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Background: Darunavir is a second-generation protease inhibitor and is registered for the treatment of HIV-1 infection. The aim of this study was to develop and validate a darunavir population pharmacokinetic model based on data from daily practice.
Methods: Data sets were obtained from 2 hospitals: ASST Fatebenefratelli Sacco University Hospital, Italy (hospital A), and University Medical Center Groningen, the Netherlands (hospital B). A pharmacokinetic model was developed using data from the largest data set using the iterative two-stage Bayesian procedure within the MWPharm software package. External validation was conducted using data from the smaller data set with Passing-Bablok regression and Bland-Altman analyses.
Results: In total, data from 198 patients from hospital A and 170 patients from hospital B were eligible for inclusion. A 1-compartment model with first-order absorption and elimination resulted in the best model. The Passing-Bablok analysis demonstrated a linear correlation between measured concentration and predicted concentration with r = 0.97 (P < 0.05). The predicted values correlated well with the measured values as determined by a Bland-Altman analysis and were overestimated by a mean value of 0.12 mg/L (range 0.23-0.94 mg/L). A total of 98.2% of the predicted values were within the limits of agreement.
Conclusions: A robust population pharmacokinetic model was developed, which can support therapeutic drug monitoring of darunavir in daily outpatient settings.
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http://dx.doi.org/10.1097/FTD.0000000000000576 | DOI Listing |
J Med Chem
September 2025
Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
New treatment strategies are required to combat the spread of drug-resistant malaria. The synthesis and preclinical evaluation of novel 3-hydroxy-propanamidines (HPAs), with modifications of the phenanthrene and the 4-fluorobenzamidine moieties, has yielded several analogs exhibiting excellent in vitro growth inhibition of drug-sensitive or resistant fresh clinical isolates and culture-adapted strains. No cytotoxicity in the human HepG2 cell line was observed, demonstrating notable parasite selectivity.
View Article and Find Full Text PDFPLoS Pathog
September 2025
State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Coronavirus, a large family of positive-sense RNA viruses, are responsible for both mild and severe respiratory illnesses, ranging from the common cold to life-threatening conditions. Despite significant advances in vaccine and antiviral development, the high mutability of human coronaviruses (HCoVs), such as SARS-CoV-2, presents a major challenge in treating these infections. Effective, broad-spectrum antiviral drugs are urgently needed to address both current and future HCoV outbreaks.
View Article and Find Full Text PDFTarget Oncol
September 2025
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Background: Population pharmacokinetic models can potentially provide suggestions for an initial dose and the magnitude of dose adjustment during therapeutic drug monitoring procedures of imatinib. Several population pharmacokinetic models for imatinib have been developed over the last two decades. However, their predictive performance is still unknown when extrapolated to different populations, especially children.
View Article and Find Full Text PDFAdv Ther
September 2025
Teva Branded Pharmaceutical Products R&D LLC, West Chester, PA, USA.
Introduction: Pharmacokinetic differences between long-acting injectable antipsychotic (LAI) formulations, combined with a lack of clinical switch studies, contribute to clinician uncertainty when transitioning between LAIs. This analysis employed a population pharmacokinetic (popPK) modeling approach to characterize dosing conversions and switching strategies from intramuscular paliperidone palmitate once monthly (PP1m) to TV-46000, a long-acting subcutaneous formulation of risperidone, once monthly (q1m), with a secondary analysis of PP1m to TV-46000 every 2 months (q2m).
Methods: For PP1m and TV-46000, concentration-time profiles for paliperidone and TV-46000 total active moiety (TAM; risperidone + paliperidone) were simulated on the basis of published popPK models with virtual populations of 5000 patients.
J Med Chem
September 2025
Applied Pharmaceutical Science, Inc., Building 10-1, No.2, Jingyuan North Street, BDA, Beijing 100176, China.
This study reports the discovery and preclinical activity of APS03118, a novel selective RET inhibitor featuring a novel tricyclic pyrazolo[3',4':3,4]pyrazolo[1,5-]pyridine hinge-binding scaffold designed to overcome acquired resistance to first-generation selective RET inhibitors (SRIs). By enhancing hydrogen bonding with conserved hinge residues (Glu805, Ala807), APS03118 potently inhibits wild-type RET and diverse resistance mutations, including solvent-front (G810R/S/C), gatekeeper (V804M/L/E), roof (L730I/M), and hinge (Y806C/N/H) variants. In preclinical models, APS03118 induced complete tumor regression in KIF5B-RET and CCDC6-RET V804 M patient-derived xenografts (PDXs) and significantly prolonged survival in an intracranial CCDC6-RET metastasis model.
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