Model-based predictions of the serum biokinetics during therapy were compared to actual measurements

Model-based predictions of the serum biokinetics during therapy were compared to actual measurements. Results Variability of the RM time-integrated activity coefficients ((37.37.5) h) indicates the need for patient-specific dosimetry. and estimated red marrow antigen numbers.(XLSX) pone.0127934.s003.xlsx (47K) GUID:?EB00CDC3-6214-4651-B1B2-78C10BFDA6D3 S1 Text: Model Equations and Parameters. Model equations and parameters for the description of the biodistribution of fully-, half- and non-immunoreactive labeled and unlabeled anti-CD66 antibodies.(PDF) pone.0127934.s004.pdf (411K) GUID:?1AA4D594-9340-4583-AC64-9C5EE5F2E174 Data Availability StatementAll relevant data are within the paper and its Supporting Information files. Abstract Introduction Radioimmunotherapy (RIT) with 90Y-labeled anti-CD66 antibody is used to selectively irradiate the red marrow (RM) before blood stem cell transplantation of acute leukemia patients. To calculate the activity to administer, time-integrated activity coefficients are required. These are estimated prior to therapy using gamma camera and serum measurements after injection of 111In labeled anti-CD66 antibody. Equal pre-therapeutic Reactive Blue 4 and therapeutic biodistributions are usually assumed to calculate the coefficients. However, additional measurements during therapy had shown that this assumption had to be abandoned. A physiologically based pharmacokinetic (PBPK) model was developed to allow the prediction of therapeutic time-integrated activity coefficients in eight patients. Aims The aims of the study were to demonstrate using a larger patient group 1) the need to perform patient-specific dosimetry in 90Y-labeled anti-CD66 RIT, 2) that pre-therapeutic and therapeutic biodistributions differ, and most importantly 3) that this difference in biodistributions can be accurately predicted using a refined model. Materials and Methods Two new PBPK models were developed considering fully, half and non-immunoreactive antibodies and constraints for estimating the RM antigen number. Both models were fitted to gamma camera and serum measurements of 27 patients. Akaike weights were used for model averaging. Time-integrated activity coefficients for total body, liver, spleen, RM and serum were calculated. Model-based predictions of the serum biokinetics during therapy were compared to actual measurements. Results Variability Reactive Blue 4 of the RM time-integrated activity coefficients ((37.37.5) h) indicates the need for patient-specific dosimetry. The relative differences between pre-therapeutic and therapeutic serum time-activity curves were (-2516)%. The prediction accuracy of these differences using the refined PBPK models was (-320)%. Conclusion Individual treatment is needed due to biological differences between patients in RIT with 90Y-labeled anti-CD66 antibody. Differences in pre-therapeutic and therapeutic biokinetics are predominantly caused by different degrees of saturation due to different amounts of administered antibody. These differences could be predicted using the PBPK models. Introduction Radioimmunotherapy (RIT) is a cancer treatment method were radiolabeled antibodies are used to selectively irradiate tumor cells. Thus, the dose is delivered predominantly to the target while the burden to organs at risk remains acceptable [1]. 90Y-labeled anti-CD66 antibodies are used in conditioning before blood stem cell transplantation of acute (myeloid and lymphoblastic) leukemia patients [1C4]. LSP1 antibody The mean range of the 90Y beta particles of 3.6 mm allows systematic and selective irradiation of leukemic cells from normal granulocytes which express CD66 on the cell surface. To ablate the marrow without disrupting the stroma, the targeted total red marrow dose is 35 Gy ([5]). The prescribed absorbed doses for red marrow from RIT are 23 Gy or 35 Gy depending Reactive Blue 4 on additional total body irradiation Reactive Blue 4 (TBI) with a prescribed absorbed dose of 12 Gy [4]. The absorbed dose to the liver was constrained to be lower than 12 Gy (TBI) or 20 Gy (no TBI), respectively. Treatment planning, i.e. the determination of the activity to administer, is performed individually as the biokinetics for red marrow and the organs Reactive Blue 4 at risk (kidneys, liver) differ considerably between patients. After injection of 111In-labeled anti-CD66 antibodies, a series of pre-therapeutic measurements are used to obtain the time-activity curves of the total body, red marrow, liver, spleen and serum. Before the introduction of physiologically based models, a sum of exponential functions was fitted to the measured pre-therapeutic biokinetic data. Subsequently, time-integrated activity coefficients were determined by (analytical) integration of the fit functions. These coefficients represent the input quantities for commonly applied nuclear medicine dosimetry software (e.g. OLINDA/EXM (Vanderbilt University, Tennessee, USA)) for the estimation of absorbed doses to the target and the organs at risk. In this dosimetric process equal pre-therapeutic and therapeutic biodistributions of the administered antibodies are assumed. However, serum measurements during therapy in a small patient group showed that the assumption of equal biodistributions is not justified. Consequently, to be able to predict therapeutic biodistributions based on the pre-therapeutic measurements, a physiologically based pharmacokinetic (PBPK) model describing the biodistribution of radiolabeled CD66 antibodies was recently developed [3]. On the basis of the biokinetic data of eight patients, it was found that the administered number of anti-CD66 antibodies is in the same order of magnitude as the number of CD66 antigens in the patients. Thus, saturation effects occur.