AAPS Journal最新文献

Crizotinib exhibits a complex drug-drug interaction as it is a CYP3A4 substrate and acts as both a time-dependent inhibitor and inducer of the enzyme. Absorption of crizotinib is also complex as it exhibits a prolonged absorption phase. The primary objective of this research was to develop a comprehensive physiologically based pharmacokinetic (PBPK) model to mechanistically describe both metabolism and absorption of crizotinib. The established crizotinib adult PBPK model was extrapolated to pediatric population using the modified CYP3A4 ontogeny profile to evaluate the pharmacokinetic (PK) profile after a single dose administration of crizotinib under the fasted condition in pediatric population age between 1 to 6 years old. The model was further applied to conduct virtual bioequivalence (BE) trials including clinically observed intra-subject coefficient of variation (ICV%) in both adult and pediatric populations. In adult subjects, the estimated geometric mean ratio for AUC_inf and C_max for oral solution (OS) vs granules formulation was 98.33 and 89.94, respectively with probability of demonstrating BE in adults of 100% for AUC_inf and 90.3% for C_max. In pediatric subjects, the probability of demonstrating BE success was 99.7% for both AUC_inf and C_max. The high probability of BE was replicated with the assumed higher ICV of 29% in pediatrics for both AUCinf and C_max. The granules (commercial formulation) can be considered BE to OS (Phase 3 clinical formulation) in adults, as well as pediatric subjects aged between 1 to 6 years old.

Gastric emptying plays a crucial role in the dissolution and absorption of oral drugs, particularly those with pH-dependent solubility, such as dipyridamole. This study evaluates the impact of gastric emptying kinetics on dipyridamole dissolution using a Gastrointestinal Simulator. A dynamic dissolution model incorporating first-order and Weibull kinetics was applied to simulate different gastric emptying profiles. Results indicate that dissolution behavior is significantly influenced by the rate and pattern of gastric emptying, affecting drug solubility and potential bioavailability. The Weibull model provided a more flexible fit to experimental data, but the external control shows that significant differences exist between theorical and experimental gastric volumes. These findings highlight the importance of integrating physiologically relevant gastric emptying models into biopharmaceutical assessments to improve the prediction of in vivo drug performance. This approach could enhance the design of oral formulations by optimizing dissolution profiles for weak base drugs.

Difluprednate is marketed as an emulsion due to its poor aqueous solubility. Emulsions are known to cause ocular discomfort and require frequent dosing to show therapeutic activity. Nanomicelles are well known to improve the solubility and permeation of water-insoluble drugs. Therefore, to enhance the water solubility and reduce the dosing frequency by improving difluprednate permeation across the cornea, we formulated nanomicelles. Difluprednate loaded nanomicelles (Dicel) was prepared by thin film hydration method and optimized using Box-Behnken design. The Dicel formulated had a particle size, polydispersity index, zeta potential and entrapment efficiency of 21.9 nm, 0.15, -7.55 mV and 75.4%, respectively. Transmission electron microscopy analysis showed spherical nanomicelles. The Dicel showed a sustained release profile for 48 h. The difluprednate permeation across the cornea from Dicel was enhanced by twofold compared to commercially available emulsion. Also, it was found to be stable upon dilution with simulated tear fluid and was biocompatible. Further, Dicel improved the anti-inflammatory activity of difluprednate at one and two times a day administration compared to four times a day administration of difluprednate emulsion. The present study highlights the role of topical nanomicelles in delivering difluprednate, which is better than the existing marketed emulsion in the management of ocular inflammation.

Cardiovascular diseases (CVDs) have become one of the leading threats to human health due to their high incidence and mortality rates. Their pathological mechanisms are complex, involving inflammation, oxidative stress, energy metabolism, and other factors. Catechins are a group of flavanol derivatives originally extracted from the traditional Chinese medicine Acacia catechu (L.f.) Willd. Their unique polyhydroxy chemical structure endows catechins with a range of biological activities, such as anti-inflammatory properties, antioxidant properties, and the regulation of nutrient homeostasis. Recent studies have shown the beneficial effects of catechins in atherosclerosis, hypertension, heart failure, cardiomyopathy, and other cardiovascular conditions. Therefore, catechins present significant potential as a therapeutic approach for CVDs. This review provides an overview of the structure, pharmacological mechanisms, and recent research developments of catechins in cardiovascular diseases, with the goal of offering insights for the future medicinal study of catechins.

As process analytical technology (PAT) and real-time release testing (RTRT) are gaining momentum in the pharmaceutical industry, there is an increasing need for developing methods for the non-destructive and real-time characterization of the in vitro dissolution of pharmaceuticals. In recent years, several surrogate models relying on PAT measurements and advanced chemometric techniques have been published addressing this task. Nevertheless, methodologies for the fair comparison of the model performance and setting relevant acceptance criteria are still not well established. Therefore, this study aims to draw attention to appropriate model comparison when developing and applying surrogate dissolution models and highlight the limitations of the widely used dissolution curve comparison metrics, including the f₂ similarity value. A set of 10 different artificial neural network (ANN) models were developed for the prediction of the dissolution profiles of clopidogrel tablets produced through hot-melt granulation and tableting. Models were fitted with diverse input data, including granulation nominal experiment settings and real recorded process parameters (e.g., air and material temperature, humidity, granulation and lubrication time, tableting pressure) and near-infrared spectra. The models' goodness was compared using the f₂ factor, coefficient of determination (R²) and root mean square error (RMSE). The results demonstrated that these measures do not sufficiently reflect the discriminating ability of the models. We proposed for the first time the use of the sum of ranking differences (SRD) method for the comparison of the prediction models, which proved to be an effective tool to assess the discriminatory power of surrogate dissolution models during model development.

Human health and the environment are continuously impacted by anthropogenic activities, particularly those involving emerging compounds. As these compounds are newly identified or not yet fully documented in the literature, comprehensive knowledge of their specific toxicities remains limited. Among these, pharmaceutical compounds are of particular concern, as their mechanisms of action and the effects of their pharmaceutical impurities remain insufficiently understood. In this context, this study aimed to evaluate the behavior of the antineoplastic pharmaceutical doxorubicin (DOX) under stress conditions, including acid and base hydrolysis, oxidation, photolysis, and temperature variations. The goal was to identify the major degradation pathways and elucidate the structures of the main degradation products. A stability-indicating HPLC-DAD-MS method was developed and validated for this purpose. Throughout method development, several degradation products were identified, including 7-deoxydehydrodoxorubicinone, formed through acid hydrolysis, and a major thermal degradation product with a mass-to-charge ratio (m/z) of 530. This thermal degradation product was also detected in analyses of expired pharmaceutical formulations. Furthermore, the in vitro toxicity assessment of samples containing degradation products from thermal decomposition revealed cytotoxic effects on mononuclear cells. These findings underscore the importance of not only understanding the degradation pathways of pharmaceutical compounds but also evaluating the potential environmental and human health impacts of these degradation products.

Over the past three years, we have published a series of nine manuscripts demonstrating that all relevant pharmacokinetic relationships may be simply derived independent of differential equations, offering an alternative to traditional pharmacokinetic analyses. These derivations are based on an understanding of parallel and in series rate-defining processes, and account for all relevant drivers, including organ blood flow and drug delivery clearance kinetics, across both linear and nonlinear scenarios. In this tutorial, we present the simple derivation of renal clearance and hepatic clearance directly relevant to clinical pharmacokinetics, as applied to making drug dosing decisions based on measures of systemic exposure. We further advocate for a more streamlined and practical approach to teaching and applying clinical pharmacokinetics, noting that compartmental modeling, protein binding in hypothetical compartments, trapezoidal AUC calculations, and alternative volume of distribution parameters, aside from (the unfortunately misnamed) volume of distribution steady-state, often overcomplicate pharmacokinetics in practice. The key advantage of this simplified methodology is the ability to directly incorporate clearance from the drug delivery site into systemic pharmacokinetic relationships. This enables a clear understanding of how entering clearance can influence systemic AUC, helping explain: enhanced pharmacodynamic outcomes of slow drug delivery versus immediate-release formulations; systemic bioavailability measures exceeding unity, statistically significant discrepancies between urinary and systemic bioavailability measures; and changes in renal clearance as a function of drug clearance from the delivery site. These key concepts are illustrated by applying the proposed methodology to an example drug, analyzing all relevant clinical pharmacokinetic relationships required for dosing decisions.

In vitro dissolution testing is commonly performed to ensure that oral solid dosage medicines are of high quality and will achieve their targeted in vivo performance. However, this testing is time and material consuming. Therefore, pharmaceutical companies have been developing predictive dissolution models (PDMs) for drug product release based on fast at- and/or on-line measurements, including real-time release testing of dissolution (RTRT-D). Recently, PDMs have seen acceptance by major regulatory bodies as release tests for the dissolution critical quality attribute. In this paper, several methodologies are described to develop and validate a fit-for-purpose model, then to implement it as a surrogate release test for dissolution. These approaches are further exemplified by real-life case studies, which demonstrate that PDMs for release are not only viable but more sustainable than in vitro dissolution testing and can significantly accelerate drug product release. The rise of continuous manufacturing within the pharmaceutical industry further favors the implementation of real-time release testing. Therefore, a steep uptake of PDMs for release is expected once this methodology is globally accepted. To that end, it is advantageous for global regulators and pharmaceutical innovators to coalesce around a harmonized set of expectations for development, validation, implementation, and lifecycle of PDMs as part of drug product release testing.

The six-minute walk test (6MWT) is a common method to assess submaximal exercise capacity in children and adults with pulmonary arterial hypertension (PAH) and other chronic diseases. There is no guideline specifically for 6MWT in children. In this observational pilot study, we evaluated the impact of procedural variations on the outcome of the 6MWT in the real-world clinical setting at pediatric PAH programs. We collected 6MWT data from 33 children with PAH participating in a multicenter, prospective, non-interventional study. Data range/quantiles and standard deviation (SD) were used to describe distribution of the six-minute walk distance (6MWD) and data variability. Levene's test was used to test for heterogeneity of variance with the two sites of similar altitude and their age/height/weight-matched Panama Function Class II participants. We analyzed all 33 eligible participants and their qualified first walks at five centers (A-E) with 6MWD ranges of 420-570, 357-683, 418-481, 400-700, 377-549 m, respectively. Site D performed the 6MWT in a busy hallway and allowed parental/caregiver's cheering, while Site E performed the 6MWT in a secluded area with no parental/caregiver involvement. Mean 6MWD and SD for Sites D and E were 547 (125) and 432 (67.5) meters, respectively (p = 0.03). In conclusion, procedural variations seem to associate with 6MWD data variability. Although interpretation of our results is limited by the small sample size, our findings suggest that standardizing pediatric 6MWT procedures are needed.