Intrinsic and Extrinsic Factors in Drug Development

Personalized medicine (also known as precision medicine) is one of today’s biggest drug development buzzwords. It certainly stirs the imagination – the notion that one day we may live in a world where drug regimens are exquisitely tailored to an individual’s own biology. For some cancers, infectious diseases, and genetic diseases, we are already realizing this vision. For many other diseases, attaining the goals of personalized medicine could be years into the future. At the core of personalized medicine is the fundamental realization that not all drugs work at the same dose for everyone. But why? In this post, we will explore intrinsic and extrinsic factors, which are characteristics that can dramatically affect how our bodies process the drugs we take, how well we respond to therapy, and whether we will have side effects.

Intrinsic Factors

Intrinsic factors include the genetic, physiological, and pathological characteristics of an individual; in other words, these are traits that are “intrinsic” to a person rather than being determined by that person’s environment. Intrinsic factors are central to the growing fields of pharmacogenetics, pharmacogenomics, and personalized medicine. Genetic intrinsic factors are hard coded into a person’s DNA and include biological sex, race, and ethnicity. Genetic polymorphisms (i.e., differences in DNA sequences between individuals) are also included in this group and can be a critical consideration for certain diseases and drug types. In addition, there can be genetic differences in the diseases themselves (e.g., tumors, infections) that may require distinct treatments. In contrast to genetic intrinsic factors, physiological and pathological intrinsic factors are not dictated by DNA but are still individual-level characteristics leading to differences in drug response that are not environmentally driven. These factors include a person’s age, organ function (e.g., liver, kidney, cardiovascular), and co-morbid diseases. Finally, intrinsic factors also include characteristics that can be influenced by both genetics and a person’s physiology/pathology, such as height, body weight, and receptor sensitivity.

Extrinsic Factors

While intrinsic factors act from within an individual, extrinsic factors wield their influence from the outside (i.e., they are environmental, cultural, or related to lifestyle). Extrinsic factors can have a sizeable impact on a person’s health and can affect medical decision-making. Extrinsic factors as a category can be rather broad, although drug developers tend to be most concerned with a subset that includes diet, concomitant medication use, and smoking habits. The interaction between food and drugs is a key concern for some types of medications, as some foods can alter the pharmacokinetics (PK) of certain drugs in a way that can affect patient safety and/or drug effectiveness. Grapefruit juice is a well-known example of a food that can affect drug PK. In addition, because patients often suffer from more than one disease, they may be taking concomitant medications to treat multiple diseases. This is important because of potential drug-drug interactions, including impacts on drug exposure, safety, and effectiveness. This not only applies to prescription drugs, but also if a patient is taking an over-the-counter (OTC) drug (e.g., taking an antihistamine for a cold could inhibit drug metabolism). Smoking can sometimes affect the PK and/or pharmacodynamics (PD) of drugs. For example, some compounds in tobacco smoke are potent inducers of drug metabolizing enzymes and can therefore increase the metabolism of certain drugs (including caffeine). Smoking can also affect how well drugs work and can increase safety risks.

Predicting a Drug’s Sensitivity to Intrinsic and Extrinsic Factors

Intrinsic and extrinsic factors can have marked effects on safety and/or efficacy for particular drugs and diseases, while others remain largely unaffected. So, is there a way to predict whether your drug is likely to be affected? The International Council for Harmonisation (ICH) E5 guidelines summarize a number of properties that make a drug more likely to be sensitive to the influence of intrinsic and extrinsic factors. These include drugs that exhibit:

• Nonlinear PK
• Steep PD curve (efficacy and safety)
• Narrow therapeutic range
• High metabolism, especially via a single pathway
• Metabolism by enzymes with known genetic polymorphisms
• Administration as a prodrug
• High inter-subject variation in bioavailability
• Low bioavailability
• High likelihood for use with multiple concomitant medications

Pharmacokinetic, Pharmacodynamic, and Exposure-Response Considerations

The most palpable information for any drug is how the patient responds to treatment. This includes both the desirable and undesirable effects that a drug may cause. How patients respond to various drug doses is captured in the PK and the exposure-response relationship for a specific drug. Exposure-response examines the relationship between drug dose/concentration and response, which includes safety and efficacy endpoints. For most drugs, there is marked inter-individual variability in drug exposure following drug administration that can be related to intrinsic and extrinsic factors. This includes not only variability in the maximum concentrations observed (i.e., Cmax), but also the exposure to the drug over time (i.e., the area under the concentration versus time curve or AUC). This means that when the same dosing regimen is given to numerous people within the population, some may have low concentrations and be less likely to respond while others may have high concentrations and may be more likely to have an adverse event. As with PK, relationships between concentrations in the blood and PD response (i.e., the physiological changes caused by the drug) can vary from one individual (or population) to the next. PD effects are commonly impacted by both intrinsic and extrinsic factors. Thus, even if the concentrations are similar in a group of patients, the safety and efficacy may differ due to differences in the patients’ receptors or in interactions between drugs at the receptor. Because differences in drug exposure and response can have serious implications for drug safety and effectiveness, it is important to understand the sources of PK/PD variability and to consider this information when making dosing recommendations. Population PK and PK/PD modeling and simulation are among the most widely accepted and effective methods for understanding this variability and what it means for clinical practice. These activities should begin before Phase 1 and continue to be updated throughout drug development. During early drug development, inclusion/exclusion criteria are more strict, whereas during Phase 3, the inclusion/exclusion criteria tend to be looser. This loosening tends to increase inter-subject variability and provides a rich dataset where the effects of intrinsic and extrinsic factors on the drug’s PK and exposure-response relationship can be evaluated. This information can help drug developers understand whether the dose will be appropriate in different patient subpopulations.

Study Design Considerations

As drug development programs become more global, careful consideration must be given to variability in drug exposure and response resulting from intrinsic and extrinsic ethnic factors. This is true whether a Sponsor is planning multiregional clinical trials (MRCT) or whether they wish to submit for marketing approval in multiple countries or in a single country where there is significant ethnic heterogeneity (e.g., U.S.). Key clinical study design considerations include the following goals:

• Recruiting representative study populations and ensuring sufficient sample size (overall and by subgroup) to allow evaluation of overall treatment effect
• Ensuring adequate PK comparisons between subpopulations known to be associated with PK differences
• Collecting genetic data to examine effects of genetic factors on PK/PD
• Ensuring a sufficiently broad dose range in dose-response studies
• Ensuring that there remains an adequate safety margin, that all dose adjustments are scientifically justified in the study protocol, and that the dose rationale is prospectively planned when dose adjustments are necessary to produce similar therapeutic effects across groups
• Engaging in advance consultations with regulatory authorities about dose-selection strategies, study endpoints, and planned statistical analyses

Conclusions

Not all people respond to the same drug at the same dose with the same efficacy and tolerability. Intrinsic and extrinsic factors lie at the root of inter-individual and population level variability and can have marked effects on PK, PD, and the exposure-response relationship. Because of this variability, careful consideration should be given to the potential impact of intrinsic and extrinsic factors, especially when the properties of the drug make these impacts more likely. For certain subpopulations, it may be necessary to make dosage adjustments or even consider alternative therapies to ensure patient safety and an adequate therapeutic response. Allucent has many years of experience helping our clients generate effective drug development strategies across a wide variety of drugs and therapeutic areas. Allucent leverages this experience and the deep subject matter expertise of our consultants to provide our clients with advice that is specifically tailored to the needs of each development program. This expertise includes population PK, PK/PD, modeling and simulation, study design, regulatory affairs, and many others. Contact us today to learn how Allucent can help you understand the effects of intrinsic and extrinsic factors on your product, as well as implications for ongoing development and regulatory approval.

Key References and Further Reading

1. ICH Harmonised Tripartite Guideline. Dose-Response Information to Support Drug Registration E4. 1994.
2. ICH Harmonised Tripartite Guideline. Ethnic Factors in the Acceptability of Foreign Clinical Data E5(R1). 1998.
3. FDA Guidance for Industry. E5 – Ethnic Factors in the Acceptability of Foreign Clinical Data – Questions and Answers. 2006.
4. FDA Guidance for Industry and FDA Staff. Collection of Race and Ethnicity Data in Clinical Trials Guidance for Industry and Food and Drug Administration Staff. 2016.
5. ICH Harmonised Guideline. General Principles for Planning and Design of Multiregional Clinical Trials. 2017.