A Whole-Body Physiologically Based Pharmacokinetic Model for Alpha Particle Emitting Bismuth in Rats

Zaid, Nouran; Kletting, Peter; Winter, Gordon; Beer, Ambros; Glatting, Gerhard

doi:10.1089/cbr.2021.0028

Cited by 3 publications

(6 citation statements)

References 49 publications

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“…The absorbed doses in non-SSTR2 expressing tissues are due to the distribution of [ 212 Pb]Pb-DOTAMTATE and its progeny mainly in the vascular and interstitial compartments. Of note, the reported high uptake rate of free 212 Bi in bone explains the high contribution of free radionuclides to total absorbed dose in Table 2 [29].…”

Section: Discussionmentioning

confidence: 96%

“…The parameters of the 212 Pb-SSTA-PBPK model are classified into mice-specific and 212 Pb-SSTA-specific parameters with values taken from literature (Supplementary Material Table S1) [4,16,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Briefly, the main mice-specific parameters considered in the model are blood flow, tissue volumes, relevant volumes of tissue compartments (vascular, interstitial, early endosomes and sorting (late endosomes) compartments) and SSTR2 expression on cell membranes.…”

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

“…Each compartment in the 212 Pb-SSTA-PBPK model represents the in vivo alpha particle generator model described before [23]. The biodistribution of free 212 Bi is described by integrating a PBPK model for free 212 Bi into the 212 Pb-SSTA-PBPK model [29]. In short, the 212 Bi-PBPK model describes the interaction of free 212 Bi with red blood cells (RBC), high molecular weight plasma proteins (HWPP) and intracellular biological thiols.…”

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

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A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice

et al. 2021

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In vivo alpha particle generators have great potential for the treatment of neuroendocrine tumors in alpha-emitter-based peptide receptor radionuclide therapy (α-PRRT). Quantitative pharmacokinetic analyses of the in vivo alpha particle generator and its radioactive decay products are required to address concerns about the efficacy and safety of α-PRRT. A murine whole-body physiologically based pharmacokinetic (PBPK) model was developed for 212Pb-labeled somatostatin analogs (212Pb-SSTA). The model describes pharmacokinetics of 212Pb-SSTA and its decay products, including specific and non-specific glomerular and tubular uptake. Absorbed dose coefficients (ADC) were calculated for bound and unbound radiolabeled SSTA and its decay products. Kidneys received the highest ADC (134 Gy/MBq) among non-target tissues. The alpha-emitting 212Po contributes more than 50% to absorbed doses in most tissues. Using this model, it is demonstrated that α-PRRT based on 212Pb-SSTA results in lower absorbed doses in non-target tissue than α-PRRT based on 212Bi-SSTA for a given kidneys absorbed dose. In both approaches, the energies released in the glomeruli and proximal tubules account for 54% and 46%, respectively, of the total energy absorbed in kidneys. The 212Pb-SSTA-PBPK model accelerates the translation from bench to bedside by enabling better experimental design and by improving the understanding of the underlying mechanisms.

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Section: Discussionmentioning

confidence: 96%

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

Section: Pb-ssta-pbpk Model Structurementioning

confidence: 99%

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A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice

et al. 2021

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“…[33][34][35][36] Lastly, SAAM II is frequently used in isotope and radio tracing PK/PD and PBPK modeling. [37][38][39] The most recent tutorial publication for SAAM II dates to 1998, written by Barrett et al, 9 and since then, the software's application range has significantly expanded. This growth aligns with the rise of model-informed drug development (MIDD) and the growing integration of PK/ PD principles in contemporary therapeutic research, also known as pharmacometrics.…”

Section: Applicationsmentioning

confidence: 99%

“…PBPK models based on SAAM II were recently used to study the nonlinear absorption and distributions of anticancer drugs 31,32 ; another use is in the rapid prototyping of alternative PBPK mechanisms for nanoparticles or macromolecule distribution 33–36 . Lastly, SAAM II is frequently used in isotope and radio tracing PK/PD and PBPK modeling 37–39 …”

Section: Introductionmentioning

confidence: 99%

SAAM II: A general mathematical modeling rapid prototyping environment

Perazzolo

2024

CPT Pharmacom & Syst Pharma

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Simulation Analysis and Modeling II (SAAM II) is a graphical modeling software used in life sciences for compartmental model analysis, particularly, but not exclusively, appreciated in pharmacokinetics (PK) and pharmacodynamics (PD), metabolism, and tracer modeling. Its intuitive “circles and arrows” visuals allow users to easily build, solve, and fit compartmental models without the need for coding. It is suitable for rapid prototyping of models for complex kinetic analysis or PK/PD problems, and in educating students and non‐modelers. Although it is straightforward in design, SAAM II incorporates sophisticated algorithms programmed in C to address ordinary differential equations, deal with complex systems via forcing functions, conduct multivariable regression featuring the Bayesian maximum a posteriori, perform identifiability and sensitivity analyses, and offer reporting functionalities, all within a single package. After 26 years from the last SAAM II tutorial paper, we demonstrate here SAAM II's updated applicability to current life sciences challenges. We review its features and present four contemporary case studies, including examples in target‐mediated PK/PD, CAR‐T‐cell therapy, viral dynamics, and transmission models in epidemiology. Through such examples, we demonstrate that SAAM II provides a suitable interface for rapid model selection and prototyping. By enabling the fast creation of detailed mathematical models, SAAM II addresses a unique requirement within the mathematical modeling community.

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Dosimetry of [212Pb]VMT01, a MC1R-Targeted Alpha Therapeutic Compound, and Effect of Free 208Tl on Tissue Absorbed Doses

et al. 2022

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[212Pb]VMT01 is a melanocortin 1 receptor (MC1R) targeted theranostic ligand in clinical development for alpha particle therapy for melanoma. 212Pb has an elementally matched gamma-emitting isotope 203Pb; thus, [203Pb]VMT01 can be used as an imaging surrogate for [212Pb]VMT01. [212Pb]VMT01 human serum stability studies have demonstrated retention of the 212Bi daughter within the chelator following beta emission of parent 212Pb. However, the subsequent alpha emission from the decay of 212Bi into 208Tl results in the generation of free 208Tl. Due to the 10.64-hour half-life of 212Pb, accumulation of free 208Tl in the injectate will occur. The goal of this work is to estimate the human dosimetry for [212Pb]VMT01 and the impact of free 208Tl in the injectate on human tissue absorbed doses. Human [212Pb]VMT01 tissue absorbed doses were estimated from murine [203Pb]VMT01 biodistribution data, and human biodistribution values for 201Tl chloride (a cardiac imaging agent) from published data were used to estimate the dosimetry of free 208Tl. Results indicate that the dose-limiting tissues for [212Pb]VMT01 are the red marrow and the kidneys, with estimated absorbed doses of 1.06 and 8.27 mGyRBE = 5/MBq. The estimated percent increase in absorbed doses from free 208Tl in the injectate is 0.03% and 0.09% to the red marrow and the kidneys, respectively. Absorbed doses from free 208Tl result in a percent increase of no more than 1.2% over [212Pb]VMT01 in any organ or tissue. This latter finding indicates that free 208Tl in the [212Pb]VMT01 injectate will not substantially impact estimated tissue absorbed doses in humans.

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A Whole-Body Physiologically Based Pharmacokinetic Model for Alpha Particle Emitting Bismuth in Rats

Cited by 3 publications

References 49 publications

A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice

A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice

SAAM II: A general mathematical modeling rapid prototyping environment

Dosimetry of [212Pb]VMT01, a MC1R-Targeted Alpha Therapeutic Compound, and Effect of Free 208Tl on Tissue Absorbed Doses

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