Journal of Clinical Pharmacology最新文献

Anti-tuberculosis drug-induced liver injury (ATLI) is the most harmful to anti-tuberculosis (TB) treatment. This study aims to construct and validate a binary ATLI risk prediction model based on clinical data through seven machine learning algorithms (logistic regression, decision tree, support vector machine, random forest, gradient boosting decision tree, extreme gradient boosting, and light gradient boosting machine [LightGBM]). A retrospective cohort of 2356 TB patients followed between January 2017 and December 2024 was used to develop and evaluate the prediction model. Random undersampling was performed to address class imbalance problem. Least absolute shrinkage and selection operator (LASSO) regression was used to select features and retained 27 of 31 original features. Seven ML algorithms were trained and the LightGBM model demonstrated optimal performance in testing set based on the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity (AUC = 0.789, sensitivity = 0.734, and specificity = 0.706). The model exhibited optimal simplicity and stability when incorporating the 8-feature combination comprising baseline high-density lipoprotein cholesterol (HDLC), γ-glutamyl transpeptidase (GGT), triglycerides, total cholesterol (TCHOL), uric acid, total bilirubin (TBIL), globulin (GLB), and liver disease history (AUC = 0.764, sensitivity = 0.758, and specificity = 0.610), and Shapely additive explanations analysis also revealed that these variables were the most influential contributors. The optimal model maintained robust predictive ability in the external validation cohort (AUC = 0.721, sensitivity = 0.828, and specificity = 0.604). This study determined that the combination of baseline HDLC, GGT, triglycerides, total cholesterol (TCHOL), uric acid, TBIL, GLB, and liver disease history was an important predictor of ATLI through LightGBM model, which could help clinicians in the early identification of ATLI.

Linezolid is a widely used antimicrobial agent in clinical practice; however, its usage is often limited by linezolid-induced thrombocytopenia (LIT). While prior studies have assessed linezolid plasma concentrations, the clinical relevance of its metabolites, PNU-142300 and PNU-142586, remains unclear. This study aimed to investigate the association between these metabolite concentrations and LIT, and to identify predictive thresholds. This study retrospectively analyzed patients treated with linezolid at Osaka Metropolitan University Hospital between January 2017 and December 2024. Patient characteristics, trough concentrations (C_trough), AUC₂₄, and pharmacokinetic parameters of linezolid and its metabolites were compared among patients with and without thrombocytopenia. Receiver operating characteristic (ROC) analysis identified thresholds for LIT prediction. Risk factors were assessed using multivariate logistic regression analysis. Forty-eight patients were included, with thrombocytopenia developing in 26 patients (54.2%). C_trough and AUC₂₄ of PNU-142300 and PNU-142586 were significantly higher in the thrombocytopenia group; meanwhile, linezolid C_trough and AUC₂₄ did not differ significantly. ROC analysis identified C_trough ≥1.43 µg/mL and AUC₂₄ ≥37.8 mg h/L for PNU-142586 as predictive thresholds. Multivariate analysis revealed that linezolid therapy ≥14 days (OR = 9.53, P =  .044) and PNU-142586 C_trough ≥1.43 µg/mL (OR = 37.60, P =  .002) as independent risk factors. Elevated PNU-142586 concentrations were associated with a higher cumulative incidence of LIT. Accumulation of linezolid metabolites, especially PNU-142586, is closely associated with LIT. Monitoring of PNU-142586 may improve the safety of linezolid therapy and support individualized dosing strategies.

GS-1427 is the oral prodrug of GS-1069518, an inhibitor of the α4β7 integrin, and is currently in development for the treatment of ulcerative colitis (UC). This first-in-human, phase 1, placebo-controlled study evaluated the pharmacokinetics, safety, and tolerability of GS-1427 and GS-1069518 after single oral doses (20-1000 mg) or multiple once-daily doses (20-500 mg) of GS-1427 for 14 days. The bioavailability of tablet versus capsule formulations and the effect of food and an acid-reducing agent (omeprazole) on exposure were also assessed. Overall, 148 healthy participants were enrolled, and 143 completed the study. GS-1427 was quickly converted to GS-1069518 during absorption. Upon repeated once-daily dosing of GS-1427 under nonfasting conditions, steady-state exposure to GS-1069518 was reached by day 5 with limited accumulation observed. At steady state, the median time to maximum concentration for GS-1069518 was 1-3 h and the mean terminal half-life was 6.7-28.3 h. Bioavailability was lower in the tablet than in capsule formulation. Food intake and omeprazole coadministration reduced the exposure to GS-1069518 by approximately 20%-40%. Overall, 26/122 participants (21.3%) who received GS-1427 and 8/26 participants (30.1%) who received placebo experienced at least one treatment-emergent adverse event (AE). Of the 148 participants, 10 (6.8%) experienced a treatment-related AE, the most common being nausea (5/148, 3.4%) and diarrhea (3/148, 2.0%). All AEs were grade 1 in severity and no serious AEs or deaths were reported. The pharmacokinetics, safety, and tolerability results from this study support further evaluation of GS-1427 in a phase 2 trial in patients with UC.

Despite the ability of radionuclide therapy to significantly prolong progression-free survival and overall survival in several different cancer types, most patients show only partial tumor responses or stable disease, while some patients show progressive disease in spite of therapy. Co-administration or sequential administration of selected drugs whose mechanism of action complement the properties of radionuclide therapy may provide a pharmacological basis to potentially overcome some of the limitations of radiopharmaceutical therapy and may enhance clinical efficacy by additive or synergistic cytotoxic effects. The rational design and evaluation of novel radiopharmaceutical-drug combinations and optimization of dosage and administration schedules, within the complex context of individualized multimodal cancer treatment, requires a multidisciplinary approach, principally including clinical pharmacology. Potential strategies include upregulation of target receptors, co-administration of cytotoxic chemotherapeutic drugs, co-administration of drugs that inhibit DNA damage repair, co-administration of drugs that inhibit the mammalian (or mechanistic) target of rapamycin signaling pathway, co-administration of drugs that activate immune responses, and co-administration aimed at modifying pharmacokinetics to prolong retention time of radiopharmaceuticals and increase the absorbed radiation dose. Several phase II trials are currently underway, highlighting a role for clinical pharmacology in the exploration of methods to further improve efficacy of radionuclide therapy.

Developing therapeutics for multiple immune-mediated indications has become a prominent strategy, driven by advances in disease biology, pharmacology, clinical and regulatory science. We analyzed 34 FDA-approved small molecular and antibody-based drug products with more than one adult immune-mediated inflamamatory indication by December 2024. A clear trend toward pathway-driven development was seen, with shared targets (e.g., TNFα, IL-17, IL-23, and JAKs) enabling indication expansion. Approved indications per product ranged from 2 to 8 (median: 3). Over time, the median gap between subsequent indication approvals decreased from 3.2 years (range 1.1-12.8) for products first approved in 1998-2008 to 1.7 years (range 0.67-2.75) for those approved after 2018, reflecting improved efficiency likely due to broader adoption of pathway-based strategies. Route of administration also evolved for antibody-based therapies, with median delays of 5.8-6.0 years for intravenous-to-subcutaneous (IV-to-SC) and 4.4-8.5 years for subcutaneous-to-intravenous (SC-to-IV) transitions. Fewer than 25% of therapies kept the same dosing regimen across indications, with small molecules more likely to retain dosing (62.5%, 5/8) than antibodies (11.5%, 3/26), indicating the need for tailored approaches based on disease context, tissue involvement, and patient characteristics. Key clinical pharmacology considerations include rational dose selection, surrogate and extrapolation strategies, and model-informed bridging, leveraging existing data to inform subsequent indications. Early regulatory engagement, strategic target selection, robust trial design, harmonized safety database, and cross-functional coordination are critical. Our analysis provides insights to guide multi-indication development to improve patient access to therapies for diverse immune-mediated disorders.

New drugs are urgently needed to treat drug-resistant tuberculosis in combination regimens. Ganfeborole demonstrated bactericidal activity and good tolerability in clinical trials. In preclinical studies, ganfeborole showed embryofetal developmental effects, currently mandating highly effective non-user dependent contraception in women of childbearing potential. We conducted a Phase 1, open-label, single-center, fixed sequence, 1-way drug-drug interaction (DDI) study in 20 healthy women of non-childbearing potential aged 18-65 years. The primary objective was to assess ganfeborole's effect at steady-state (20 mg daily) on single dose pharmacokinetics of ethinyl estradiol [EE] 0.03 mg/levonorgestrel [LNG] 15 mg (Bayer). Endpoints were EE and LNG area under the plasma concentration-time curve extrapolated to infinity (AUC_(0-inf)) and maximum concentration (C_max). Unexpected fluctuations in individual EE and LNG plasma concentration-time profiles limited the number of acceptable endpoints for the analysis. Geometric mean ratios (GMR; EE/LNG+ganfeborole versus EE/LNG alone) and respective 90% confidence intervals (CI) for EE C_max (0.96, 0.85-1.09), LNG AUC_(0-inf) (1.10, 0.98-1.23) and LNG C_max (1.08, 0.97-1.19) met criteria for lack of DDI (90% CI 0.80-1.25). However, the GMR for EE AUC_(0-inf) was 0.88, with 90% CI 0.55-1.41. While post-hoc analyses on partial AUCs (up to 8 and 24 h) provided GMR 90% CIs within 0.80-1.25, a lack of DDI could not be concluded. No treatment-related adverse events were reported. Further assessments of potential DDI between ganfeborole and combined oral contraceptives are warranted. Future trials will maintain strict contraception requirements. Clinical Trial Registration: NCT06354257 (registration date: 2024-04-03); EudraCT: 2023-507839-38-00.

Dordaviprone (ONC201) is a small molecule protease activator being developed for gliomas. The aim of this work was to evaluate the pharmacokinetics and safety of dordaviprone when administered to participants with moderate hepatic impairment compared to healthy matched participants. A non-randomized, open-label, single-dose study was conducted in eight participants with moderate hepatic impairment classified according to Child-Pugh criteria, and eight healthy participants matched based on age (+10 years), body mass index (BMI; +20%), and sex. Plasma concentrations of dordaviprone and the major inactive metabolite, ONC207, were determined by a validated liquid chromatography-tandem mass spectrometry method. Exposure following oral administration of 125 mg dordaviprone was increased in participants with moderate hepatic impairment relative to healthy matched participants, with the largest impact occurring on AUC. Ratios of geometric means and 90% confidence intervals (CIs) of dordaviprone exposure for C_max, AUC_last, and AUC_inf in the moderate hepatic impairment cohort compared to the healthy matched cohort were 1.21 (0.88, 1.67), 1.50 (1.02, 2.20), and 1.55 (1.05, 2.29), respectively. Treatment-emergent adverse events were mild in nature and considered not related to dordaviprone administration. While administration of dordaviprone in participants with moderate hepatic impairment led to increased dordaviprone exposures, the anticipated increase after the recommended 625 mg dose is within exposures assessed in the thorough QT study. Therefore, no dose adjustment in patients with mild or moderate hepatic impairment is recommended.