A physiologically based pharmacokinetic model for [Ga-68]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients

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A physiologically based pharmacokinetic model for [Ga-68]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients

Siebinga, Hinke (author): Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands.;Netherlands Canc Inst, Dept Nucl Med, Amsterdam, Netherlands.

de Wit-van der Veen, Berlinda J. J. (author): Netherlands Canc Inst, Dept Nucl Med, Amsterdam, Netherlands.

Beijnen, Jos H. (author): Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands.

Dorlo, Thomas P. C., PhD, 1983- (author): Uppsala universitet,Institutionen för farmaci,Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands.

Huitema, Alwin D. R. (author): Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands.;Univ Utrecht, Univ Med Ctr Utrecht, Dept Clin Pharm, Utrecht, Netherlands.;Princess Maxima Ctr Pediat Oncol, Dept Pharmacol, Utrecht, Netherlands.

Hendrikx, Jeroen J. M. A. (author): Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands.;Netherlands Canc Inst, Dept Nucl Med, Amsterdam, Netherlands.

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Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands;Netherlands Canc Inst, Dept Nucl Med, Amsterdam, Netherlands. Netherlands Canc Inst, Dept Nucl Med, Amsterdam, Netherlands. (creator_code:org_t)

2023-02-03
2023
English.
In: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 13:1

Related links:: https://doi.org/10.1...; show more...; https://uu.diva-port... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

Background: Little is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various Ga-68-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compare organ and tumor distribution of [Ga-68]Ga-DOTATATE and [Ga-68]Ga-HA-DOTATATE using a physiologically based pharmacokinetic (PBPK) model and to identify factors that might cause biodistribution and tumor uptake differences between both peptides. In addition, the effect of tumor burden on peptide biodistribution in gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients was assessed.Methods: A PBPK model was developed for [Ga-68]Ga-(HA-)DOTATATE in GEP-NET patients. Three tumor compartments were added, representing primary tumor, liver metastases and other metastases. Furthermore, reactions describing receptor binding, internalization and recycling, renal clearance and intracellular degradation were added to the model. Scan data from GEP-NET patients were used for evaluation of model predictions. Simulations with increasing tumor volumes were performed to assess the tumor sink effect.Results: Data of 39 and 59 patients receiving [Ga-68]Ga-DOTATATE and [Ga-68]Ga-HA-DOTATATE, respectively, were included. Evaluations showed that the model adequately described image-based patient data and that different receptor affinities caused organ uptake dissimilarities between both peptides. Sensitivity analysis indicated that tumor blood flow and blood volume impacted tumor distribution most. Tumor sink predictions showed a decrease in spleen uptake with increasing tumor volume, which seemed clinically relevant for patients with total tumor volumes higher than similar to 550 mL.Conclusion: The developed PBPK model adequately predicted tumor and organ uptake for this GEP-NET population. Relevant organ uptake differences between [Ga-68]Ga-DOTATATE and [Ga-68]Ga-HA-DOTATATE were caused by different affinity profiles, while tumor uptake was mainly affected by tumor blood flow and blood volume. Furthermore, tumor sink predictions showed that for the majority of patients a tumor sink effect is not expected to be clinically relevant.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

PBPK
Ga-68-DOTATATE
Ga-68-HA-DOTATATE
Whole-body distribution
Tumor sink effect

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