In this Special Issue, "Development of Physiologically Based Pharmacokinetic (PBPK) Modeling", readers can find a selection of articles that discuss the most current challenges and advances in this area [...].
In this Special Issue, "Development of Physiologically Based Pharmacokinetic (PBPK) Modeling", readers can find a selection of articles that discuss the most current challenges and advances in this area [...].
Background/Objectives: Vitamin B12 deficiency is common in individuals with type 2 diabetes mellitus (T2DM) receiving long-term metformin therapy, primarily due to impaired intestinal absorption. Conventional oral B12 supplementation is often associated with delayed or inconsistent biochemical correction. A lipid-based Sucrosomial® delivery system has been shown to improve circulatory vitamin B12 levels in healthy adults with deficiency, and the present study evaluates its performance in the clinically challenging context of metformin-treated individuals with T2DM, a population characterized by pharmacologically impaired intestinal vitamin B12 absorption. Methods: This multicentre, double-blind, placebo-controlled, parallel-group randomized clinical trial evaluated the efficacy, safety, and tolerability of a Sucrosomial® vitamin B12 formulation in adults with T2DM receiving metformin and presenting with vitamin B12 deficiency. Participants were randomized (1:1) to receive oral Sucrosomial® vitamin B12 (1000 µg daily; n = 25) or placebo (n = 25) for three weeks. Serum total vitamin B12 and holotranscobalamin (HoloTC), the biologically active fraction of vitamin B12, were assessed at baseline and during follow-up, with time-to-normalization and safety analyses performed. Results: Sucrosomial® vitamin B12 supplementation resulted in rapid and sustained increases in circulating vitamin B12 levels, with early separation from placebo, and a substantially higher proportion of participants achieved normalization of serum vitamin B12 concentrations within the three-week period. Parallel improvements in HoloTC levels indicated enhanced biologically active vitamin B12 availability, and the intervention was well tolerated with no clinically relevant safety concerns. Conclusions: These findings demonstrate that an oral Sucrosomial® vitamin B12 formulation can achieve rapid and reliable biochemical repletion of both total and biologically active vitamin B12 in metformin-treated adults with T2DM, despite pharmacologically impaired intestinal absorption, while maintaining a favourable safety and tolerability profile.
Background: Lyotropic liquid crystal (LLC) systems provide sustained release and convenient administration for peptide delivery. Octreotide, a first-line somatostatin analogue, has previously been formulated into LLC systems mainly using the hydrochloride salt. Here, we investigated the acetate salt, which is widely used in marketed products, but presents unique challenges in LLC formulation due to poor stability. Methods: We demonstrate that pH adjustment is a critical determinant for successfully incorporating octreotide acetate into a stable LLC system. By employing 3M HCl-EtOH to adjust pH to approximately 5.7, we obtained a formulation that maintained >90% drug content after 3 months at 40 °C and >98% after 12 months at 4 °C. Results: Structural analyses confirmed the coexistence of cubic and hexagonal mesophases, supporting controlled release. In vivo pharmacokinetic studies in rats further demonstrated sustained-release behavior, as evidenced by prolonged systemic exposure and an extended half-life. Pharmacokinetic profiles were comparable to those of an octreotide hydrochloride LLC. Conclusions: These findings highlight pH modulation as an essential strategy for stabilizing octreotide acetate in LLC systems, providing a foundation for extending LLC technology to clinically relevant salt forms of peptide therapeutics.
Background/Objectives: Lamotrigine is an anticonvulsant and mood stabilizer with wide interindividual pharmacokinetic variability, necessitating therapeutic drug monitoring (TDM). Patient-based quality control (PBQC) strategies, such as tracking median drug concentrations, may complement traditional quality assurance in routine laboratory practice. Methods: We retrospectively analyzed 15,963 lamotrigine results collected between February 2011 and December 2025 at Uppsala University Hospital, Uppsala. Data included age, sex, sampling date, and lamotrigine concentrations. Assays were performed using the Architect platform from February 2011 to January 2021, after which the Cobas Pro c 503 platform was implemented. Yearly patient medians were calculated, and trends, seasonal variation, and method agreement were assessed. Results: Of all the results, 5967 were from males and 9996 from females. Median concentrations were slightly higher in males (15.20 µmol/L) than in females (13.71 µmol/L), representing a weak but statistically significant difference (Spearman R = -0.048; p < 0.0001). The total number of reported results increased steadily over time, from 402 in 2011 to more than 1500 annually by 2024-2025. Median lamotrigine concentrations increased from 11.85 µmol/L in 2011 to 17.40 µmol/L in 2025 (Spearman R = 0.047; p < 0.0001). Seasonal variation in sample volume was observed, with peaks in November and troughs in July and December, but median concentrations remained stable (CV = 3.49%). Method comparison showed strong agreement between Architect and Cobas assays (R2 = 0.97). Conclusions: Patient median lamotrigine concentrations serve as a robust PBQC tool, capable of detecting subtle analytical shifts while remaining resilient to seasonal fluctuations and platform transitions. This approach enhances confidence in assay reliability and supports safer therapeutic decision-making in real-world TDM practice.
In the original published paper [...].
Background: Pentamidine isethionate (PTM) and miltefosine (MF) are clinically relevant antiparasitic agents whose use is limited by toxicity, emerging resistance, and the lack of effective co-delivery strategies. Tetronic® 1307 (T1307), an amphiphilic and thermoresponsive block copolymer, was investigated as a carrier to enable their combination therapy. Methods: PTM and MF were formulated in T1307-based micelles and thermoresponsive gels. The systems were characterized by small-angle neutron scattering (SANS), dynamic light scattering (DLS), and nuclear magnetic resonance spectroscopy (NMR). Antiparasitic activity was evaluated against Leishmania major promastigotes. Results: MF formed stable micelles that efficiently incorporated PTM, generating a "drug-in-drug" architecture. While T1307 alone showed limited PTM loading, MF promoted mixed micelle formation and enhanced PTM incorporation. At physiological temperature and adequate copolymer concentrations, drug-loaded micelles formed thermoreversible gels suitable for topical application. The combined formulations preserved drug activity and exhibited synergistic effects against L. major.Conclusions: T1307 is a promising platform for the co-delivery of PTM and MF, enabling synergistic combination therapy and thermoresponsive gel formation with potential to reduce systemic toxicity and improve treatment administration.
Glioblastoma is the most common and aggressive brain tumour in adults, and despite ongoing efforts, effective treatment remains limited. Standard therapies often face challenges because of the tumour's specific biology, its aggressive nature, and the presence of certain physiological barriers in the brain that impede chemotherapeutics from reaching their target. Emerging research in circadian biology highlights the role of the internal circadian clock in tumour progression and treatment response. Evidence suggests that aligning therapy to patients' chronotypes could potentially improve treatment outcomes. At the same time, advances in nanotechnology-including functionalized nanoparticles for drug and/or gene delivery-show promising results while reducing side effects. Additionally, evolving and prominent artificial intelligence tools may significantly contribute to progress in the design of next-generation personalised therapies. This review provides a unique and integrative perspective by examining the hurdles in treating GB and exploring innovative strategies, such as the integration of nanotechnology into chronotherapy protocols, to enhance therapeutic efficacy. The Chronobiology-Nanotechnology combination could not only improve GB patients' survival rates but also lead to a more effective and less toxic personalised approach, distinguishing this work from previous reviews.
Background/Objectives: The precise elimination of Schistosoma japonicum eggs within host tissues poses a significant therapeutic obstacle due to the ineffectiveness of existing drugs in penetrating the eggs' protective shields. This investigation sought to create a surface-modified magnetic nanoparticle (MNP) framework to surmount this hurdle and realize targeted theranostics for combating schistosomiasis. Methods: Fe3O4 MNPs, MNP-NH2, and MNP-COOH were synthesized and characterized before systematically studying their interactions with parasites. The intrinsic autofluorescence of eggs and adult worms served as an optical background for the investigation. In vitro co-incubation assays, confocal microscopy, and Prussian blue staining were utilized to quantify both adsorption and internalization. The in vivo efficacy was assessed in a Schistosoma japonicum murine model following tail vein injection. Results: A pronounced surface chemistry-dependent interaction was noted. Fe3O4 MNP and MNP-NH2 displayed remarkable adsorption and effective internalization into eggs in vitro, while MNP-COOH exhibited limited uptake. This varying effectiveness was similarly observed in vivo, with Fe3O4 MNP and MNP-NH2 predominantly gathering in hepatic granulomas and effectively infiltrating deposited eggs. Within adult worms, Fe3O4 MNP and MNP-COOH exhibited distribution on the tegument and within adult worms. Conclusions: We developed a functional MNP platform in which surface charge governs parasiticidal targeting. Among the candidates investigated, MNP-NH2 proved to be the most efficient for egg-targeted theranostics. This study introduces an innovative nanotechnology-based approach for accurate diagnosis and treatment of schistosomiasis by specifically tackling the challenge of impermeable eggs.
Background/Objectives: Fluvoxamine is commonly prescribed for depressive disorders in elderly patients, a population that frequently exhibits variable drug responses and increased susceptibility to adverse effects due to age-related physiological changes. CYP2D6 polymorphisms may further affect fluvoxamine pharmacokinetics in elderly patients, complicating dose optimization for this group. Previous pharmacogenetic studies examining the impact of CYP2D6 phenotype on fluvoxamine treatment outcomes have primarily focused on younger adults, leaving a gap in understanding its effects on the elderly. Methods: The impact of CYP2D6 phenotypes on fluvoxamine exposure in geriatrics was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach incorporating geriatric-specific physiological parameters. Results: The fluvoxamine PBPK model was verified using clinical pharmacokinetic data from younger and older adults, along with phenotype-dependent exposure differences between CYP2D6 poor metabolizers (PMs) and extensive metabolizers (EMs). Simulations showed that steady-state exposure in elderly patients was 1.8-fold higher than those in younger adults, and 2.1-fold higher in CYP2D6 PMs compared with EMs. Based on these simulations, doses of approximately 50 mg/day for PMs, 50-100 mg/day for intermediate metabolizers (IMs), 100 mg/day for EMs, and 150-200 mg/day for ultrarapid metabolizers (UMs) may be appropriate for elderly patients, accompanied by cautious dose escalation and clinical monitoring. Conclusions: These findings suggest that CYP2D6 genotype-guided dosing may be a useful strategy for optimizing fluvoxamine therapy in elderly patients, with the potential to improve treatment outcomes while minimizing the risk of adverse drug reactions in this high-risk population.
Background/Objectives: Antisense oligonucleotides (ASOs) hold great therapeutic potential due to their precise ability to modulate gene expression, particularly for treating genetic and neurological disorders. However, effective delivery of ASOs remains a major challenge. While most recent research focused on lipid nanoparticles (LNPs) as ASO carriers, alternative formulations, preparation methods and lipid compositions on delivery optimization are not fully explored. In this study, we investigated two types of formulations, lipoplexes (LPXes) and LNPs, prepared using lysine-type cationic lipids, K3C14 or K3C16, selected from a lysine-type lipid mini-library for their superior formulation stability and distinct cellular entry mechanisms. Methods: The physicochemical properties of the formulations were characterized using dynamic light scattering. Cytotoxicity was evaluated in spleen and liver cell lines. LPXes and LNPs were assessed for ASO delivery efficiency using an engineered HEK293 split-luciferase cell line, while immune response was evaluated in human peripheral blood mononuclear cells. Cryogenic electron microscopy (Cryo-EM) images were captured for structural analysis. Results: Lysine-type lipid mini-library screening identified lipids with either a hydrocarbon spacer K3 or C14 fatty acid tail exhibiting great stability and safety. Among the tested LPX and LNP formulations, the K3C16 lipoplex demonstrated ASO delivery efficiency and immune responses comparable to the benchmark SpikeVax LNP formulation. Notably, Cryo-EM imaging revealed novel structures that have not been reported previously; the K3C14 lipoplex formed a rouleaux-like structure, whereas the K3C16 lipoplex exhibited a lipid nanosheet-like structure, distinct from the conventional LNP structure. Conclusions: These results highlight the potential of an unconventional type of lipid assembly for efficient ASO delivery.
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