PBRPK modeling of radiopharmaceutical therapies

Ali Fele-Paranj, Babak Saboury, Carlos Uribe, Arman Rahmim. Physiologically based radiopharmacokinetic (PBRPK) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding. EJNMMI Radiopharmacy and Chemistry 9, 6 (2024).
DOI · Open access (PMC) · Correction

The question

In radiopharmaceutical therapy (RPT) a drug carrying a radioactive atom is injected, binds to receptors on tumor cells, and irradiates them from inside. The amount to inject is usually decided from an imaging scan done with a tiny amount of a similar drug. But the therapy amount is much larger, and the radiolabelled (hot) and unlabelled (cold) molecules compete for the same receptors. So does the scan really predict the therapy?

The model

A whole-body PBRPK model: organs connected by blood flow, and inside each organ the binding, unbinding, internalization, and decay of hot and cold ligands. It has more than 150 ODEs, written with a “reaction graph” notation so that each organ is a small, readable module.

What we found

Non-linearity. The absorbed dose is not proportional to the injected activity. Curves of equal tumor dose (iso-dose curves) in the plane of hot vs cold injected amount show the trade-off.

Fig. 1 of the paper, CC BY 4.0.

How the iso-dose curves twist depends on the receptor density of the tumor:

Fig. 4 of the paper, CC BY 4.0.

Multi-bolus injections. Splitting the activity into several injections raises the dose to organs as well as tumors, so there is no differential gain for tumors.

Fig. 6 of the paper, CC BY 4.0.

Albumin binding. A higher albumin affinity keeps the drug in the blood longer and gives tumors a larger dose relative to organs at risk.

Fig. 10 of the paper, CC BY 4.0.

Cite

@article{feleparanj2024pbrpk,
  title   = {Physiologically based radiopharmacokinetic ({PBRPK}) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding},
  author  = {Fele-Paranj, Ali and Saboury, Babak and Uribe, Carlos and Rahmim, Arman},
  journal = {EJNMMI Radiopharmacy and Chemistry},
  volume  = {9},
  pages   = {6},
  year    = {2024},
  doi     = {10.1186/s41181-023-00236-w}
}

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