By Dr. Bill F. Hodnick, DABT
Microdose radiopharmaceutical drugs are a unique class of drugs characterized by single or infrequent administration of a very small dose (microdose) of a radiolabeled compound. These radiopharmaceuticals are intended to target and allow the imaging of pathophysiological processes or tissues. Diseases or indications include radiodiagnostic drugs used to image neuroendocrine tumors (NETs) and prostate cancer via single photon emission computed tomography (SPECT) and positron emission tomography (PET). Examples of FDA-approved drugs in this category include In-111-pentetreotide (OctreoScan™), Ga-68-DOTATOC (edotreotide Ga-68 Injection), and fluciclovine F-18 injection (Axumin®), to name a few.
Radiopharmaceutical Drug Doses and Their Characteristics
Depending on the types of radiation emitted, the doses of the radiopharmaceutical drug administered can range from nanograms to micrograms. Typically, these drugs are either degraded or metabolized or excreted intact. No pharmacologically active metabolites are formed. Even if a metabolite had pharmacological effects, these effects would only manifest at much higher doses than those needed for diagnostic purposes.
For typical small molecule or biologic drugs, the nonclinical development program includes a number of lab bench and animal studies. However, as defined in the CDER Guidance for Industry – Microdose Radiopharmaceutical Diagnostic Drugs: Nonclinical Study Recommendations (August 2018), a microdose is 1/100 of the dose needed for a drug to have a pharmacological effect, with a maximum dose of ≤100 micrograms (μg). The maximum dose for protein products is less than or equal to 30 nanomoles (nmol). Due to the low dose of the drug, radiodiagnostic drugs have a simpler but highly specific nonclinical development path.
Nonclinical Development for Microdose Radiopharmaceutical Drugs
Like other investigational new drugs, the pharmacological, pharmacokinetic, and toxicologic properties of radiopharmaceuticals need to be evaluated. Pharmacology studies typically include benchtop and animal studies (e.g., receptor/target/off-target profiling and imaging properties). While standard safety pharmacology studies are generally not required, this is product-specific. The pharmacokinetic (PK) behavior and absorption, distribution, metabolism, and excretion (ADME) properties should be characterized.
Additionally, potential drug interactions must be evaluated before exposing large numbers of human subjects to the investigational drug. In most cases, a Developmental and Reproductive Toxicity (DART) waiver is requested for these products due to the inherent radiation risk to the fetus.
Nonclinical Requirements for Therapeutic Use of Radiopharmaceuticals
Radiopharmaceuticals intended for use as a therapeutic treatment for cancer follow a somewhat simpler nonclinical development path compared to most new drugs. However, there are additional requirements for evaluating the pharmacological and toxicological effects of the ligand, as the amount of ligand administered is typically greater than that of a radiodiagnostic agent. If there is prior experience or publicly available information regarding the nonradioactive component(s) of the radiopharmaceutical, this can help reduce the nonclinical requirements, though this is not always the case.
Pharmacological studies for these therapeutics will focus on efficacy/proof of concept studies and target/off-target binding of the radioactive compound. This data, combined with PK, biodistribution, and dosimetry data in animals, can help generate estimates of human organ radiation absorbed doses.
Assessing Radiation Risks & Toxicity
When it comes to systemically administered radiopharmaceuticals, the radiation dose to each organ is determined primarily by the PK and biodistribution of the radiopharmaceutical agent and the type of radiation emitted. Consequently, the risk of radiation injury to an organ depends on the intrinsic radiosensitivity of the organ, the amount of radioactivity in that organ, and the amount in surrounding organs over time.
An assessment of late radiation toxicities is particularly important for patients with long life expectancies, as these effects could impact their quality of life. Toxicity studies in animals are acceptable when it is not ethical to perform testing in humans.
Simplified Nonclinical Development for Microdose Radiopharmaceutical Drugs
In summary, microdose radiopharmaceutical drugs are administered in very small, single, or infrequent doses (ranging from nanograms to micrograms) to target and image pathophysiological processes or tissues using imaging techniques like SPECT and PET. These drugs are primarily used for diagnosing various cancers and other diseases.
Due to their low doses, radiodiagnostic drugs follow a simplified nonclinical development path compared to traditional drugs. This includes evaluating pharmacological properties (e.g., receptor profiling, imaging), pharmacokinetics (PK), absorption, distribution, metabolism, excretion (ADME), and dosimetry. Standard safety pharmacology studies are often not required, and potential drug interactions must be assessed. A developmental and reproductive toxicity (DART) waiver is typically requested due to radiation risks to fetuses.
Radiopharmaceuticals intended for therapeutic use, such as for cancer treatment, require additional nonclinical testing before receiving FDA approval. Experienced toxicologists can assist Sponsors in understanding the necessary requirements to bring both diagnostic and therapeutic radiopharmaceutical products to the clinic and secure FDA approval. They can help design a streamlined and efficient nonclinical package that will be acceptable to FDA.
Partnering with Facet Life Sciences for Radiopharmaceutical Success
At Facet Life Sciences, we specialize in providing expert guidance throughout the nonclinical development of radiopharmaceutical drugs. With years of experience navigating the complexities of regulatory requirements, our team helps Sponsors streamline the development process, ensuring that your diagnostic and therapeutic radiopharmaceuticals move efficiently from concept to FDA approval.
Our comprehensive radiopharmaceutical services, including pharmacokinetics, dosimetry, and safety evaluations, are tailored to meet the specific needs of your drug development program. Whether you are developing new imaging agents or therapeutic radiopharmaceuticals for cancer treatment, we work alongside you to design robust, data-driven strategies. We help you confidently navigate the intricacies of nonclinical development, reduce time to market, and bring innovative treatments to patients faster. Let us support your journey with our scientific knowledge, regulatory expertise, and commitment to driving your success in the radiopharmaceutical space. Complete the contact form below to talk to a radiopharmaceutical expert at Facet today.
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