Basic considerations in the dermatokinetics of topical formulations

Assessing the bioavailability of drug molecules at the site of action provides better insight into the efficiency of a dosage form. However, determining drug concentration in the skin layers following topical application of dermatological formulations is a great challenge. The protocols followed in oral formulations could not be applied for topical dosage forms. The regulatory agencies are considering several possible approaches such as tape stripping, microdialysis etc. On the other hand, the skin bioavailability assessment of xenobiotics is equally important for topical formulations in order to evaluate the toxicity. It is always possible that drug molecules applied on the skin surface may transport thorough the skin and reaches systemic circulation. Thus the real time measurement of molecules in the skin layer has become obligatory. In the last two decades, quite a few investigations have been carried out to assess the skin bioavailability and toxicity of topical/dermatological products. This review provides current understanding on the basics of dermatokinetics, drug depot formation, skin metabolism and clearance of drug molecules from the skin layers following application of topical formulations

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Background:Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and Findings:1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial Registration:http://www.ClinicalTrials.gov NCT00084136

Modelling the effect of mixture components on permeation through skin

A vehicle influences the concentration of penetrant within the membrane, affecting its diffusivity in the skin and rate of transport. Despite the huge amount of effort made for the understanding and modelling of the skin absorption of chemicals, a reliable estimation of the skin penetration potential from formulations remains a challenging objective. In this investigation, quantitative structure-activity relationship (QSAR) was employed to relate the skin permeation of compounds to the chemical properties of the mixture ingredients and the molecular structures of the penetrants. The skin permeability dataset consisted of permeability coefficients of 12 different penetrants each blended in 24 different solvent mixtures measured from finite-dose diffusion cell studies using porcine skin. Stepwise regression analysis resulted in a QSAR employing two penetrant descriptors and one solvent property. The penetrant descriptors were octanol/water partition coefficient, log. P and the ninth order path molecular connectivity index, and the solvent property was the difference between boiling and melting points. The negative relationship between skin permeability coefficient and log. P was attributed to the fact that most of the drugs in this particular dataset are extremely lipophilic in comparison with the compounds in the common skin permeability datasets used in QSAR. The findings show that compounds formulated in vehicles with small boiling and melting point gaps will be expected to have higher permeation through skin. The QSAR was validated internally, using a leave-many-out procedure, giving a mean absolute error of 0.396. The chemical space of the dataset was compared with that of the known skin permeability datasets and gaps were identified for future skin permeability measurements. © 2010 Elsevier B.V

Development of a multi-route physiologically based pharmacokinetic (PBPK) model for nanomaterials: A comparison between a traditional versus a new route-specific approach using gold nanoparticles in rats.

BACKGROUND: Physiologically based pharmacokinetic (PBPK) modeling is an important tool in predicting target organ dosimetry and risk assessment of nanoparticles (NPs). The methodology of building a multi-route PBPK model for NPs has not been established, nor systematically evaluated. In this study, we hypothesized that the traditional route-to-route extrapolation approach of PBPK modeling that is typically used for small molecules may not be appropriate for NPs. To test this hypothesis, the objective of this study was to develop a multi-route PBPK model for different sizes (1.4-200&nbsp;nm) of gold nanoparticles (AuNPs) in adult rats following different routes of administration (i.e., intravenous (IV), oral gavage, intratracheal instillation, and endotracheal inhalation) using two approaches: a traditional route-to-route extrapolation approach for small molecules and a new approach that is based on route-specific data that we propose to be applied generally to NPs. RESULTS: We found that the PBPK model using this new approach had superior performance than the traditional approach. The final PBPK model was optimized rigorously using a Bayesian hierarchical approach with Markov chain Monte Carlo simulations, and then converted to a web-based interface using R Shiny. In addition, quantitative structure-activity relationships (QSAR) based multivariate linear regressions were established to predict the route-specific key biodistribution parameters (e.g., maximum uptake rate) based on the physicochemical properties of AuNPs (e.g., size, surface area, dose, Zeta potential, and NP numbers). These results showed the size and surface area of AuNPs were the main determinants for endocytic/phagocytic uptake rates regardless of the route of administration, while Zeta potential was an important parameter for the estimation of the exocytic release rates following IV administration. CONCLUSIONS: This study suggests that traditional route-to-route extrapolation approaches for PBPK modeling of small molecules are not applicable to NPs. Therefore, multi-route PBPK models for NPs should be developed using route-specific data. This novel PBPK-based web interface serves as a foundation for extrapolating to other NPs and to humans to facilitate biodistribution estimation, safety, and risk assessment of NPs

Probabilistic Physiologically Based Pharmacokinetic Model for Penicillin G in Milk From Dairy Cows Following Intramammary or Intramuscular Administrations

Item does not contain fulltextPenicillin remains one of the most frequently identified violative drug residues in food-producing animals. The predominant violations of penicillin were found in cull dairy cows. In the United States, procaine penicillin G is approved to be used in dairy cows through intramuscular (IM) and intramammary (IMM) administrations. Physiologically based pharmacokinetic (PBPK) models are useful tools to predict withdrawal intervals and tissue residues of drugs in food animals to ensure food safety, especially for extralabel drug use due to the scarcity of experimental data after extralabel administrations. Currently, no PBPK model is available to predict penicillin concentrations in milk. A population PBPK model with a physiologically based compartment for the mammary gland was established for penicillin G in dairy cows. The model predicted the tissue and milk residues well based on comparison with data from previous pharmacokinetic studies. The predicted milk discard interval of procaine penicillin G administered at 10 times the label dose for 3 repeated IM administrations was 182 h, and 122 h at 4 times the label dose after 3 repeated IMM infusions. Predicted results showed that even 4 times label dose did not lead to violative tissue residues in healthy dairy cows with IMM infusions. The predominant violations found in cull dairy cows may be caused by altered pharmacokinetics due to mastitis, other diseases, and/or interactions with other drugs, which have impacts on penicillin distribution and elimination. The current PBPK model can help predict milk discard interval for penicillin following extralabel use through IM and IMM administrations

Toxicity of jet fuel aliphatic and aromatic hydrocarbon mixtures on human epidermal keratinocytes: evaluation based on in vitro cytotoxicity and interleukin-8 release

Jet fuels are complex mixtures of aliphatic (ALI) and aromatic (ARO) hydrocarbons that vary significantly in individual cytotoxicity and proinflammatory activity in human epidermal keratinocytes (HEK). In order to delineate the toxicological interactions among individual hydrocarbons in a mixture and their contributions to cutaneous toxicity, nine ALI and five ARO hydrocarbons were each divided into five (high/medium/low cytotoxic and strong/weak IL-8 induction) groups and intra/inter-mixed to assess for their mixture effects on HEK mortality and IL-8 release. Addition of single hydrocarbon to JP-8 fuel was also evaluated for their changes in fuel dermatotoxicity. The results indicated that when hydrocarbons were mixed, HEK mortality and IL-8 release were not all predictable by their individual ability affecting these two parameters. The lowest HEK mortality (7%) and the highest IL-8 production were induced with mixtures including high cytotoxic and weak IL-8 inductive ARO hydrocarbons. Antagonistic reactions not consistently correlated with ALI carbon chain length and ARO structure were evident and carried different weight in the overall mixture toxicities. Single addition of benzene, toluene, xylene or ethylbenzene for up to tenfold in JP-8 did not increase HEK mortality while single addition of ALI hydrocarbons exhibited dose-related differential response in IL-8. In an all ALI environment, no single hydrocarbon is the dominating factor in the determination of HEK cytotoxicity while deletion of hexadecane resulted in a 2.5-fold increase in IL-8 production. Overall, decane, undecane and dodecane were the major hydrocarbons associated with high cytotoxicity while tetradecane, pentadecane and hexadecane were those which had the greatest buffering effect attenuating dermatotoxicity. The mixture effects must be considered when evaluating jet fuel toxicity to HEK