What is it?
It is unavoidable for patients to have no other substances in their body when being administered a treatment. Whether it is a daily vitamin, over the counter drug, prescribed medication or even the food patients eat daily, it is important to understand if and how administered drugs interact with these substances. Drug-drug interactions, DDIs, refer to the interactions of co-administered drugs that result in one having an altered uptake, metabolism or ultimately the resulting outcome. These interactions have the potential to impact the pharmacokinetics and pharmacology of the altered drug.
Current study results indicate that the conjugation of antisense or siRNA oligos can lead to higher levels in cells. This is due to the conjugated drug being highly soluble and negatively charged, leading them to exhibit a higher uptake into hepatocytes and being unable to passively cross plasma membranes. This results in a lower likelihood of binding to proteins and inducing or inhibiting CYP450 enzymes or drug transporters. However, if there is no historical data or not enough current data to fully understand the expected outcome patterns of potential interactions, siRNA drugs are treated like small molecules, and further DDI studies are necessary. These additional studies not only provide more data for these novel therapeutics, but ultimately also ensure patient safety, and confirm drug efficacy resulting from any unexpected interactions.
Why are they important?
As mentioned, understanding if and how siRNA drugs interact with other drugs is especially important regarding both patient safety and the efficacy of the therapeutic. Although it is unlikely, any drug-drug interaction will any cause major changes in outcomes, the possibility must be addressed. The likelihood of interactions depends on the properties of both the drug and the secondary substance the patient has taken prior to treatment.
Drug-drug interactions can affect the absorption, distribution, metabolism, or elimination of other drugs, unexpectedly changing their levels in the body. These interactions can lead to various outcomes, enhanced effects of the drug(s), potentially leading to overdose or toxicity; reduced effects effectiveness, leading to inadequate treatment; unexpected side effects, which may be severe or life-threatening. This adds an additional layer of complexity to obtaining approval from the regulatory agencies.
Other important points
Ensuring that drugs are safe when used together is essential to avoid harm to patients. Knowledge of potential interactions helps in designing treatment regimens that minimize risks. Healthcare providers need to be aware of potential interactions when prescribing multiple medications to a patient, especially those with complex medical conditions. Understanding DDIs helps them make informed decisions about drug choices and dosages.
Interactions can impact the effectiveness of a drug. Understanding these interactions can lead to the development of more effective treatment strategies. Often, drug interactions can lead to the discovery of new therapeutic uses for existing drugs. Sometimes, the interactions between two drugs can be harnessed for beneficial effects.
Assessment of DDIs:
To assess potential drug interactions, researchers and pharmaceutical companies conduct comprehensive studies during drug development. These studies involve in vitro (laboratory-based) testing, animal studies, and clinical trials. Additionally, post-market surveillance helps identify previously unrecognized interactions that may emerge when a drug is used by a broader population.
Who decides what DDI studies are required? Regulatory agencies, like the U.S. Food and Drug Administration (FDA) require drug developers to thoroughly assess potential drug interactions during the drug approval process. Failing to identify and address significant interactions can result in the rejection of a new drug. Down the road, information about drug interactions is included in drug labels to guide healthcare professionals and patients which helps prevent adverse events and improve patient care.
How are DDIs detected and measured?
To assess potential drug interactions, researchers and pharmaceutical companies conduct comprehensive studies during drug development. These studies involve in vitro (laboratory-based) testing, animal studies, and clinical trials. Additionally, pharmacokinetic modeling and post-market surveillance helps identify previously unrecognized interactions that may emerge when a drug is used by a broader population.
In vitro metabolism studies include:
- Cytochrome P450 (CYP) enzyme inhibition or induction studies, which assess whether the drug candidate inhibitor induces specific CYP enzymes responsible for metabolizing other drugs.
- Transport inhibition studies, which investigate whether the drug interacts with drug transporters to affect the absorption and distribution of other drugs or its own interactions with other drugs.
Pharmacokinetic studies include:
- Preclinical animal studies can provide insights into potential DDIs, especially when investigating drugs metabolized or transported similarly to humans.
- Clinical drug-drug Interaction trials which involve administering the drug to healthy volunteers in combination with a known interacting drug. Researchers monitor pharmacokinetic parameters, like drug levels in the blood, to assess the impact of the interaction.
- Pharmacokinetic modeling using mathematical models based on the drug’s physicochemical properties, metabolism, and known interactions with enzymes and transporters to predict which drug interactions might occur in different patient populations.
The U.S. FDA provides guidance on how to design and conduct DDI studies during drug development to ensure patient safety. The goal of these assays and studies is to identify and understand potential DDIs so that appropriate precautions can be taken to minimize risks when the drug is used in clinical practice.
In summary, understanding drug-drug interactions is critical in drug development and clinical practice to ensure patient safety, maximize therapeutic benefits, and comply with regulatory requirements. It’s essential to consider potential interactions when prescribing or administering multiple medications simultaneously.