marrow 0.34 Gy. The mouse doses for Y-90 were for spleen 2.10 Gy/MBq, for lung 2.11 Gy/MBq, for kidneys 2.84 Gy/MBq and for whole body 0.84 Gy/MBq. Thus the difference e.g. in spleen dose (mouse vs. man) was 178-fold and effective whole body dose 199-fold. The patient dosimetry calculations, are extremely individual, as shown here. The blood kinetics calculations gave the bone marrow dose 0.30 Gy when using 43 MBq Y-90 based on In-111-MoAb radiopharmacokinetics; The existing MIRD software gave bone marrow dose of Gy; The dedicated 3-D program software system gave an actual bone marrow dose of 0.34 Gy in a volume of 9.4 cm 3 in the SPECT/CT MoAb image field. Between mice and men, organ mean residence times may have correlation, and even uptakes may be similar, but dosimetry does not correlate. Further work should be dedicated for mouse-mird (OLINDA) intercomparisons. At this point, no conclusions can be drawn from mouse data for clinical RIT, even though these experiments should be performed.

25 Acknowledgments Prof. Darrell Fisher, Pacific Northwest National Laboratory, Richland, WA, USA Dr. Tomi Heiskanen, Helsinki University of Technology, Finland Prof. Glenn Flux, Insitute of Cancer Research and The Royal Marsden NHS Trust, Sutton, UK Dr. Mark Lubberink, University of Amsterdam, The Netherlands Joakim Pyyry, Varian Medical Systems Finland EU COST Action BM 0607 Kairemo KJA, Lindahl H, Merenmies J, et al. Anti-alphafetoprotein imaging is useful for staging hepatoblastoma. Transplantation 2002;73: Laitinen JO, Kairemo KJA, Jekunen AP, Korppi-Tommola T, Tenhunen M. The effect of threedimensional activity distribution on the dose planning of radioimmunotherapy for patients with advanced intraperitoneal pseudomyxoma. Cancer 1997;80: Pyyry JO, Merenmies J, Tenhunen M, Heikinheimo M, Parto K, Arola M, Rönnholm K, Isoniemi H, Karikoski R, Kämäräinen E-L, Seppänen M, Heikkonen J, Augensen F, Wegener WH, Goldenberg DM, Kairemo K. Radioimmunotherapy for recurrent childhood hepatoblastoma after liver transplantation. World J Nucl Med 2008; 7: Heiskanen T, Heiskanen T, Kairemo K. Development of a PBPK model for monoclonal antibodies and simulation of human and mice PBPK of a radiolabelled monoclonal antibody. Curr Pharm Des 2009; 15:

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