Inside The Altascientist: Understanding Drug Interaction Factors for Safer, More Effective Therapies

Intrinsic factors such as age, biological sex, comorbidities, or genetics can potentially alter drug exposure, as can extrinsic factors such as concomitant drugs, supplements, the environment, and food and beverages.

One of the most important factors to consider during the course of your early-phase clinical research is drug-drug interactions (DDIs), which occurs when one drug alters the effect of another, either by reducing its effectiveness or elevating systemic concentrations to potentially dangerous levels—ultimately causing side effects. In some cases, these side effects could be life-threatening, such as drops in blood pressure, irregular heartbeats, or organ damage.

In Issue 7 of The Altascientist, we delve into these factors, the importance of drug interaction studies, and how to limit adverse effects and maximize treatment response. Listen to the audiobook or download the PDF below, to learn more about:

• key factors to consider in drug development (age, biological sex, genetics, DDIs);
• examples of common DDI involving the cytochrome P450 enzyme system; and
• drug interactions and guidance for marketed drugs.

The issue also features a drug-drug interaction case study, in which the effects of two doses of a sponsor’s investigational product on the pharmacokinetics of multiple oral doses of clopidogrel, and a single dose of warfarin in healthy adult subjects were evaluated.

Identifying Drug-Drug Interactions (DDIs)

The increasing number of drugs on the market has led to a greater potential for drug-drug interactions, and more complex drug regimens with multiple compounds administered to treat one condition or different compounds given to treat comorbidities, are also contributing factors. These interactions must be identified during the development process as part of the assessment of the drug’s risks and benefits.

According to the FDA’s 2024 guidance titled M12 Drug Interaction Studies, clinically significant DDIs between investigational and other drugs should be addressed at various stages of drug development. They should also be thoroughly understood through nonclinical and clinical studies by the time the drug is approved, monitored after approval, and clearly communicated in the drug's labeling to ensure proper management strategies for clinically significant DDIs and safety.

“The potential for an investigational drug to cause DDIs should be investigated in a stepwise manner during drug development. The potential for an investigational drug to cause pharmacokinetic interactions both as an object (effect of other drugs on the investigational drug) and as a precipitant (effect of the investigational drug on concomitant drugs) should be evaluated.” 

-  The FDA, 2024 FDA guidance M12 Drug Interaction Studies, pg. 3 of The Altascientist Issue 7
 

Genetic Variations and Other Intrinsic Factors in Drug Interaction Studies

Genetic variations in drug exposure result from different alleles of enzymes that metabolize or transport drugs, particularly in the cytochrome P450 (CYP) group. Six key enzymes, including CYP3A4 and CYP2D6, metabolize 90% of drugs, with genetic polymorphisms causing significant variability in drug response among individuals and across ethnic groups.

In recent years, pharmacogenetics research has shown significant differences in the pharmacokinetics among Caucasians, African Americans, Hispanics, and Asians, or at individual levels by stratifying groups based on genetic analysis. This has prompted regulatory agencies to encourage clinical trials that include diverse ethnic groups to better predict drug efficacy, and dosage adjustments based on genetic factors.

“Clinical pharmacokinetic data can help determine if the target drug may need to be substituted, or a dose adjustment required, to account for the potential decrease or increase in metabolism.” 

–  The  Altascientist, Issue 7, pg. 2

Age is one intrinsic factor in drug development. It can present physiological changes in renal and/or hepatic function, as well as nutritional deficiencies that may result in pharmacokinetic alterations that alter the bioavailability of drugs. Per the FDA’s recommendation, drugs should be studied in all age groups, including the elderly.  

Other intrinsic factors in drug development, such as biological differences between male and female metabolisms, can significantly impact drug absorption rates, and several regulations require the inclusion of both sexes throughout all phases of clinical trials, with sex-based differences. In addition, lipid distribution and renal blood flow both have the potential to greatly modify the rate of absorption. 
 

Partnering With Altasciences for Your Drug-Drug Interaction Studies

For decades, Altasciences has designed, conducted, analyzed, and reported on thousands of studies exploring the effects of intrinsic and extrinsic factors in healthy normal volunteers, special populations, and patients. From the simplest to the most complex study designs, we have clinical experience with all common substrates.

“Our highly experienced scientific and clinical teams are exceptionally well versed in the conduct of a wide range of DDI trials. The delivery of high-quality data on time and as promised is a particular strength for Altasciences.” 

– Ingrid Holmes, Vice President, Global Clinical Operations

With a database of over 400,000 participants and access to over 2,600 genotyped volunteers, we can rapidly recruit and enroll participants for your DDI studies. Our turnkey solution for DDI studies includes protocol review and writing, clinical conduct, CRA/clinical monitoring, bioanalytical services, data services and reporting, and regulatory consulting. 
 

What is The Altascientist?

The Altascientist is a scientific journal written by the scientific and research experts at Altasciences. In each issue, they share their decades of knowledge to help sponsors along their early-phase drug development journeys, as well as explore the latest challenges and innovations in the industry.  

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