Pharmaceutics

Background/Objectives: This study investigated the treatment-dependent dynamics of FAP expression in human pancreatic ductal adenocarcinoma (PDAC) and preclinical xenografts to inform optimal patient selection and timing for fibroblast activation protein (FAP)-targeted theranostics. Methods: FAP expression was assessed by immunofluorescence (IF) staining of human PDAC samples, including treatment-naïve (n = 7), chemotherapy- and chemoradiotherapy-responsive tumors (n = 8), and adjacent pancreatic tissues (n = 4), and validated at the transcript level by RNA sequencing (seq). The institutional bulk RNA-seq data were integrated with a published PDAC cohort from the Human Tumor Atlas Network, together including treatment-naïve (n = 54), treatment-sensitive (n = 9), partially resistant (n = 14), treatment-resistant (n = 56), and adjacent pancreas (n = 4) tissue samples. In parallel, dynamic FAP expression was evaluated in FOLFIRINOX-sensitive PANC-1 and FOLFIRINOX-resistant SU8686 PDAC xenografts by IF. Results: IF quantification showed increased FAP expression in treatment-sensitive human PDAC compared to treatment-naïve tumors and adjacent pancreas. Integrated transcriptomic analysis revealed therapy-dependent FAP modulation, with higher FAP transcripts in treatment-sensitive tumors compared to resistant and naïve tumors. Cell-type deconvolution showed reduced inflammatory cancer-associated fibroblasts in treatment-sensitive tumors and enrichment in resistant ones, while myofibroblastic cancer-associated fibroblasts remained consistently abundant across all treatment states. In xenografts, FAP expression remained unchanged in PANC-1 tumors throughout treatment, whereas SU8686 tumors showed transient FAP upregulation on days 9 and 15 that did not persist. Conclusions: Findings highlight FAP as an abundant and actionable theranostic biomarker for PDAC patients across treatment states. Mouse models of human PDAC may not reliably recapitulate FAP changes in humans. These findings provide a framework for treatment-informed patient selection for FAP-directed theranostics in PDAC.

Objectives: To develop a physiologically based pharmacokinetic (PBPK) model of voriconazole for pediatric patients with hepatic impairment, evaluate the effects of varying degrees of hepatic impairment on voriconazole pharmacokinetics, and provide a rational basis for dose optimization. Methods: PBPK models of voriconazole were developed using GastroPlus™ version 9.9. An adult model was first developed and extrapolated to children. Physiological parameters of different hepatic impairment (Child–Pugh class A, B, and C) were then integrated to develop models for both pediatric and adult patients with hepatic impairment. The models were further adjusted and verified using data from pediatric patients with or without hepatic impairment at our hospital, followed by population simulations and pharmacodynamic evaluation. Results: The models demonstrated satisfactory predictive performance. For the literature datasets, the fold error (FE) ranged from 0.6 to 2.0 and the geometric mean fold error (GMFE) < 2.0; for in-hospital datasets, the mean absolute prediction error (MAPE) was 15.13% (normal hepatic function) and 17.27% (hepatic impairment). Simulations showed that area under the concentration-time curve (AUC) increased progressively with worsening hepatic impairment, with increases of 49–83% in Child–Pugh class A and 74–86% in class B compared with normal hepatic function. Pharmacodynamic evaluation showed that at minimum inhibitory concentration (MIC) ≤ 2 mg/L, optimized regimens and the Child-Pugh class C regimen achieved target trough concentrations with probability of target attainment (PTA) ≥ 90% and ≥ 80%, respectively. Conclusions: A PBPK model of voriconazole was successfully developed for pediatric patients with hepatic impairment, which may be useful for providing guidance for individualized dosing.

Background/Objectives: Although hydrodynamic heterogeneity in USP Apparatus II has been extensively studied, few experimental studies have examined how it affects the dosage form. This study investigated how paddle rotation speed, radial tablet position, and bottom-surface exposure affect dissolution and post-dissolution erosion patterns of paracetamol model tablets, and whether residual tablet shape provides complementary information on local hydrodynamic heterogeneity. Methods: Two paracetamol model tablet types were used: model tablets (MT) for visualization of post-dissolution shape by micro-computed tomography and photography, and MT with an embedded steel washer (SW-MT) for height measurements. SW-MT dissolution was tested at 25–75 rpm at 0D, 0.5D, and 1D positions, with and without bottom-surface coating, and evaluated using the fraction dissolved after 40 min (Q₄₀), while height changes were quantified using erosion height loss (EH) and height asymmetry (AH). Computational fluid dynamics (CFD) results aided erosion-pattern interpretation. Results: Increasing paddle rotation speed increased dissolution and erosion extent, whereas radial displacement affected erosion distribution. At 0D, residual MT shapes were comparatively symmetrical, while 0.5D and 1D produced pronounced erosion patterns. Greater erosion extent did not correspond to greater asymmetry: for uncoated SW-MT at 75 rpm, EH increased from 36% at 0.5D to 40% at 1D, whereas AH decreased from 19% to 9%. Directional erosion in MT was consistent with spatial differences in velocity and predicted surface erosion rate from CFD. Conclusions: Post-dissolution tablet shape complements dissolution profiles by revealing the spatial distribution of material loss and may serve as a complementary approach to assessing local hydrodynamic heterogeneity in USP Apparatus II.