Background/Objectives: Interindividual pharmacokinetic (PK) variability remains a daunting challenge for effective and safe drug therapy. Despite the widespread use of direct oral anticoagulants (DOACs) and calcium channel blockers (CCBs), a substantial number of adverse drug reactions have been reported for both classes. Herein, this study aimed to assess and analyze the PK variability of DOACs and CCBs across diverse clinical and demographic profiles under both single- and multiple-dose conditions. Methods: A PubMed search identified clinical PK studies reporting maximum plasma concentration (Cmax) and/or area under the concentration-time curve (AUC). The coefficient of variation (CV%) was calculated and used as a measure of PK variability. A CV% < 40% indicated low-to-moderate variability, and a CV% > 40% was defined as high variability. Results: A total of 264 studies were included following systematic screening, and the dataset was further characterized according to population features and clinical context. Among DOACs, edoxaban exhibited the lowest PK variability, whereas dabigatran showed the highest. CCBs demonstrated a broad variability spectrum, ranging from predictable agents (amlodipine and felodipine) to highly variable compounds (nisoldipine, isradipine, nimodipine, diltiazem, and verapamil). Studies evaluating drug-drug interactions, ethnicity, and specific drug-related factors were associated with increased PK variability. Conclusions: These findings suggest that fixed-dose strategies may not be universally appropriate for DOACs and CCBs, particularly in high-risk subgroups where altered exposure may lead to sub- or supratherapeutic concentrations and compromise clinical outcomes. Therefore, clinicians should avoid evaluating individual risk factors in isolation and instead consider the patient's complete profile when selecting and adjusting pharmacotherapy.

The treatment of post-traumatic osteomyelitis (PTO) is impeded by bacterial biofilms and disruption of drug delivery systems in acidic lesions. Here, we develop an acid-resistant amine-linked heteroporous covalent organic framework (ARCOF) using a reductive amination strategy. This approach overcomes the insufficient chemical stability and drug delivery capacity of conventional COFs arising from the trade-off between high bond strength and crystalline reversibility. The pre-designed hetero-environmental channels of ARCOF enable synergistic loading of vancomycin and the anti-biofilm agent felodipine. When combined with calcium phosphate cement, both drugs exhibit sustained release over 240 h under inflammatory conditions. The therapeutic efficacy is evaluated in a rat PTO model, where the co-delivery system significantly enhances antibacterial efficacy by disrupting biofilm integrity and concurrently modulates the local inflammatory microenvironment to support bone tissue recovery. This strategy provides an integrated local delivery approach to overcome pharmacokinetic barriers and biofilm resistance in osteomyelitis treatment.

Micelle-based drug delivery systems offer a promising strategy for enhancing the solubility and bioavailability of poorly water-soluble therapeutics. Among these, nonionic surfactants such as Triton X-100 are particularly attractive due to their biocompatibility and capacity to encapsulate structurally diverse small molecules. In this work, all-atom molecular dynamics simulations were employed to investigate the encapsulation of three drugs (aspirin, atenolol, and felodipine) within Triton X-100 micelles. The selected molecules span a broad range of hydrophobicities and hydrogen-bonding capabilities, enabling a systematic comparison of how physicochemical properties influence solubilisation behaviour and micelle morphology. The simulations reveal that drug-micelle interactions are dominated by the hydrophilic ethylene-oxide headgroups, with limited penetration into the hydrophobic core. Hydrophobicity correlates positively with total drug loading; however, deviations from this trend highlight the competing roles of polarity and conformational flexibility. Atenolol, the most polar compound, penetrates deepest into the micelle core and induces the greatest deformation, whereas felodipine's extended aromatic surface stabilises more spherical aggregates. Overall, this work demonstrates that Triton X-100 micelles adapt dynamically to chemically diverse guest molecules. The results establish quantitative structure-property relationships linking molecular features, including hydrophobicity, polarity and topology, to encapsulation efficiency and micelle shape. These insights provide molecular-level understanding of the physicochemical principles governing solubilisation in nonionic micellar systems and support the broader application of molecular simulation as a predictive tool for micelle-based drug delivery formulations.

The bioavailability of highly lipophilic, poorly soluble drugs can be improved effectively, when formulated in lipid-based systems. Solid lipids generally offer greater physical robustness than liquid lipids but slower release. Hot-melt extrusion (HME) and additive manufacturing (AM) enable personalized release by tailoring composition and geometry. However, the limited availability of suitable solid lipid-based materials, particularly for processing thermolabile and lipophilic drugs, restricts their application. Polyglycerol esters of fatty acids (PGFAs) represent a promising class of lipids due to their stable α-form, tunable hydrophilicity, and printability. Nevertheless, the interplay between lipid processing, solid state, and rheological behavior remains insufficiently understood for HME and AM. In this study, felodipine (Biopharmaceutics Classification System (BCS) class II drug) was incorporated into a PGFA matrix to obtain a fully dissolved system at the minimum processing temperature. Drug loading induced melting point depression, delayed crystallization, and introduced disorder in crystal packing, thereby weakening the crystal network and enhancing filament flexibility, enabling printability. Printable filaments were achieved at 95 °C, while an undetectable crystalline drug was observed at 120 °C. This work demonstrates that drug-lipid interactions can be employed to enhance processability: while low-temperature processing of PGFA was feasible, drug modifications into the lipid solid state impacted the rheological and mechanical properties essential for additive manufacturing. Beyond this specific system, this study provides a rational proof of concept for processing solid and liquid lipids via continuous melt-based technologies.

Amorphous solid dispersions (ASDs) are an effective formulation approach for improving the solubility of poorly water-soluble drugs. Nevertheless, their drug-release performance depends on the phase separation morphology during the dissolution process. Although the addition of surfactants has been experimentally reported to improve the dissolution behavior of ASDs, experimental methods alone are insufficient to resolve the complex and heterogeneous intermolecular interactions between drugs and excipients in multicomponent systems at the molecular level. In this study, we used dissipative particle dynamics simulations, which efficiently analyze mesoscopic phenomena such as phase separation, to elucidate the mechanisms of drug aggregation, water uptake, and phase separation, and to discuss their potential implications for drug-release behavior. Interaction parameters (χ) were derived from quantum chemical calculations and used to parameterize the coarse-grained model. We compared binary ASDs composed of felodipine and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) with ternary ASDs that additionally contained the surfactant d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), focusing on the functional role of the surfactant. Results suggested that the balance between water uptake and drug aggregation may influence drug release behavior from ASDs, potentially through interfacial liquid-liquid phase separation (LLPS)-related organization. In particular, simulations of the ternary system containing TPGS showed reduced mesoscale drug aggregation through accelerated hydration, suppression of interfacial energy growth, and steric stabilization by TPGS molecules. These structural features may facilitate drug diffusion into the aqueous phase. These simulation-derived behaviors are consistent with previous experimental observations. Overall, this study provides a mechanistic, simulation-based framework for understanding phase separation behavior and its potential influence on drug release processes in ASDs, drug release processes in ASDs, thereby guiding formulation design, particularly for surfactant-containing systems.

While self-nanoemulsifying drug delivery systems (SNEDDS) spontaneously generate nanosized emulsions, they are susceptible to thermodynamic destabilization. Characterizing the spatiotemporal fate of drug molecules during this transition remains challenging due to the limited chemical resolution of conventional particle analysis. Herein, we employed solution-state [1]H NMR to elucidate the redistribution of three model drugs, fenofibrate (FFB), felodipine (FEL), and lopinavir (LPV), during the destabilization of a Labrafac PG-based nanoemulsion. While dynamic light scattering and cryo-transmission electron microscopy confirmed the progressive phase separation of the oil carrier into large oil droplets, NMR analysis revealed that drug redistribution is highly drug-specific rather than simple oil migration. FFB exhibited a redistribution profile proportional to the degree of oil phase separation, migrating into large droplets (∼38% redistribution), reflecting its higher solubility in the oil phase compared to the other drugs. In contrast, FEL and LPV were retained within the residual smaller droplets (∼89% and ∼99% retention, respectively), despite comparable separation of the oil phase. This retention suggests a higher affinity for the surfactant-rich interface relative to the oil core, rendering the drug redistribution independent of the oil phase separation. These findings demonstrate that monitoring the physical separation of the carrier is insufficient to determine the molecular state and localization of the drug. Consequently, quantitative [1]H NMR offers a powerful, noninvasive framework to overcome the analytical limitations of conventional methods, thereby enabling molecular-level design of robust lipid-based formulations.

Calcium channel blockers (CCBs), particularly amlodipine, are among the most widely prescribed antihypertensive agents globally. However, no comprehensive disproportionality analysis has quantified this association. This pharmacovigilance study utilized the FDA Adverse Event Reporting System (FAERS) to evaluate the reporting association between CCBs and pseudolymphoma. The FAERS database was parsed through its 14 104 743 adverse event reports. Five CCBs were evaluated: three dihydropyridines (amlodipine, nifedipine, and felodipine) and two non-dihydropyridines (diltiazem, verapamil). Disproportionality was quantified using reporting odds ratios (RORs). The MedDRA preferred term "pseudolymphoma" was employed for case identification. Among 319 pseudolymphoma reports, 44 were associated with dihydropyridines and 1 with non-dihydropyridines. Amlodipine demonstrated the strongest signal (ROR 38.08, 95% CI 27.60-52.54; n = 42), followed by nifedipine (ROR 18.61, 95% CI 4.64-74.74; n = 2). Diltiazem showed a non-significant signal (ROR 5.47, 95% CI 0.77-38.93; n = 1). Felodipine and verapamil yielded no reports. Dihydropyridines exhibited 7- to 70-fold greater RORs compared with non-dihydropyridines. This analysis establishes a robust, though not causal, class-specific safety signal linking dihydropyridine CCBs, particularly amlodipine, to pseudolymphoma risk. The substantial disproportionality suggests a pharmacologically mediated mechanism requiring heightened clinical surveillance, prompt recognition, and timely drug discontinuation to prevent potential malignant transformation.

The Human cytomegalovirus (HCMV) US21 protein is a calcium-conducting viroporin that modulates intracellular Ca2+ homeostasis, safeguards cells from apoptosis, stimulates cell migration, and supports efficient HCMV replication. To validate pUS21 as a novel target for the identification of antiviral agents, in silico structure-based virtual screening was performed using its predicted structure to identify small molecules capable of engaging the inner part of the pore. Four dihydropyridine compounds (azelnidipine, efonidipine, lercanidipine, and niguldipine) were selected from 249 Calcium Channel Blockers (CCBs) in the DrugBank database. Molecular dynamics simulations of pUS21-ligand complexes predicted that the four selected CCBs formed dynamically stable and low-mobility interactions within the US21 pore, whereas the weak CCB binder felodipine remained highly mobile, supporting the predicted docking-based binding mode. The selected CCBs showed dose-dependent inhibition of HCMV replication in both fibroblasts and endothelial cells, with low micromolar EC50 values. Their antiviral effect was neither cell type- nor strain-dependent, as confirmed against two different clinical isolates, TRwt and VR1814, and was observed to be reduced against a US21-deficient virus, suggesting the specificity of pUS21 as a molecular target. Consistent with the predicted engagement within the pUS21 pore, CCBs prevented pUS21-mediated Ca2+ leakage from the endoplasmic reticulum and impaired both pUS21-induced cell migration and anti-apoptotic activity. Finally, drug combination studies revealed synergistic interactions between CCBs and maribavir treatment. Together, these findings support the hypothesis that clinically used CCBs may target pUS21 viroporin activity and hamper HCMV replication, thus offering a novel and promising antiviral strategy against HCMV, including drug-resistant strains.

Background: Amorphous drug formulations are commonly used to improve the solubility and bioavailability of poorly soluble molecular pharmaceuticals, yet less is known about their molecular conformations and local bonding interactions than their crystalline phases. Methods: High-energy X-ray diffraction structure factor measurements have been made on liquid and glassy nifedipine (NIF), felodipine (FEL), NIF 1:3 polyvinylpyrrolidone (PVP), and FEL 1:3 PVP wt.% mixtures. The corresponding X-ray pair distribution functions have been interpreted using empirical potential structure refinement using different models and density functional theory conformer calculations. Results: In both NIF and FEL, the NH···O inter-molecular hydrogen bonds between the pyridyl nitrogen and ester carbonyls are found to be considerably weaker than those observed in the crystalline polymorphs. For nifedipine, it is proposed that either inter-molecular NH…ON nitro bonds are present and/or a fraction (<20%) of conformational changes, with the aryl ring flipped, occur in the liquid state. For felodipine, the models indicate significant disorder associated with the methyl and ethyl side chains in the liquid state, with the main peak intensity at 3.0 Å arising from intra-molecular Cl-Cl atom pairs. When nifedipine molecules are incorporated into PVP, our models show they possess stronger NH···O bonds to the PVP polymer than felodipine molecules, which have stronger affinity for bonding to the polymer than to other felodipine molecules. Conclusions: The amorphous forms of both NIF and FEL show much weaker hydrogen bonding than found in their crystalline phases. Liquid NIF also exhibits configurations which are not observed in the crystal phases.

Objectives: As widely used first-line antihypertensive drugs, dihydropyridine calcium channel blockers (DHP-CCBs) have relatively few studies comparing their adverse reactions based on real-world data. This study aims to identify and compare the potential adverse drug reaction (ADR) signals of four DHP-CCBs (amlodipine, felodipine, nicardipine, and nifedipine) through the US Food and Drug Administration Adverse Event Reporting System (FAERS), providing a reference for further drug safety assessment and clinical medication risk awareness. Methods: Adverse event reports from medical professionals (Q3 2014-Q4 2024) were analyzed using signal detection methods, including reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and the Medicines and Healthcare Products Regulatory Agency (MHRA) methods. Risk signals for the four DHP-CCBs were compared with both the full database and the DHP-CCBs background. For high-risk signals in amlodipine, multivariate logistic regression was used for validation. The analysis reveals distinct ADR profiles for the four DHP-CCBs. Results: Amlodipine is strongly linked to suicide-related risks, confirmed by logistic regression. Nicardipine and nifedipine show significant risks for pregnancy-related events, such as premature delivery and exposure during pregnancy. Nicardipine is also associated with hyponatremia, hyperkalemia, and lactic acidosis. These adverse events are not yet included in the FDA labeling for any of the DHP-CCBs. Although palpitations and angioedema are listed for felodipine, their signal strength is much higher compared to the other DHP-CCBs. Conclusions: The ADR risk profiles of the four DHP-CCBs differ significantly. This study identified several high-risk adverse events not included in current labels. Clinical use should consider each drug's risk profile and patient-specific factors, with particular attention to serious risk signals. For pregnant and postpartum women, the benefits and risks of using nicardipine and nifedipine should be carefully evaluated.

This study investigated the drug-drug interaction (DDI) between the human immunodeficiency virus (HIV) medication lopinavir and the antihypertensive drug felodipine using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In vitro assays showed the Michaelis constant (Km) values of lopinavir were measured at 32.59 μM and 14.04 μM in rat liver microsomes (RLM) and human liver microsomes (HLM), respectively. The half maximal inhibitory concentration (IC50) of felodipine for lopinavir was 21.84 μM and 19.47 μM in RLM and HLM, respectively. The results indicated that felodipine significantly inhibited the metabolism of lopinavir. In the metabolic stability experiment of RLM and HLM, the clearance rate was decreased by 97.28% and 53.32%, while the elimination half time (t1/2) was increased by 35.80 and 1.14 times, respectively. Further experiments indicated that felodipine inhibited lopinavir via competitive inhibition and mixed inhibition in RLM and HLM. Pharmacokinetic studies in rats demonstrated that the AUC(0-t) and AUC(0-∞) of lopinavir in the presence of felodipine was increased by 1.56-fold and 1.55-fold, respectively, compared with those in the control group. In addition, plasma clearance (CLz/F) in the co-administration group was decreased to 65.71% compared to the control group. However, felodipine did not significantly alter the pharmacokinetic parameters of ritonavir. This study explored the interaction between lopinavir and felodipine in vitro and in vivo, enhancing the data backing for clinical research.

The antihypertensive drug felodipine (FEL) suffers from poor solubility, leading to low bioavailability, and is also known to undergo photodegradation. Co-amorphous formulations represent a promising strategy for simultaneously enhancing the physicochemical properties and stability of drugs. This study aimed to develop and characterize a novel co-amorphous system composed of FEL and puerarin (PUE) to address these challenges. The screened co-amorphous with an FEL:PUE ratio of 1:2 was obtained by solvent rotary evaporation and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR), and Raman spectroscopy. The formation of co-amorphous is supported by the typical halo pattern in the PXRD, as well as a single Tg of 51.9 °C. FT-IR and Raman spectroscopy revealed that this co-amorphous supramolecular system was connected by CO···H-O and N-H···OC interactions. The results of the dissolution experiment showed that the dissolution rate of FEL was significantly accelerated after co-amorphization. By measuring the oil-water partition coefficient, increased hydrophilicity of FEL and lipophilicity of PUE in the co-amorphous form were observed. Multiple tests suggested that the co-amorphous material had superior physical stability under accelerated or illumination conditions. Encouragingly, the enhanced in vitro physicochemical properties were effectively converted into the in vivo pharmacokinetic performance with the expedited Cmax, enhanced AUC0-t and AUC0-∞ for both FEL and PUE in co-amorphous. The current contribution not only proves that co-amorphization can improve drug bioavailability but also provides a new idea for combined treatment using traditional Chinese and chemical medicines.

Felodipine (FEL), an antihypertensive drug, is being repurposed as an anticancer drug. It has low oral bioavailability due to its extensive metabolism in the liver and poor water solubility. This study aimed to develop hyaluronic acid-coated cetylosomes (HCCs) for parenteral delivery of FEL to boost its solubility and anticancer efficacy. FEL-HCCs were prepared by the thin-film hydration technique based on Box-Behnken design. Amounts of cetyl alcohol, Brij 97, and hyaluronic acid were the independent factors. The optimized HCC (OHCC) formula which showed the highest desirability value (0.626), was composed of 100 mg Brij 97, 32.44 mg CA, and 10 mg HA. It showed the minimum vesicle size (156.72 nm) and polydispersity index (0.134), and the maximum entrapment efficiency% (72.04%) and zeta potential (-30.58 mV). After lyophilization and sterilization of the OHCC formula, it showed a 2.01-fold enhancement in FEL release compared to the market tablet, with no significant difference in release before and after lyophilization or sterilization. The sterilized OHCC was stable for six months. The OHCC showed an enhanced cytotoxicity against MCF-7 cells with 6.61-fold compared to pure FEL powder. Additionally, the OHCC potentiated the antiproliferative effect of doxorubicin, as evidenced by a raised Bax/Bcl-2 ratio and caspase 9 content, and suppressed VEGF levels. In vivo, the OHCC markedly reduced tumor growth, particularly in combination with doxorubicin. The histopathological investigation supported the apoptotic and necrotic death of cancer cells. These findings suggest that HCCs represent a promising nanocarrier system for the targeted parenteral delivery of FEL in cancer therapy.