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Gene Therapy and Pharmacokinetics

How and When to Incorporate PK Design into Your Gene Therapy Development Plan

Gene therapy, which was in its infancy around 30 years ago, is fast gaining prominence in many therapeutic areas, from personalized therapy to mass vaccinations against COVID-19. When developing a clinical development program for these increasingly popular therapies, it is important that sponsors use modeling and pharmacokinetic (PK) analysis to evaluate parameters that can be measured while dosing with gene therapy drugs to characterize exposure-response data and inform rational dosing.

Gene therapy definition

Gene therapy is a therapeutic approach in which genes are used to treat or prevent diseases. It is a comprehensive term that encompasses a large variety of therapy products including viral and bacterial vectors, plasmid DNA, human gene editing technology, and patient-specific cellular gene therapy.

The technology of gene therapy is possible due to extensive DNA research and our resulting understanding of many diseases on the genetic level, and it encompasses several mechanisms such as introducing new genes (gene addition) and inactivating or replacing mutated genes (gene editing). Viruses and bacteria can first be modified to prevent them from causing infectious diseases and then implemented into human tissues as therapeutic gene vectors. Similarly, DNA molecules can be genetically modified and introduced into human cells, or individual patient cells can be genetically modified and reintroduced to the body. Additionally, gene editing allows us either to remove or modify harmful genes.

Research and development in this area is growing quickly, and the National Institute of Health reports hundreds of clinical trials to test gene therapies for genetic diseases, immune system disorders, oncology treatments, neurogenerative diseases, infectious diseases, and more. While most gene therapy clinical studies are ongoing, a number of products are in advanced clinical development, and several are approved by the FDA.

PK planning for gene therapy development programs

As with any standard drug treatment, gene therapies carry potential risks, including adverse events, unexpected gene modification (activation or inactivation), undesired immune responses, and complications with the genetic material. Therefore, when planning a new treatment based on a gene therapy, whatever the type, it is important to evaluate the PK of the drug to match it to the efficacious dose and provide input into its safety and efficacy.

Formulation considerations

PK assessments must be planned not only for genetic material such as adenoviral vectors, mRNA, or DNA plasmid, but also for the formulation components that ensure proper delivery of the drug. For example, cationic lipids that are a part of the delivery system for mRNA and oligonucleotides exhibit a separate distribution and elimination pattern from the nucleic acid they deliver, and they sometimes have a longer and higher exposure that lasts long after nucleic acid is gone. Knowledge of their disposition also helps in understanding the cells where the genetic material was delivered.

Route of administration considerations

Administration routes for gene therapies can differ depending on the indication target’s delivery needs. For example, it is beneficial to administer RNA treatments for some lung diseases directly to the disease site through inhalation. In this case, wherein the drug is not measured in blood but in the sputum samples, systemic exposure may be low, and PK takes on another meaning as it links the samples’ concentrations to the action at the target site and tries to predict the efficacious dose.

Adenoviral vectors have become a popular choice for delivering gene therapies in patients expressing defective genes such as in sickle cell anemia, cystic fibrosis, and many other fatal or debilitating conditions. However, dose selection in such cases is quite complicated and frequently limited to one attempt. Many patients with such genetic disorders are children without a proper adult model in whom to test the drug first, due to safety and a lack of patients. Thus, in addition to all other efficacy and dose considerations in gene therapy, modeling often must include factors associated with the maturation of children. Proper modeling also can allow for efficient PK sampling, accounting for multiple analytes and biomarkers along with the need to reduce the number of needle sticks and the amount of blood drawn, especially in pediatric patients.

Gene expression considerations

Genetic material, when embedded in cells for long-term functioning, can be tested if a target-tissue biopsy is possible. However, characterizing PK for such therapies involves not only the initial genetic material, but also products of gene expression without the inherent original mutation being treated, such as proteins. Successful treatments can mean that this expression lasts for years, so it needs to be tested to help future patients with this and similar conditions. An immune response to the expressed perfect — but not native — protein can arise. It should then be estimated over the course of a patient’s life to treat any safety concerns and to inform future drug development.

Exposure-response considerations

The relationship between exposure to a therapy and the duration of response informs the dosing regimen in the loading and maintenance phase and can be tailored to specific diseases. When silencing RNA (siRNA) is used to treat a disease or its symptoms, for example, the patient sometimes requires frequent dosing because the genetic material is eliminated relatively quickly. It is possible, however, that treatment with siRNA for infectious diseases such as hepatitis B can lead to a full recovery. In such cases, treatment can be stopped, and available exposure-response data analyzed to inform the future application of siRNA in new patients.

Regulatory considerations

In 2020 the FDA issued a guidance document for long-term follow-up on genetic therapies. It requires that long-term plans for monitoring patients who receive gene therapies be included in study protocols for specific cases described by a decision tree in the guidance. Modeling and PK analysis can aid the planning for these protocols as well.

As these examples demonstrate, for the dosing of nontraditional drugs like gene therapies, a pharmacometric approach is very useful and frequently necessary. Premier Consulting can help you use measured PK of genetic materials and PD responses to optimize dose selection and justification based on modeling and simulation. Depending on the type of gene therapy, the patient population, and the clinical endpoints, we can perform comprehensive modeling and use PK assessments to inform your drug development for more efficacious use with less effort and lower costs. Contact us to find out how.


Agnieszka Marcinowicz, PhD
Manager, Pharmacokinetics