So, in a previous post I spoke about systemic pharmacokinetics (PK) and you might be wondering how in the world cutaneous PK might be different. Well, it is and it isn’t – confusing right?. Systemic PK has been investigated and studied well over 100 years. Hypotheses have been tried and validated to develop the concepts on which the industry operates today. Of course, there will always be exceptions to a rules of thumb, which intrinsically provide additional research areas.
In the grand scheme of things, pharmacokinetics will always be the study of drugs in motion. However, cutaneous PK is a niche subdomain and has not been thoroughly investigated/characterized. (For a detailed description of the skin see this post)
Why?” or “So what?” you might ask. To answer the why, we need to briefly understand that the limitations in the sampling methodologies have significantly hindered this investigation. Plasma concentrations have been used to inform the processes occurring within cutaneous PK. Is this the proper way to evaluate cutaneous PK? For the industry – yes. In my opinion – not really. The advances in analytical capabilities have opened the door for in vivo cutaneous PK monitoring with the likes of microdialysis and open flow microperfusion (post to come about these methodologies, among others). Before we dive into how we can monitor/measure cutaneous PK, we must understand what ultimately impacts the observed concentration-time profiles. The overall PK concepts of absorption, distribution, metabolism, and elimination all hold true in cutaneous PK but need to be thought about more closely on which concepts can be applied. Let’s take a deep dive into cutaneous ADME.
Absorption
If we start at the top and examine what goes into the absorption (or permeation) of an API after topical or transdermal application, we will see that this is a very complex process. Let’s recall the absorption of a simple tablet with a non-acid-labile API. The tablet is ingested and then begins to disintegrate in the stomach. The API is liberated from excipients and is available in solution to be absorbed once the stomach empties into the duodenum.
The API must escape the formulation and penetrate the stratum corneum for topical delivery, which is the rate-limiting step for API absorption. As the API penetrates the SC and permeates deeper into the skin, it might be conceivable that depots form in the upper layers that provide an extended-release to the layers below. We can understand the absorption delivery kinetics very simply with tape stripping (Hoppel et al). How formulations are designed is a balance of solubilized API within the formulation and an API’s affinity for the stratum corneum. Without a greater affinity for the SC, the API will prefer to stay in the formulation rather than penetration the SC; this severally limits the amount of API that may be absorbed into the skin, which is already between 10-30% depending on the commercial formulation. Once the API has penetrated the SC, the API then permeates deeper into the skin based upon a concentration gradient.
The formulation plays a vital role in the absorption of the API as with systemic drug delivery; however, the question remains – does it affect the distribution, metabolism, or elimination of the API once inside the skin.
Distribution
The volume of distribution is not an actual volume per se but rather a proportionality constant between the amount of drug in the body and the drug concentration within the plasma. The volume of distribution within the skin is affected by similar factors in systemic drug delivery – protein binding, charge at physiological pH, log p, and pKa. Considering the concepts from systemic drug delivery, if the volume of distribution is larger than 42L (the amount of blood in the body), the drug is said to be highly distributed and resides in the tissues as opposed to the plasma (i.e., the volume of distribution is less than 4L).
Something interesting is how the volume of distribution from systemic drug delivery compares to that after topical drug delivery. Of course, we know that the volume of the skin and the body are very different. Suppose the systemic volume of distribution is used in the modeling of cutaneous PK data. In that case, there may be a vast under/over prediction of concentration and clearance (considering the elimination rate constant is the same). In a rapid comparison, I would like to bring your attention to the volume of distribution of systemic administered Metronidazole (0.5-1.1 L/kg) and the recently estimated volume of distribution within the skin (0.12 mL) which has not been adjusted for the area. Even after adjusting for the skin area (0.068 cm2), the volume of distribution is still only 1.76 mL/cm2. In comparison, an adjustment for the total body surface area of a 150 lb person estimates the volume of distribution to be 7.48 mL/cm2.
Overall, the drug’s distribution is related to the protein binding and enzymatic activity, both of which are relatively unknown when it comes to cutaneous pharmacokinetics. Therefore, these parameters will help us model the data further and adequately understand how the formulation may affect the distribution of a drug.
Metabolism
The liver is the main metabolizing organ in the body, yet there also have been suggestions that APIs can be metabolism within the skin after topical/transdermal drug product application. However, this is a relatively under-investigated area of research in the realm of bioavailability and bioequivalence. Of course, some pro-drugs are applied in transdermal API delivery, but most, if not all, are metabolized after systemic circulation.
Several studies have quantified cutaneous metabolism either in the plasma as the concentrations were above the LLOQ or in bulk at a specific time point through tape stripping. This would also be possible with other methodologies such as IVPT (depending on the “freshness” of the skin), dMD/dOFM, Raman technologies.
It would be helpful to understand the local metabolism time-course of a parent API to gain insight into how these metabolites might contribute to the efficacy of a drug product. Further, if the expression of these metabolic enzymes changes with disease state, and the metabolite contributes to the product’s efficacy, this would undoubtedly be an area of research that would improve the community’s knowledge toward topical drug product development.
Elimination
In systemic drug delivery, it is a reasonably straightforward task to estimate the plasma elimination; however, this is quite the opposite in topical drug delivery. One may postulate that the elimination can be calculated from the plasma clearance after topical administration (if the concentration is above the LC-MS/MS assay’s LLOQ) by simply estimating the terminal phase from the concentration-time profile. While this might be a valid approach, the assumption that the clearance in the plasma is the same as the cutaneous clearance might lead to significant over/under prediction of the concentration-time profiles.
One way to estimate the dermal clearance is to directly deliver the API into the dermis via a microdialysis probe (dermal infusion). Using this novel approach, we were able to estimate the dermal disposition function of metronidazole, and this has the potential to apply to other APIs. A fundamental PK principle is that the concentration-time profile results from an absorption function and disposition function. If you can estimate the disposition function (distribution and elimination), then one needs to optimize the release rate (absorption function) to develop a formulation utilizing a quality by design approach. This can be done with a caveat that inactive ingredients do not alter the API’s disposition.
Takeaways
There are PK principles that can be transferred from systemic PK to cutaneous PK without further investigation. However, many of the assumptions that we make as a community are just that – assumptions. This might lead to unexpected concentration levels within the target site or lack thereof. While the absorption component of the concentration-time profiles has been thoroughly investigated via IVRT/IVPT, there ought to be an investigation into the second component of concentration-time profiles – the disposition function.
This was only a tiny glimpse into the processes that occur once a drug product is applied. Subsequent blog posts will look at specific instances that affect the permeation process and evaluate different aspects of the permeation process in vivo.
TL;DR
We, as a community, have made significant progress in cutaneous pharmacokinetics but there are still many unknowns that ultimately affect the permeation, biodistribution and localization of drug.
Pharmacokinetics with Ben Kuzma 