Radiopharmaceuticals play a crucial role in both diagnostic and therapeutic applications. The unique utilization of radioactive isotopes necessitates a nuanced approach to dose determination, taking into account specific clinical indications, patient characteristics, and the intricate interplay between the physical properties of the radiopharmaceutical and biological responses. The critical determination of an appropriate dose for radiopharmaceuticals is paramount for ensuring efficacy and safety in clinical use and advancing both the field of nuclear medicine and the quality of patient care. This article delves into the multifaceted landscape of radiopharmaceutical dose determination, exploring the principles, methodologies, and challenges associated with achieving optimal doses for diagnostic imaging and therapeutic interventions.

1. Factors that Impact Dose Determination

Factors that affect the dose determination for radiopharmaceuticals include CMC factors (especially the half-life of radionuclides), clinical indications, patient populations, dosing regimens, previous human experience, and impact on the environment. The unique features of each radiopharmaceutical should be considered during the dose determination, such as its use in diagnosis or treatment, radionuclide and ligand composition, and whether it is a chemical entity (drug) or biological product.

2. The Impact of CMC on Dose Determination

CMC (Chemistry, Manufacturing and Controls) process that dictates the final product of the radiopharmaceuticals is likely to have a greater impact on the dose calculation of radiopharmaceuticals compared to other entity drugs. Generally, for radiopharmaceuticals, the radioactivity per unit mass is expressed in a wide range, and the mass per volume also has a certain range. Whether the calculation is based on the highest or lowest point in the range depends on the clinical applications. For example, the injection volume is restricted by maximum limits depending on the method of injection. In such cases, the maximum mass volume is usually calculated using the lowest radioactivity concentration. The physical half-life of the radionuclide is also a factor to be considered as the amount of radioactivity per unit mass changes over time. Therefore, the distance between the clinical trial site and the manufacturing site, as well as the preparation time for the final formulation, need to be considered for dose calculation.  The nature of radiopharmaceuticals determines that the final dose administered to the patient is affected by multiple variables.

3. Dose Determination in Various Types of Radiopharmaceuticals

3.1 Principles for Development and Dose Selection of Diagnostic Radiopharmaceuticals

A diagnostic radiopharmaceutical is designed for diagnosing or monitoring diseases or their manifestations in humans. It demonstrates spontaneous disintegration of unstable nuclei, emitting nuclear particles or photons. This category also includes nonradioactive kits or nuclide generators specifically intended for preparing such drugs. Diagnostic radiopharmaceuticals can be used for patients or potential healthy individuals, so the safety requirements are strict. The administered dose should be at the low end of the dose-response curve. The practical principle is to calculate the lowest dose that can provide diagnostic images based on the “as-low-as-reasonably-achievable” (ALARA) principle, that is, the tracer dose.

For microdose diagnostic radiopharmaceuticals, the regulatory requirements are not as stringent as those for non-microdose diagnostic radiopharmaceuticals (as shown in Figure 1). A microdose is less than 1/100 of the dose of a test substance calculated (based on animal data) to yield a pharmacologic effect of the test substance with a maximum dose of less than or equal to 100 micrograms (µg). The maximum dose for protein products is less than or equal to 30 nanomoles (nmol). Under the premise of microdose, the clinical dose still needs to consider both the toxicity safety window and the radioactive dose.

Figure 1. Developmental Overview of a Diagnostic Radiopharmaceutical

3.2 Principles for Development and Dose Selection of Therapeutic Radiopharmaceuticals

A therapeutic radiopharmaceutical is a product that contains a radionuclide and is used in patients with cancer to treat the disease or palliate tumor-related symptoms. In principle, the radiation dose administered in patients should be adjusted based on the tolerated absorbed radiation doses in human organs. Threshold from external radiation therapy can be used as a starting point. However, because therapeutic radiopharmaceuticals are usually administered systemically, such as commonly used injections, systemic exposure may cause long-term irreversible side effects. Ideally, long-term/late radiation toxicity studies should be completed before the start of Phase 2 dose escalation clinical trials. An overview of the development of a therapeutic radiopharmaceutical is shown below.

Figure 2. Developmental Overview of a Therapeutic Radiopharmaceutical

4. Dosimetry Studies and Dose Calculation

Dosimetry is the measurement and characterization of the effects of radiation in organs — including activity and/or absorbed radiation dose in an organ and its biological effects — after administration of a radiopharmaceutical. Commonly used concepts in dosimetry studies and dose calculation are listed below.

Administered dose: The amount of radioactivity administered to animals or to patients and expressed as the unit of activity. The unit in the International System of Units (SI) is Becquerel (Bq) and the legacy unit is Curie (Ci). One mCi equals 37 MBq.

Absorbed dose: The ionizing-radiation energy deposited per unit mass of an organ or tissue. The SI unit of absorbed dose is Gray (Gy) and the legacy unit of absorbed dose is rad. One rad is equivalent to 0.01 Gy.

Equivalent dose: A measure of biological effect of the radioactive dose that takes into account both the absorbed dose and biological effectiveness of the radiation, and hence, the radiation type. The SI unit is Sievert (Sv) and the legacy unit is rem. One rem equals to 0.01 Sv.

Effective dose: The sum of the weighted equivalent doses in all the tissues and organs of the body, defined in 1990 by the International Commission on Radiological Protection, allows the conversion of the risk from partial body irradiations to those of whole-body irradiations. The SI unit is Sievert (Sv) and the legacy unit is rem. Effective dose can be calculated using dosimetry platform that is cleared by 510(k). Software name and version should be specified in IND dossiers.

Calculations of radioactive doses can be extrapolated from animal data to humans. The figure below illustrates an example of scaling doses in source organs from animal data to humans.

Figure 3. Extrapolating Doses from Animal Studies to Humans

In summary, the general dose calculation process involves the measurement of the radioactivity of animal source organs, estimate the activity in human source organs, calculate the absorbed dose of human target organs, convert it into equivalent doses and effective doses, and apply the pre-specified regulatory parameters to establish the first in human doses. It should be noted that the regulatory requirements for the first-in-human doses are completely different for diagnosis and therapeutic applications. The choice of regulatory standards is determined by the indication, subject population, dose regimens, and the characteristics of the radiopharmaceutical itself.

5. Summary

To determine radiopharmaceutical dose, both the radioactivity and the activity of the drug ligand need to be considered, as well as drug manufacturing and formulation of the final dosage form. Radiopharmaceuticals for different applications are subject to different dose selection principles and regulatory standards. This underscores the intricate nature of radiopharmaceutical research and development, where the entirety of CMC, nonclinical, and clinical research necessitates thorough planning, meticulous evaluation, and adherence to regulatory standards based on drug characteristics.