AAPS Journal最新文献

Food effects on intestinal drug solubility and dissolution are a critical consideration in drug development, commonly investigated using simulated intestinal fluids (SIF) such as FaSSIF and FeSSIF. While these media represent average fasted- and fed-state conditions, their lack of a lipid fraction and disregard for compositional variability limit their physiological relevance and predictive power. To address these limitations, this proof-of-concept study introduces a novel set of fed-state SIF, termed digestion-induced SIF (DiSIF), featuring two key enhancements: (i) inclusion of a physiologically relevant lipid fraction generated through in vitro digestion of a liquid meal, and (ii) incorporation of variability via modulation of bile salt concentration and stage of digestion. Nine DiSIF media were developed to reflect both the average composition and the variability observed in fed-state human intestinal fluids (HIF). Overall, DiSIF media adequately predicted the micellar solubility of seven poorly water-soluble model compounds. Unlike commonly used SIF, they also enabled estimation of drug solubilization in total samples containing both micellar and lipid fractions, as observed in fed-state HIF. Furthermore, the media's compositional variability allowed for the prediction of compound sensitivity to physiological variability with relative accuracy. These findings support further refinement and validation of DiSIF media as a versatile tool for formulation development and food-effect prediction in oral drug delivery.

Controlled release of multiple herbal bioactives from electrospun polymeric fibers involves complex coupling of diffusion, polymer relaxation, swelling, and erosion within porous mat architectures. This work establishes the Multicomponent Interactive Release (MIR) model, a comprehensive framework integrating component-specific transport mechanisms with molecular interactions and mat-scale structural effects. I revisited first-principles constitutive equations for three physicochemical regimes: rigid matrices (diffusion-controlled), swollen matrices (anomalous transport), and eroding matrices (degradation-controlled). The model addresses multi-scale release from intra-fiber radial diffusion to inter-fiber transport through tortuous pore networks governed by mat porosity (ε), tortuosity (τ), fiber diameter, and packing density. Critical analysis reveals that established empirical models (Higuchi, Korsmeyer-Peppas, Peppas-Sahlin, Hopfenberg) emerge as limiting cases, with the release exponent n arising from the Deborah number. Validation against dexamethasone/PLGA and dual contraceptive drug systems demonstrates superior predictive capability (R² = 0.9847-0.9992) compared to seven conventional models. Additional model selection criteria including adjusted R² (0.9762-0.9988), root mean square error (RMSE = 0.89-2.47%), and Akaike Information Criterion (AIC) confirmed MIR superiority while accounting for model complexity. Mechanistic weighting functions deconvolute transport contributions, revealing that fiber diameter governs diffusion-erosion balance while polymer composition dictates degradation kinetics. A practical workflow for implementing the MIR model and sensitivity analysis of key parameters are provided to guide rational formulation design. This framework enables rational design of electrospun systems for complex herbal formulations and combination therapies, directly linking electrospinning process parameters to controlled release performance.

Challenges to medication administration arise in children when pediatric-friendly (PF) formulations are lacking. This study examines the extent to which PF formulations were developed for use in pediatric trials of drugs awarded 6-months of patent extension under a written request (WR). Publicly accessible and proprietary data were aggregated to characterize the formulations used in studies submitted to the U.S. FDA in support of pediatric labeling for WRs issued through September 2025. From 1998-2025, exclusivity was awarded to 321 unique sponsor:drug pairs satisfying the requirements of a WR. A majority, (235/321), received a new or updated pediatric indication and nearly all (310/321) resulted in pediatric labeling. Drugs intended for oral administration (n = 213) were supported by 304 studies. The majority (173/304) exclusively studied adult solid dosage forms (SDF), a minority (129/304) used at least one PF dosage form, and 2 accomplished labeling without the conduct of clinical trials. SDF were exclusively used in 26.3%, 44.9%, 85.1%, and 94.1% of studies in children < 2 yr, 2-5 yr, 6-12 yr and > 12 yr, respectively. Of trials employing an oral PF formulation, 85% were associated with a marketed PF product at labeling. Marketed oral PF formulations were also associated with 8% of cases where studies relied exclusively on a s SDF. Nearly all non-enteral drug studies were supported by existing commercial formulations with only investigational inhalation formulations making their way to market. Legislative provisions enacted to incentivize pediatric drug development incompletely extend to pediatric reformulation efforts despite the associated financial gains.

Pharmacokinetic (PK) and pharmacodynamic (PD) models are essential tools in drug development, making the selection of an appropriate model critically important. When using likelihood ratio tests (LRTs) to compare nested models, it is crucial to ensure their validity, especially when parameters are fixed. This work examines the continuity of likelihood functions as a necessary condition for LRT validity within the framework of population modeling. By decomposing the Objective Function Value (OFV), we identify scenarios where parameter fixing leads to non-continuous likelihood behavior, potentially invalidating the LRT application. A proof and numerical examples illustrate that while fixing population parameters maintains continuity through compensatory behavior of terms within the OFV, fixing individual parameters introduces discontinuities. Overall, this work underscores the need for careful consideration of parameter fixation in population models: It shows that population parameters can be fixed without violating the continuity condition for LRTs and suggests that introducing covariates may provide a viable alternative for fixing individual parameters. Further investigation into the sufficiency of continuity as a condition for the LRT's validity is needed.

Accurate prediction of oral drug absorption is essential for anticipating variability in bioavailability and guiding clinical development. Physiological factors, such as gastric pH, gastric emptying, and intestinal transit time, influenced by food intake and acid-reducing agents (ARAs), play critical roles in the dissolution and absorption of drugs with pH-dependent solubility. Intestinal transporters and metabolizing enzymes also affect systemic exposure by regulating drug absorption, metabolism, and excretion in the intestine. Species differences in gastrointestinal physiology, including pH profiles, transporter expression, and motility patterns, present challenges when translating nonclinical data to humans. Physiologically based pharmacokinetic (PBPK) modeling offers a mechanistic framework to address these variations by integrating drug- and species-specific parameters. By calibrating in vitro and in vivo data, PBPK models can simulate human gastrointestinal conditions and more accurately predict oral absorption dynamics, enhancing translational relevance. These models facilitate early evaluation of food and ARA impacts, transporter-related absorption variabilities, and drug-drug interactions (DDIs), supporting the rational development of formulation and dose selection. Verifying model performance in nonclinical species, commonly in dogs, can further enhance confidence in human predictions. This review highlights drug- and species-specific factors and illustrates how PBPK modeling can address uncertainties regarding drug absorption in humans using nonclinical in vitro and in vivo data. Despite challenges such as parameter uncertainty and interspecies differences, PBPK modeling remains a valuable tool for estimating drug exposure and informing biopharmaceutical and clinical pharmacology strategies.

Tissue biodistribution characterization represents a critical component of monoclonal antibody (mAb) development, yet industry practices remain fragmented despite regulatory emphasis on comprehensive exposure assessment. The IQ Consortium Tissue Concentration Working Group surveyed eleven pharmaceutical companies to evaluate current methodologies in mAb tissue concentration analysis and establish consensus recommendations. Organizations demonstrated heterogeneous portfolio compositions, with traditional monospecific IgG1 and IgG4 platforms dominating 81.8% of companies while next-generation multispecific formats and antibody-drug conjugates gained prominence. Strategic approaches to biodistribution evaluation differed markedly, as 72.7% implemented compound-dependent assessment protocols versus systematic screening paradigms. Peak measurement activity occurred during lead optimization phases (63.6%) and pre-clinical candidate advancement (54.5%), reflecting resource optimization rather than mechanistic investigation priorities. Universal adoption of ligand binding methodologies complemented mass spectrometry integration in 81.8% of programs, though analytical validation standards exhibited substantial inconsistency. Blood contamination correction procedures were systematically implemented by merely 18.2% of respondents, indicating widespread methodological gaps. While tissue concentration datasets informed translational pharmacokinetic modeling across 81.8% of organizations, physiologically-based modeling frameworks remained underutilized. Results underscore urgent requirements for analytical harmonization to strengthen regulatory submissions and accelerate therapeutic development timelines.

The U.S. Food and Drug Administration (FDA) introduced the Quality Management Maturity (QMM) initiative to promote quality practices in pharmaceutical manufacturing that extend beyond basic good manufacturing practices (GMP), as a response to the ongoing drug shortage crisis. As the FDA has yet to formalize a QMM assessment tool, this study evaluated the Parenteral Drug Association's (PDA) Quality Culture Assessment Tool (QCAT) as a potential surrogate framework. Using anonymized data from 58 life sciences companies, we assessed internal consistency and examined whether the QCAT constructs differentiated responses across organizational, regional, and manufacturing modalities characteristics. Four of five domains-Employee Ownership and Engagement, Continuous Improvement, Technical Excellence, and Communication & Collaboration-demonstrated acceptable internal consistency (Cronbach's α ≥ 0.70), whereas Leadership Commitment yielded a lower reliability coefficient (α = 0.49). Technical Excellence scores significantly differed by business function (p = 0.02), with higher ratings reported by innovator firms compared to contract manufacturing organizations (CMO). These findings suggest that the PDA QCAT offers a promising model for operationalizing QMM principles, although refinement may be needed to enhance measurement of leadership constructs.

Approximately 25% of human urothelial carcinoma (UC) cases progress to high-grade, muscle-invasive bladder cancer (MIBC), for which treatment response remains difficult to predict. To address the need for more predictive platforms, we developed an integrated in vitro-in silico system using canine UC derived organoids, which closely mirror human MIBC at the histological, molecular, and clinical levels. Organoids were irradiated at doses of 0, 5, 9, or 15 Gy and cisplatin was administered at concentrations of 0, 10, 25, 50, or 100 μM at 24 and 72 h post-plating, respectively. Cell viability was assessed one week later using a PrestoBlue metabolic activity assay. Combined effects of radiation and cisplatin were estimated using a two-dimensional Hill model, which disentangles synergism in magnitude of effect (efficacy) and potency, with directly interpretable parameters. Implementation within a Bayesian hierarchical model accommodated both between-subject and between-assay variation. The model showed inter-patient variability in response to both radiation and cisplatin, with varying potency for the radiation dose (posterior median ED50: 0.55-7.6 Gy) and cisplatin concentration (posterior median EC50: 40-174 μM), although in some cases the maximum effect fell outside the observed data range. Radiation had a generally greater contribution to the combined inhibitory effect than cisplatin. In selected cases, synergistic effects of chemoradiation were also identified, primarily in the efficacy dimension. These preliminary results establish a robust in vitro platform for assessing chemoradiation efficacy and potency, and provide essential data for the future development of personalized and optimized chemoradiation strategies in canine and human. UC.

While external factors can significantly influence the rate and extent of drug absorption from transdermal products, some of these factors are not typically accounted for in the development process. In this study, oxybutynin gel (OXY GEL) was used as a model formulation to understand the impact of a short 3 h occlusion period on the oxybutynin absorption profile both in vitro and in vivo. Using the in vitro permeation test (IVPT) design with skin from 4 human donors, OXY GEL provided significantly greater flux and cumulative amounts of oxybutynin after occlusion was applied, as compared to the unoccluded formulation. These results were in agreement with the clinical pharmacokinetic (PK) study conducted with 12 healthy volunteers when temperature, dosing, and timepoints were harmonized between in vitro and in vivo studies to help develop an in vitro-in vivo correlation (IVIVC). Described herein are the IVPT and clinical PK study methods and results used to establish the Level A IVIVC.