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Background: Oral and inhalation-based cannabidiol (CBD) administration has been clinically evaluated for various therapeutic indications, alongside widespread off-label use. However, the long-term exposure kinetics and varied bioavailability have not been fully characterized. Methods: Human CBD plasma concentration-time profiles from six studies evaluating the oral administration of Epidiolex ® and three studies evaluating inhalation-based delivery were obtained. A four-compartment pharmacokinetic (PK) model with Weibull-based oral absorption kinetics was employed to describe the long-term PKs of CBD. Furthermore, a Cedergreen-Ritz-Streibig model was applied to evaluate nonmonotonic oral bioavailability. Results: CBD was extensively distributed into tissue compartments with varied kinetics resulting in a long plasma terminal elimination half-life of >134 h in humans. For once-a-day oral dosing, the plasma trough concentrations require >70 days to reach a steady state. The oral bioavailability of CBD for different doses administered in fasted state follows a nonmonotonic pattern with an inverted U-shaped profile. Oral administration of CBD under fed state or subjects with hepatic impairment yields higher oral bioavailability with varied exposure. In contrast, inhalation-based delivery of CBD, while delivering a similar systemic delivered dose compared with oral dosing due to high device losses, bypasses first-pass metabolism and can be efficient. Conclusion: CBD PKs vary across different doses due to nonmonotonic oral bioavailability, and inhalation-based delivery could minimize such variability in humans. The delayed attainment of steady state and prolonged terminal half-life, resulting from differential but extensive tissue distribution, needs to be considered when dosing CBD in the long term. These fundamental findings are critical for establishing dose-exposure relationship for further clinical evaluation of novel CBD-based therapies.

In the past few years, technological advancements enabled the development of novel electronic nicotine delivery systems (ENDS). Several empirical measures such as "nicotine flux" are being proposed to evaluate the abuse liability potential of these products. We explored the applicability of nicotine flux for clinical nicotine pharmacokinetics (PK) and 52-week quit success from cigarettes for a wide range of existing nicotine delivery systems. We found that the differences in nicotine flux for various nicotine delivery systems are not related to changes in PK, as nicotine flux does not capture key physiological properties such as nicotine absorption rate. Further, the 52-week quit success and abuse liability potential of nicotine nasal sprays (high nicotine flux product), and nicotine inhalers (nicotine flux similar to ENDS) are low, suggesting that nicotine flux is a poor metric for the assessment of nicotine delivery systems. PK indices are more dependable for characterizing nicotine delivery systems, and a nicotine plasma C max T max > 1 could improve 52-week quit success from cigarettes. However, a single metric may be inadequate to fully assess the abuse liability potential of nicotine delivery systems and needs to be further studied. A combination of in vitro and in silico approaches could potentially address the factors influencing the inhaled aerosol dosimetry and resulting PK of nicotine to provide early insights for ENDS assessments. Further research is required to understand nicotine dosimetry and PK for ad libitum product use, and abuse liability indicators of nicotine delivery systems. This commentary is intended to (1) highlight the need to think beyond a single empirical metric such as nicotine flux, (2) suggest potential PK-based metrics, (3) suggest the use of in vitro and in silico tools to obtain early insights into inhaled aerosol dosimetry for ENDS, and (4) emphasize the importance of considering comprehensive clinical pharmacology outcomes to evaluate nicotine delivery systems., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aditya R. Kolli reports financial support was provided by Philip Morris International. Jed E. Rose reports a relationship with Philip Morris International that includes: funding grants. Aditya R. Kolli, Emilija Veljkovic, Florian Calvino-Martin, Arkadiusz K. Kuczaj, Marco Esposito, and Ondrej Koumalare employees of Philip Morris International. Manuel C. Peitsch was an employee of Philip Morris International when this work was performed. Jed E. Rose discloses research support from Foundation for a Smoke-Free World, Philip Morris International, Altria, Embera Neurotherapeutics, Inc., Otsuka Pharmaceutical, and JUUL Labs; consulting with Revive Pharmaceuticals; and consulting and patent purchase agreements with Philip Morris International., (© 2024 The Author(s).)

Numerous commercially available inhalable products claim to improve sleep-wake cycle-related target indications by delivering a wide variety of chemicals like caffeine and melatonin. The resulting exposure-responses from inhaling different doses are unknown and obtaining early understanding of resulting pharmacokinetics is beneficial. This study applied a physiologically based pharmacokinetic modeling approach to predict the inhalation pharmacokinetics of caffeine and melatonin for different target indications related to the sleep-wake cycle. The model predicted rapid systemic delivery of caffeine and melatonin based on airway regional deposition of inhaled aerosol. A low inhaled dose of 1 mg of caffeine resulted in a 72.3-times lower plasma maximal concentration and was predicted to not improve cognitive performance task outcomes compared to oral consumption of coffee containing 80 mg of caffeine. Conversely, 2-mg oral and inhaled doses of melatonin under recommended directions of use result in more than 25.1- and 645-times higher plasma concentrations compared to endogenous melatonin, respectively. The recommended doses for inhalation products for potential improvement in the target indications vary widely. Additional research is needed to evaluate the human pharmacokinetics, efficacy, and safety of inhaled products. Given the lack of assessments, inhaled caffeine and melatonin must be consumed with caution as the toxicological concerns are not known and could outweigh the potential beneficial effects., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ARK, AKK, and FCM are employees of Philip Morris International. JH was an employee of Philip Morris International when this work was performed. JH is currently an employee of Vectura Fertin Pharma., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Inhalation enables the delivery of drugs directly to the lung, increasing the retention for prolonged exposure and maximizing the therapeutic index. However, the differential regional lung exposure kinetics and systemic pharmacokinetics are not fully known, and their estimation is critical for pulmonary drug delivery. The study evaluates the pharmacokinetics of hydroxychloroquine in different regions of the respiratory tract for multiple routes of administration. We also evaluated the influence of different inhaled formulations on systemic and lung pharmacokinetics by identifying suitable nebulizers followed by early characterization of emitted aerosol physicochemical properties. The salt- and freebase-based formulations required different nebulizers and generated aerosol with different physicochemical properties. An administration of hydroxychloroquine by different routes resulted in varied systemic and lung pharmacokinetics, with oral administration resulting in low tissue concentrations in all regions of the respiratory tract. A nose-only inhalation exposure resulted in higher and sustained lung concentrations of hydroxychloroquine with a lung parenchyma-to-blood ratio of 386 after 1440 min post-exposure. The concentrations of hydroxychloroquine in different regions of the respiratory tract (i.e., nasal epithelium, larynx, trachea, bronchi, and lung parenchyma) varied over time, indicating different retention kinetics. The spatiotemporal distribution of hydroxychloroquine in the lung is different due to the heterogeneity of cell types, varying blood perfusion rate, clearance mechanisms, and deposition of inhaled aerosol along the respiratory tract. In addition to highlighting the varied lung physiology, these results demonstrate the ability of the lung to retain increased levels of inhaled lysosomotropic drugs. Such findings are critical for the development of future inhalation-based therapeutics, aiming to optimize target site exposure, enable precision medicine, and ultimately enhance clinical outcomes., Competing Interests: Declaration of Competing Interest All authors were employees of Philip Morris International when this work was performed., (Copyright © 2024. Published by Elsevier B.V.)

Cigarette smoking is a major preventable cause of morbidity and mortality. While quitting smoking is the best option, switching from cigarettes to non-combustible alternatives (NCAs) such as e-vapor products is a viable harm reduction approach for smokers who would otherwise continue to smoke. A key challenge for the clinical assessment of NCAs is that self-reported product use can be unreliable, compromising the proper evaluation of their risk reduction potential. In this cross-sectional study of 205 healthy volunteers, we combined comprehensive exposure characterization with in-depth multi-omics profiling to compare effects across four study groups: cigarette smokers (CS), e-vapor users (EV), former smokers (FS), and never smokers (NS). Multi-omics analyses included metabolomics, transcriptomics, DNA methylomics, proteomics, and lipidomics. Comparison of the molecular effects between CS and NS recapitulated several previous observations, such as increased inflammatory markers in CS. Generally, FS and EV demonstrated intermediate molecular effects between the NS and CS groups. Stratification of the FS and EV by combustion exposure markers suggested that this position on the spectrum between CS and NS was partially driven by non-compliance/dual use. Overall, this study highlights the importance of in-depth exposure characterization before biological effect characterization for any NCA assessment study., (© 2024. The Author(s).)

The poor physicochemical properties of cannabidiol (CBD) hamper its clinical development. The aim of this review was to examine the literature to identify novel oral products and delivery strategies for CBD, while assessing their clinical implications and translatability. Evaluation of the published literature revealed that oral CBD strategies are primarily focused on lipid-based and emulsion solutions or encapsulations, which improve the overall pharmacokinetics (PK) of CBD. Some emulsion formulations demonstrate more rapid systemic delivery. Variability in the PK effects of different oral CBD products is apparent across species. Several novel administration routes exist for CBD delivery that may offer promise for specific indications. For example, intranasal administration and inhalation allow quick delivery of CBD to the plasma and the brain, whereas transdermal and transmucosal administration routes deliver CBD systemically more slowly. There are limited but promising data on novel delivery routes such as intramuscular and subcutaneous. Very limited data show that CBD is generally well distributed across tissues and that some CBD products enable increased delivery of CBD to different brain regions. However, evidence is limited regarding whether changes in CBD PK profiles and tissue distribution equate to superior therapeutic efficacy across indications and whether specific CBD products might be suited to particular indications.

Extracellular chemical concentrations are considered physiologically relevant for in vitro testing and are evaluated in traditional in vitro systems using cell culture media containing 5%-10% fetal bovine serum (FBS). However, depending on the physicochemical properties, and in vitro testing conditions, cells could be exposed to variable unbound extracellular concentrations. If in vitro unbound concentrations are not calculated, it is challenging to distinguish the chemical potency and concentration-driven responses. In this study, one- and two-protein binding models were used to estimate protein binding corrected chemical concentrations of various chemicals for in vitro testing. As ceftizoxime, moxifloxacin, and nicotine have low protein binding affinity, the in vitro protein binding in 5%-10% FBS is less than 5% and can be considered negligible. However, protein binding of moderate and highly protein-bound chemicals must be corrected for as the in vitro unbound concentrations in 5%-10% FBS containing cell culture media will vary over a range of chemical concentrations. In vitro pharmacological and toxicological assessments must incorporate protein binding-adjusted in vitro concentrations to ensure physiologically relevant exposures. A user-friendly Excel spreadsheet is provided to help bench scientists calculate protein binding-corrected chemical concentrations for in vitro testing., (© 2023 The Author. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Nicotine from inhaled combustible cigarette smoke is delivered rapidly to the brain, and sufficient unbound nicotine concentrations exert pharmacological effects. In addition to nicotine, combustible cigarette smoke also contains a significant number of toxicants that trigger perturbations, leading to an altered steady state due to differential expression of proteins. In this study, a physiologically based pharmacokinetic (PBPK) model for inhaled nicotine was used to simulate the influence of lysosomal change-driven tissue retention and plasma protein binding levels on nicotine pharmacokinetics (PK). A 3 × increase in tissue lysosomal volumes lowered the nicotine brain maximum concentration (C max ) by 20.8%. Similarly, a 50% increase in plasma protein binding also lowered the unbound plasma arterial nicotine C max by 39.4%. Such fundamental changes in nicotine disposition due to physiological changes in combustible cigarette smokers will lead to altered nicotine consumption and exposure-responses of other weakly basic drugs. Literature reports indicate that nicotine consumed from non-combustible products do not alter drug exposures, indicating fewer or less severe toxicant-driven perturbations with the use of these products. Although several other parameters influence nicotine PK, this PBPK modeling study shows that increased tissue retention and plasma protein binding reduce nicotine delivery to the brain and could lead to differential consumption of combustible cigarettes. These differences in physiological states among combustible cigarette smokers need to be evaluated and should be considered during therapeutic interventions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aditya R. Kolli reports financial support was provided by Philip Morris International. Aditya R. Kolli is an employee of Philip Morris International., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Absorption of inhaled compounds can occur from multiple sites based on upper and lower respiratory tract deposition, and clearance mechanisms leading to differential local and systemic pharmacokinetics. Deriving inhaled aerosol dosimetry and local tissue concentrations for nose-only exposure in rodents and inhaled products in humans is challenging. In this study we use inhaled nicotine as an example to identify regional respiratory tract deposition, absorption fractions, and their contribution toward systemic pharmacokinetics in rodents and humans. A physiologically based pharmacokinetic (PBPK) model was constructed to describe the disposition of nicotine and its major metabolite, cotinine. The model description for the lungs was simplified to include an upper respiratory tract region with active mucociliary clearance and a lower respiratory tract region. The PBPK model parameters such as rate of oral absorption, metabolism and clearance were fitted to the published nicotine and cotinine plasma concentrations post systemic administration and oral dosing. The fractional deposition of inhaled aerosol in the upper and lower respiratory tract regions was estimated by fitting the plasma concentrations. The model predicted upper respiratory tract deposition was 63.9% for nose-only exposure to nicotine containing nebulized aqueous aerosol in rats and 60.2% for orally inhaled electronic vapor product in humans. A marked absorption of nicotine from the upper respiratory tract and the gastrointestinal tract for inhaled aqueous aerosol contributed to the differential systemic pharmacokinetics in rats and humans. The PBPK model derived dosimetry shows that the current aerosol dosimetry models with their posteriori application using independent aerosol physicochemical characterization to predict aerosol deposition are insufficient and will need to consider complex interplay of inhaled aerosol evolutionary process. While the study highlights the needs for future research, it provides a preliminary framework for interpreting pharmacokinetics of inhaled aerosols to facilitate the analysis of in vivo exposure-responses for pharmacological and toxicological assessments., Competing Interests: Declaration of Interests The authors declare the following interests: ARK, FCM, AKK, ETW, BT, YX, SL, PV and JH are employees of Philip Morris International. WKS is contracted and paid by Philip Morris International., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

In vitro screening for pharmacological activity of existing drugs showed chloroquine and hydroxychloroquine to be effective against severe acute respiratory syndrome coronavirus 2. Oral administration of these compounds to obtain desired pulmonary exposures resulted in dose-limiting systemic toxicity in humans. However, pulmonary drug delivery enables direct and rapid administration to obtain higher local tissue concentrations in target tissue. In this work, inhalable formulations for thermal aerosolization of chloroquine and hydroxychloroquine were developed, and their physicochemical properties were characterized. Thermal aerosolization of 40 mg/mL chloroquine and 100 mg/mL hydroxychloroquine formulations delivered respirable aerosol particle sizes with 0.15 and 0.33 mg per 55 mL puff, respectively. In vitro toxicity was evaluated by exposing primary human bronchial epithelial cells to aerosol generated from Vitrocell. An in vitro exposure to 7.24 μg of chloroquine or 7.99 μg hydroxychloroquine showed no significant changes in cilia beating, transepithelial electrical resistance, and cell viability. The pharmacokinetics of inhaled aerosols was predicted by developing a physiologically based pharmacokinetic model that included a detailed species-specific respiratory tract physiology and lysosomal trapping. Based on the model predictions, inhaling emitted doses comprising 1.5 mg of chloroquine or 3.3 mg hydroxychloroquine three times a day may yield therapeutically effective concentrations in the lung. Inhalation of higher doses further increased effective concentrations in the lung while maintaining lower systemic concentrations. Given the theoretically favorable risk/benefit ratio, the clinical significance for pulmonary delivery of aerosolized chloroquine and hydroxychloroquine to treat COVID-19 needs to be established in rigorous safety and efficacy studies. Graphical abstract., (© 2021. The Author(s).)

Purpose: Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies., Methods: We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens., Results: At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections., Conclusion: Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections., (© 2021. The Author(s).)

Trehalose is added in drug formulations to act as fillers or improve aerosolization performance. Its characteristics as a carrier molecule have been explored; however, the fate of trehalose in human airway tissues has not been thoroughly investigated. Here, we investigated the fate of nebulized trehalose using in vitro human air-liquid bronchial epithelial cultures. First, a tracing experiment was conducted using 13 C 12 -trehalose; we measured trehalose distribution in different culture compartments (apical surface liquid, epithelial culture, and basal side medium) at various time points following acute exposure to 13 C 12 -labeled trehalose. We found that 13 C 12 -trehalose was metabolized into 13 C 6 -glucose. The data was then used to model the kinetics of trehalose disappearance from the apical surface of bronchial cultures. Secondly, we evaluated the potential adverse effects of nebulized trehalose on the bronchial cultures after they were acutely exposed to nebulized trehalose up to a level just below its solubility limit (50 g/100 g water). We assessed the ciliary beating frequency and histological characteristics. We found that nebulized trehalose did not lead to marked alteration in ciliary beating frequency and morphology of the epithelial cultures. The in vitro testing approach used here may enable the early selection of excipients for future development of inhalation products., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Natural alkaloids, a large class of plant-derived substances, have attracted considerable interest because of their pharmacological activities. In this study, the in vivo pharmacokinetics and anti-inflammatory profile of anatabine, a naturally occurring alkaloid, were characterized in rodents. Anatabine was found to be bioavailable and brain-penetrant following systemic administration. Following intraperitoneal (i.p.) administration (1, 2, and 5 mg/kg), anatabine caused a dose-dependent reduction in carrageenan-induced paw edema in rats; in mice, it inhibited the production of pro-inflammatory cytokines and simultaneously elevated the levels of an anti-inflammatory cytokine in a dose-dependent manner 2 h after lipopolysaccharide challenge. Furthermore, anatabine (∼10 and ∼20 mg/kg/day for 4 weeks; inhalation exposure) had effects in a murine model of multiple sclerosis, reducing neurological deficits and bodyweight loss. Comparative studies of the pharmacokinetics and anti-inflammatory activity of anatabine demonstrated its bioequivalence in rats following i.p. administration and inhalation exposure. This study not only provides the first detailed profile of anatabine pharmacokinetics in rodents but also comprehensively characterizes the anti-inflammatory activities of anatabine in acute and chronic inflammatory models. These findings provide a basis for further characterizing and optimizing the anti-inflammatory properties of anatabine.

One of the challenges for toxicological assessment of inhaled aerosols is to accurately predict their deposited and absorbed dose. Transport, evolution, and deposition of liquid aerosols are driven by complex processes dominated by convection-diffusion that depend on various factors related to physics and chemistry. These factors include the physicochemical properties of the pure substance of interest and associated mixtures, the physical and chemical properties of the aerosols generated, the interplay between different factors during transportation and deposition, and the subject-specific inhalation topography. Several inhalation-based physiologically based pharmacokinetic (PBPK) models have been developed, but the applicability of these models for aerosols has yet to be verified. Nicotine is among several substances that are often delivered via the pulmonary route, with varied kinetics depending upon the route of exposure. This was used as an opportunity to review and discuss the current knowledge and state-of-the-art tools combining aerosol dosimetry predictions with PBPK modeling efforts. A validated tool could then be used to perform for toxicological assessment of other inhaled therapeutic substances. The Science Panel from the Alliance of Risk Assessment have convened at the "Beyond Science and Decisions: From Problem Formulation to Dose-Response Assessment" workshop to evaluate modeling approaches and address derivation of exposure-internal dose estimations for inhaled aerosols containing nicotine or other substances. The discussion involved PBPK model evaluation criteria, challenges, and choices that arise in such a model design, development, and application as a computational tool for use in human toxicological assessments.

Transepithelial/transendothelial electrical resistance (TEER) is a widely accepted quantitative technique to measure the integrity of tight junction dynamics in cell culture models of endothelial and epithelial monolayers. TEER values are strong indicators of the integrity of the cellular barriers before they are evaluated for transport of drugs or chemicals. TEER measurements can be performed in real time without cell damage and generally are based on measuring ohmic resistance or measuring impedance across a wide spectrum of frequencies. The measurements for various cell types have been reported with commercially available measurement systems and also with custom-built microfluidic implementations. Some of the barrier models that have been widely characterized using TEER include the blood-brain barrier (BBB), gastrointestinal (GI) tract, and pulmonary models. Variations in these values can arise due to factors such as temperature, medium formulation, and passage number of cells. The aim of this article is to review the different TEER measurement techniques and analyze their strengths and weaknesses, determine the significance of TEER in drug toxicity studies, examine the various in vitro models and microfluidic organs-on-chips implementations using TEER measurements in some widely studied barrier models (BBB, GI tract, and pulmonary), and discuss the various factors that can affect TEER measurements., (© 2015 Society for Laboratory Automation and Screening.)