• Clinical and Environmental Harmonization to Enhance Absorptive Predictability from Complex Dermal Products: In Vitro Permeation Testing to Healthy Volunteers

      Zambrana, Paige Nicole; Stinchcomb, Audra L.; 0000-0002-4924-0107 (2021)
      Accurate establishment of in vitro-in vivo correlation (IVIVC) models for the bioavailability prediction of complex dermal products has been a challenge, leading to the use of multiple costly clinical studies for marketing approval. Although environmental conditions are highly controlled during in vitro permeation testing (IVPT), formulations such as lotions, gels, sprays and foams have historically generated variable absorptive profiles in vivo, making IVIVC mathematical modeling difficult. With no occlusive backing, dermal formulations undergo metamorphosis dependent upon environmental conditions, which are not typically precisely controlled during clinical testing. Since there are a wide range of formulations available on the market, sunscreens were selected as model products for translational evaluation. The goal of the present study was to examine multiple environmental and clinical factors in vitro that can alter absorption of the UV filter oxybenzone, and subsequently translate critical product testing conditions to a harmonized clinical protocol. Data from validated IVPT studies showed that temperature, dose and formulation were able to significantly alter the absorptive profile of oxybenzone. Therefore, a clinical study was designed utilizing four common dermal formulation types under un-occluded optimal dosing conditions with precise control of temperature and humidity during each procedure day. This human study data was then compared to prior sunscreen studies conducted by the US Food and Drug Administration (FDA), which did not include environmental controls during clinical assessment. The comparison showed that increased precision and harmonization between in vitro and in vivo methods for oxybenzone bioavailability assessment resulted in a decrease in variability associated with in vivo dermal product testing. Additionally, accurate IVIVC models for each formulation type tested were able to be generated. Models for in vivo exposure estimation of oxybenzone absorption from lotion, cream, solid stick and continuous spray sunscreen formulations were efficiently attained in a small number of healthy human volunteers with minimal dosage area required for predictable calculations of full body systemic exposure. This project lays the groundwork for effective pharmacokinetic (PK) safety and efficacy testing of other active pharmaceutical ingredients (API) absorbed from prescription and over-the-counter (OTC) complex dermal products.
    • Effect of Transient Heat Exposure on Drug Delivery from Transdermal and Topical Products

      Thomas, Sherin; Stinchcomb, Audra L. (2020)
      Heating pads and electric blankets are widely used for relief from pain and to provide warmth, respectively. Their unintentional application simultaneously with a transdermal or topical system can result in unexpected drug levels in systemic circulation. Designing well-characterized in vitro and in vivo methods are vital to understanding the effect of heat and hence can aid in the development and evaluation of these products. The objective of this work was to evaluate the effect of heat on products with the same active pharmaceutical ingredient (API) but different inactive ingredients. Four drug molecules with different physicochemical properties were chosen. For each drug, formulations with different excipients were selected. In vivo serum drug profile and in vitro flux profile data can provide mechanistic understanding of heat effect on these formulations. Four topical diclofenac formulations were evaluated for heat effect in vitro under continuous heat exposure. Their flux profiles demonstrated the influence of formulation design and excipients on drug permeation at elevated skin temperature. Serum profiles of two different oxybutynin formulations evaluated under heat exposure showed very different magnitude of enhancement in serum levels under similar heat exposure conditions. Another objective of this work was establishing an in vitro - in vivo correlation (IVIVC) of heat effect on topical and transdermal formulations. This will help in characterizing and predicting heat effect minimizing the need of clinical trials and support the regulatory evaluation of these dosage forms. For buprenorphine patch, study design for in vitro permeation testing (IVPT) using human skin was well characterized to align with and mimic in vivo conditions of heat exposure. Level A and Level C IVIVC were established under normal as well as elevated temperature conditions. For lidocaine patches, IVIVC was observed for early heat effect. However, poor correlation was observed for late heat effect. The findings from this work determined IVPT studies can correlate with and be predictive of in vivo results under normal temperature conditions. But under suboptimal conditions like heat exposure, IVPT may have limitations and should be used in addition to other methods to evaluate heat effect.
    • Evaluation of In Vitro-In Vivo Correlations in Topical and Transdermal Drug Delivery Systems by In Vitro Permeation Testing and Pharmacokinetic Studies for Bioavailability/Bioequivalence and Heat Effect Assessment

      Zhang, Qingzhao; Stinchcomb, Audra L.; 0000-0003-4061-0690 (2022)
      In vitro-in vivo correlation (IVIVC) has gained great attention in the biopharmaceutical field because of its potential ability to predict drug performance in vivo, eliminating costly and time-consuming clinical trials. However, the regulatory guidance on IVIVC has only been established for extended-release oral dosage forms, and not for topical and transdermal formulations. An in vitro model is necessary to establish IVIVC. The present work showed that the in vitro permeation test (IVPT) using excised human skin can quantify and distinguish bioavailability (BA)/bioequivalence (BE) between a brand-name topical metronidazole gel, a bioequivalent generic gel, and a non-bioequivalent generic cream. A harmonized pharmacokinetic (PK) study in healthy human subjects was conducted to evaluate IVIVC. The scaled average bioequivalence approach was used to establish BE between the gels and distinguish the cream from the gels. The metronidazole PK study didn’t provide reproducible serum levels; therefore, IVIVC’s predictability was weak. The present work also showed IVPT’s ability to predict BA for two rivastigmine TDS under transient heat exposure. A harmonized PK study was conducted. A Level C and a Level A IVIVC were established under baseline temperature (32.0°C). IVPT demonstrated significantly increased maximum flux for both TDS with a comparable fold enhancement. However, the PK study didn’t demonstrate a consistent heat effect on maximum serum concentrations of rivastigmine under elevated temperature (42.0 °C). The IVIVC’s predictability for the heat effect was therefore weak. Encouragingly, findings suggested that IVPT is useful in assessing BE for topical drug products. For hydrophilic drugs, such as metronidazole, it is possible that IVPT may have limited predictability in vivo if significant absorption of the drug occurs via the shunt route, and/or if significant reproducible systemic absorption can’t be quantified from dosing the semisolid over a large surface area. In conclusion, IVPT was able to quantify the magnitude of heat effect on the absorption from rivastigmine TDS, and data also suggested that under baseline temperature, IVPT will likely show good predictability of TDS performance in vivo. However, experimental conditions should be further altered to validate IVPT’s usefulness in the prediction of TDS BA in vivo under the heat exposure.
    • Evaluation of In Vitro/In Vivo Correlations for Transdermal Delivery Systems by In Vitro Permeation Testing and Human Pharmacokinetic Studies, With and Without a Transient Heat Application

      Shin, Soo Hyeon; Stinchcomb, Audra L.; Hassan, Hazem; 0000-0001-5091-8870 (2018)
      An in vitro model that exhibits in vitro/in vivo correlations (IVIVC) is a powerful tool in biopharmaceutical drug development because it can efficiently predict drug product performance in vivo. While the concept of IVIVC has been utilized mostly for oral dosage forms, demonstrations of IVIVC with in vitro permeation testing (IVPT) for transdermal delivery systems (TDS) are emerging. The objective of this work was to evaluate IVIVC for TDS using two model drugs, nicotine and fentanyl, with different physicochemical characteristics (e.g. log P). Additionally, the effect of heat exposure (42 ± 2 °C) on the rate and extent of TDS drug delivery was evaluated. IVPT studies using excised human skin and in vivo pharmacokinetic (PK) studies in human subjects were conducted under harmonized study conditions and designs to evaluate IVIVC. The correlations were evaluated in multiple ways, including a single point comparison of parameters such as steady-state concentration and heat-induced increase in partial AUCs, as well as a point-to-point correlation (Level A IVIVC). Level A IVIVC was examined using multiple approaches. A strong IVIVC was consistently observed for nicotine TDS in presence and absence of heat, suggesting the utility of IVPT as a tool to evaluate and predict in vivo performance of nicotine TDS. The IVIVC results for fentanyl were relatively weaker, especially when IVIVC for heat effects were examined, with greater in vivo heat effects observed compared to the in vitro heat effects. A separate study evaluating IVIVC for fentanyl TDS without a heat exposure component and utilization of some PK parameters obtained directly from study subjects yielded improved IVIVC results. The findings from the present research work suggest that IVPT data generally shows good predictability of in vivo performance of TDS at normal temperature conditions. However, the usefulness of IVPT for assessing and predicting external factors such as heat, especially for lipophilic drug molecules, may have some limitations that could be further improved.
    • Evaluation of skin tape stripping in healthy human volunteers as a methodology for quantifying local drug bioavailability from dermal products

      Shukla, Sagar; Stinchcomb, Audra L.; Hassan, Hazem (2020)
      Stratum corneum (SC) tape stripping is a valuable methodology that has been used for quantifying bioavailability (BA) of topical drug products at the site of action. Although the Food and Drug Administration (FDA) tape stripping guidance was withdrawn several years ago due to variable results, with an appropriate study design, tape stripping procedures can be a reproducible BA method. Therefore, the objective of this work was to investigate the use of tape stripping to quantify BA and evaluate in vitro/in vivo correlations (IVIVC) of two model compounds (lidocaine and diclofenac). These compounds were selected for their differing physicochemical properties and skin permeation rates. Two healthy human volunteer pharmacokinetic and tape stripping studies were conducted to quantify the BA in the SC and measure the elimination rate constant through the skin (kesc). Investigator variability from the in vivo tape stripping study was also examined, and the method variability potentially induced by the investigator can be mitigated by the quality by design (QBD) approach of using transepidermal water loss (TEWL) for determining when most of the SC has been removed in each individual volunteer. TEWL readings assisted the investigator by representing the SC tape stripping endpoint, and the SC masses removed from each volunteer were similar for the two investigators. Harmonized IVPT studies were also conducted and key parameter estimates were determined (absolute bioavailability (F) and (kesc)). These parameter estimates were used to simulate in vivo SC drug concentrations. The error in the SC drug concentration predictions from both in vivo studies was usually less than 20% compared to observed values, which demonstrates the predictive power of carefully harmonized IVPT studies. IVPT studies require less time and expense than human studies, and therefore these models play an important role in the early stages of drug development to predict in vivo SC drug concentrations, and absorption of drug through the skin. In this study, in vivo kesc for a quickly permeating drug (lidocaine) appears to be well predicted by IVPT; however, further work needs to be done to predict a slowly permeating drug’s (diclofenac) SC drug concentrations and kesc.