Pharmacokinetic Considerations for Topical Medications

Content updated on December 15, 2021

Topical medications are applied to the body’s surface (the skin or eyes) in order to achieve a desired local therapeutic effect. Since the skin is such a highly effective barrier, it makes the delivery of topical medications especially challenging. Topically applied medications often have different pharmacokinetic (PK) assessment requirements than orally or intravenously administered drugs. For topicals, many required studies are delayed until the final formulation is available, and the final formulation strength and dosing regimen have been established in safety and efficacy trials. However, early sampling for systemic exposure is advised to confirm assay sensitivity, safety cover, optimal dosing regimen, and optimal sampling. Many types of drugs fall under the umbrella of topical medications, including:

• lotions, creams, and ointments
• gels
• foams
• patches
• liquid drops
• and others

Drug Absorption Through the Skin Barrier

Drugs are typically applied to the skin when the skin is the desired site of action. In these cases, systemic absorption, where the drug penetrates beyond the layers of the epidermis to reach the bloodstream, is generally not desirable and can cause systemic safety concerns. Human skin is multilayered and acts as a barrier to harmful molecules and microbes. The main layer responsible for preventing skin penetration is the stratum corneum. Historically, it was believed that topically applied drugs had very little systemic absorption due to the barrier function of the skin. While this can be true, it cannot be assumed. Classic examples of topically applied drugs that readily absorb through the skin are corticosteroids, which may lead to blood concentrations that are high enough to cause systemic side effects, such as cortisol suppression. The ability of topically applied drugs to penetrate the various layers of the skin depends on a number of variables, including the physiochemical properties of the drug (e.g., hydrophobicity) and the condition of the skin (e.g., abraded, intact). The properties of drug formulation excipients can also markedly affect the ability of the active drug to penetrate the skin. Penetration enhancers, such as ethanol or propylene glycol, allow other molecules to diffuse more deeply into the underlying skin layers.

Benefits of Topical Medications

There can be benefits of using topically applied drugs over drugs that are administered by mouth or intravenously. Benefits of using topical medications can include:

• direct application to the affected area for dermatological conditions
• minimized absorption into the systemic circulation
• minimized side effects

Development Challenges for Topically Applied Drugs

There are many challenges drug developers encounter when developing topically applied drugs. Topical formulations must provide appropriate delivery levels to the site of action, have physical and chemical stability, and be aesthetically appealing without irritating the skin. A substantial change to a formulation during the drug development process will likely require studies to be repeated. As systemic exposure may be low following topical application, characterizing the PK profile will require a sensitive bioanalytical assay.

Regulatory Questions for Topical Drug Development

In the past 20 years, regulatory agencies have started requiring drug developers to answer two important questions from the FDA's guidance on maximal usage trials for topically applied drugs. Addressing these questions allows regulatory agencies to evaluate drug safety and helps inform appropriate labeling and clinical use recommendations, such as the need for further safety assessments, and considerations for dosing in special populations.

1. When the drug is applied to the skin, does it penetrate the skin barrier and result in quantifiable systemic exposure?
2. If yes, what is the extent of systemic exposure to the active ingredient?

Maximal Usage Trial Design for Topical Drugs

A common PK trial design for topically applied drugs is the Maximal Usage Trial (MUsT). MUsTs seek to maximize exposure to the drug in order to understand the full extent of systemic exposure and absorption at a clinically relevant dose, generally in the most severely affected subset of the intended patient population. These trials are important because this information may not otherwise be determined in Phase 2 or Phase 3 studies, where the majority of subjects use a moderate dose of the drug. The FDA issued a guidance for maximal usage trials for over the counter products; however, the principles outlined in this guidance are relevant for all topical products. Systemic exposure is evaluated using PK analysis which provides information about the rate and extent of absorption, distribution, and elimination from the body. This type of analysis also helps determine exposure estimates and key PK parameters such as:

• maximum blood or plasma concentration (Cmax)
• time of maximum concentration (Tmax)
• area under the concentration-time curve (AUC)
• elimination rate (half-life)

Unique Considerations in Dermal Maximal Usage Trials

• Frequency and Duration of Dosing: The frequency and duration of dosing should be designed to maximize the potential for drug absorption and should be done with the maximum proposed drug strength. Both frequency and duration should be consistent with the proposed labeling and anticipated use.  
• Body Surface Area: As a group, topical drugs can be used over a wide range of body surface areas (BSA), ranging from very small (e.g., single lesion) to very large (e.g., sunscreen covering > 90% of the skin surface). Because greater BSA coverage can lead to higher systemic absorption, the BSA tested in the MUsT should be based upon the anticipated clinical use of the drug.
• Bioanalytical Methods: Because of the importance of PK assessments for dosing recommendations and product labeling, validated and sensitive bioanalytical methods are essential for both the active ingredient(s) and key metabolites.
• Population pharmacokinetics (popPK): PopPK modeling may be employed to identify parameters and covariates such as age, disease severity, body surface area of application, and concomitant medications that may have a significant influence on the exposure. Additionally, healthy volunteer studies are rarely informative for PK, since the skin barrier may be very different than the intended patient population, resulting in a very different PK profile.

PK Parameters & Sampling Schedules in MUsTs

The overall goal of the MUsT is to obtain exposure parameters and make conclusions about the extent of systemic absorption. The blood sampling schedule should be designed such that key parameters like Cmax, Tmax, AUC0-last, AUC0-inf, and AUCtau (if the study design administers repeated doses) can be derived. However, topically applied drugs frequently have multiple (and slow) absorption phases and elimination is often limited by the absorption rate. These factors can complicate PK analysis. The study population may dictate sampling adjustments. For example, pediatric studies may necessitate reduced sampling schedules. In these cases, sampling schedules should be designed based on the expected concentration versus time profile of the drug. Finally, sampling following multiple dosing is generally required, although, if a condition improves with treatment, sampling should be collected when the skin barrier function is most relevant.

Other Considerations for Topical Drug Development

In addition to the physiochemical properties of the active drug and excipients, other factors external to the drug product itself can impact systemic exposure for topically applied medications including self-application, occlusion, and skin defects. 

Self-application

Subjects may assume that “more” product equates to faster healing, and topically applied drugs frequently have loose terminology for dosing (e.g., “pea-sized”). Subject training and observation may be required for MUsT studies in order to control variability in the quantity of drug being used.

Occlusion

The application site can impact how much drug is absorbed. Occlusion, or covering the drug once it has been applied, can enhance penetration and systemic exposure. Occlusion can be an intentional aspect of drug administration (e.g., an occlusive patch or using a bandage with an ointment) or can occur inadvertently by clothes, hair, or shoes. It is important to know if occlusion increases systemic absorption, as this can impact wording in the product label.

Skin Defects

The barrier function of the skin can be negatively impacted by skin abrasions/lesions, soaps and antiseptics, and removal of natural skin oils, which can lead to increased drug absorption. If skin barrier defects are likely during typical use of the drug, then it is important to account for this as part of the MUsT study design.   

Conclusions

PK studies are required for topical drugs, even when systemic exposure is believed to be negligible or nonquantifiable. The nature of topical drugs can make these studies more complex to design and analyze. When designing MUsT trials, consider the properties of the drug components and the anticipated use conditions. Clinical pharmacology input is essential to optimize MUsT study designs, optimize PK sampling, and to help assess potential safety risks based on systemic exposure. A well thought out and timely clinical pharmacology development plan is essential for any new topical drug product. Allucent has extensive experience in pharmaceutical dermatology drug development. Reach out to our team of experienced clinical pharmacologists and pharmacokineticists to discuss strategy, design, PK sampling schedules, noncompartmental PK analysis, and population PK for your topical medication.