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), AUC, 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 and AUC of PNU-142300 and PNU-142586 were significantly higher in the thrombocytopenia group; meanwhile, linezolid C and AUC did not differ significantly. ROC analysis identified C ≥1.43 µg/mL and AUC ≥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 ≥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.

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, AUC, and AUC 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.

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.

The poly(ADP-ribose) polymerase inhibitor talazoparib, combined with the androgen receptor inhibitor enzalutamide is approved for patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) in the US and with mCRPC in whom chemotherapy is not clinically indicated in Europe. We provide a population pharmacokinetic model for this combination in patients with mCRPC unselected for HRR deficiencies from TALAPRO-2 (NCT03395197). The pooled dataset included 811 patients treated with enzalutamide plus either talazoparib or placebo. The final enzalutamide model was a two-compartment model with first-order absorption and inter-individual variability (IIV) on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) and included effects of baseline body weight and age on CL/F and Vc/F. For the active metabolite N-desmethyl enzalutamide, a two-compartment model with IIV on CL and Vc adequately described the observed data and included the effect of body weight on CL and Vc. The final talazoparib model was well characterized by a two-compartment model with first-order absorption and IIV on talazoparib apparent base clearance (CL/F) and Vc/F. The effect of enzalutamide and N-desmethyl enzalutamide on CL/F of talazoparib was modeled through a linear relationship. The single covariate effect of baseline creatinine clearance on CL/F showed that relative to the reference value for normal renal function, CL/F decreased by 8% for mild, 27% for moderate, and 46.7% for severe renal impairment. Simulations showed that a dose reduction of enzalutamide does not require talazoparib dose modification since the magnitude of exposure reduction for talazoparib was not considered clinically significant.

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.

Currently, the same weight-based caffeine citrate dosing regimen is applied to all neonates. However, due to differences in growth trajectories by gestational age (GA) and altered caffeine elimination in neonates with renal injury, optimal dosing regimens may differ. In this study, we refined the existing physiologically based pharmacokinetic (PBPK) model for caffeine in preterm neonates (GA 25-32 weeks) using Simcyp to evaluate dosing across varying ages and renal function. Real-world data were used to generate weight-for-age growth curves and create virtual preterm populations. CYP1A2 ontogeny model was updated to better reflect the reduced metabolic activity of caffeine in preterm neonates. A 13.7-fold increase in glomerular filtration rate-adjusted renal clearance was needed to match observed data. Additionally, a higher volume of distribution (0.96 L/kg) was required to account for increased body water. The final model was verified using clinical pharmacokinetic data and used to simulate plasma concentration-time profiles. Our simulations showed that more premature neonates (≤28 weeks GA) may require lower weight-based maintenance dosing (8 mg/kg) compared with those with higher GA (10 mg/kg), and may also require an increase in doses after 4-6 weeks of therapy to maintain therapeutic levels. Neonates with significantly reduced renal function (25% of normal) may need a two- to threefold dose reduction. Future studies should aim to define optimal therapeutic targets, as caffeine use continues to expand.

This study systematically evaluated the predictive performance of 10 international warfarin dosing algorithms (originating from the United States, China, Singapore, Thailand, India, United Kingdom, Japan, and South Korea) in 87 Chinese patients, aiming to identify optimal algorithms for warfarin dose optimization. Clinical and genetic data were analyzed using mean dose error (MDE) and ideal dose prediction (IDP) rate metrics, with sensitivity analysis stratifying patients into low-dose (≤14 mg/week, n = 21), medium-dose (14-21 mg/week, n = 43), and high-dose (≥21 mg/week, n = 23) groups based on actual weekly maintenance dose (mean: 18.9 ± 8.8 mg/week). Results revealed significant variation in MDEs (-6.6 to 11.3 mg/week) across algorithms. The Chinese-developed Huang algorithm and Thai-developed Sangviroon algorithm demonstrated superior overall accuracy, both achieving MDEs <1 mg/week and IDPs >40%. In medium-dose patients, their performance was particularly robust (Huang IDP: 65.1%; Sangviroon IDP: 74.4%). However, both algorithms showed limitations at dose extremes: they overestimated doses in 90.48% of low-dose patients and underestimated doses in 60.9%-65.2% of high-dose patients. This evidence indicates that region-specific algorithms (Huang and Sangviroon) outperform internationally recommended models (e.g., IWPC/Gage endorsed by CPIC) for warfarin dosing in Chinese populations. Locally derived algorithms may thus offer greater clinical utility despite current international guidelines.

There is keen interest amongst the general population in preventing aging and age-related infirmities. Sirolimus is approved for preventing organ rejection in kidney transplant patients, has immune-modulating and growth-inhibitory properties, and is one of the therapies currently being used off-label for this purpose. There is a lack of formal guidance, such as a policy statement or position paper, on the appropriate dosing and administration of sirolimus for aging prevention. The American College of Clinical Pharmacology strongly recommends that clinicians prescribing sirolimus weigh the benefits and risks of sirolimus for off-label use in aging prevention, ensuring patients understand that such prescriptions lack any regulatory approval and rigorous supporting evidence. Health care providers are also encouraged to inform patients of the available clinical evidence and ongoing clinical trials in age-related conditions to build a stronger foundation of safety, efficacy, and optimal dosing for sirolimus in aging prevention.

Posdinemab, a humanized immunoglobulin G1/κ monoclonal antibody, binds with high affinity to phosphorylated tau protein which is associated with Alzheimer's disease (AD) pathophysiology. Posdinemab reduced tau seeding in murine models and was well tolerated in Phase-1 clinical studies. This open-label, single-arm, Phase-1 study examined the effects of posdinemab with single intravenous dose (60 mg/kg) in healthy adults from China. The main objectives were to assess posdinemab serum pharmacokinetics (PK, primary), safety and tolerability (secondary), and presence of anti-drug antibodies (ADAs; secondary). Results were compared with Phase-1 European first-in-human (NCT03375697) and Japanese (NCT03689153) studies. Healthy Chinese participants (N = 10), mean age 60.0 (SD 3.80) years and 60% female, received posdinemab. Mean posdinemab serum C was 1401 µg/mL, median t was 0.08 days, mean AUC was 18162 µg·day/mL, mean CL was 3.36 mL/day/kg, and mean elimination t was 17.5 days. Most participants (n = 8; 80%) experienced ≥1 treatment-emergent adverse event (TEAEs), most common (20%) of which were arthralgia and back pain. Four participants (40.0%) were positive for posdinemab ADAs post-dose with peak titers of 1:22.5 (n = 3) and 1:360 (n = 1). Serum posdinemab concentrations in ADA-positive and ADA-negative participants were generally comparable. In conclusion, PK profile of posdinemab in healthy participants from China was in the expected range and comparable to previous Phase-1 studies in Europe and Japan. There were no new safety concerns. These results support further global development of posdinemab in AD.

Malnutrition occurs at higher rates in children with complex medical conditions and can independently influence drug disposition and action. Yet FDA-approved product labels rarely address dosing in malnutrition. This study explores the extent to which malnourished children are expressly excluded from clinical trials. Industry-sponsored, pediatric, phase I-III studies deposited in ClinicalTrials.Gov through December 2024 with a full study protocol were reviewed. Protocols were evaluated for inclusion and exclusion (I/E) criteria related to anthropometric and clinical indicators of malnutrition. I/E criteria were fully characterized along with the study phase, intervention type, and treatment indication. 9882 studies were identified, 1759 with an uploaded protocol. 616 studies (35%) contained 777 distinct I/E criteria related to malnutrition (1-6 per study). Across all protocols, 71% exclusively restricted participation of children with evidence of undernutrition, 9% with overnutrition, and 20% with both. There were no statistical differences observed based on intervention type, though differences by study phase were observed. Restrictions were seen most frequently for respiratory, mental/behavioral, obstetric/perinatal, and emergency use indications and least frequently for dermatologic, oncologic, and eyes, ears, nose, and throat disorders. Non-specific I/E criteria suggest that these findings likely underestimate the extent of malnutrition-based exclusions. Despite growing attention paid to obesity, pediatric clinical trials are far more likely to restrict the participation of undernourished children. Though unrealistic to relax malnutrition related I/E criteria for all studies, consideration should be given for conditions where high rates of malnutrition are expected to avoid trial populations that do not reflect clinical practice.

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.

Dapoxetine is a short-acting selective serotonin reuptake inhibitor used to treat premature ejaculation. However, its clinical effectiveness is challenged by substantial inter-individual variability in pharmacokinetics, as both the drug's therapeutic efficacy and the incidence of adverse reactions are highly dependent on its exposure. This study aims to develop a population pharmacokinetic model for dapoxetine, to investigate the sources of the variability, and to identify demographic and pharmacogenetic factors that influence drug exposure. The pharmacokinetic data for this analysis were obtained from a bioequivalence study conducted in 39 healthy Chinese male subjects. As part of this study, all volunteers were genotyped for the CYP3A4*1G, CYP3A5*3, CYP2D6*10, and CYP2D6*41 allelic variants. Population pharmacokinetic modeling was performed in Monolix. The final model was then used to simulate and compare the effect of different covariate levels on dapoxetine exposure. A two-compartment model with first-order absorption and an absorption lag time best described the pharmacokinetics of dapoxetine. The population parameters for apparent clearance (CL/F), apparent intercompartmental clearance (Q/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption lag time (Tlag), and absorption rate constant (ka) were 37.8 L/h, 17.2 L/h, 65.6 L, 191.7 L, 0.68 h, and 1.29/h, respectively. CYP2D6*10 and CYP2D6*41 alleles were found to be significant covariates on CL/F. The CYP3A4*1G allele influenced Q/F, while body mass index (BMI) was a significant covariate on Vc/F. Our analysis identified CYP2D6*10 and CYP2D6*41 polymorphisms as the significant factors contributing to inter-individual variability and influencing drug exposure.

Tacrolimus is a first-line immunosuppressant used after solid organ transplantation that suffers from extensive intra- and inter-patient variability and a narrow therapeutic window. Its critical role in a fragile population, coupled with the difficulties identifying and maintaining an appropriate dose within a given patient, make it an ideal candidate for population pharmacokinetic (popPK)-guided individualized dosing approaches (i.e., model informed precision dosing, MIPD). We previously published a tacrolimus popPK model in pediatric heart transplant recipients that showed promise in its ability to predict future concentrations within an individual. Using that model, we developed a Bayesian forecasting decision support tool (DST) clinical use to more rapidly attain appropriate tacrolimus dosing in this population. After rigorous in silico testing of the DST's mathematical fidelity to the popPK model, we implemented the DST within a clinical trial (NCT04380311). Fifteen children between 6 months and 17 years of age had their tacrolimus doses guided by the DST to determine the time to stable therapeutic tacrolimus dosing (defined by three consecutive concentrations within the targeted therapeutic range). DST-guided dosing achieved stable tacrolimus dosing ∼3 days faster (6.9 days, P = .03) as compared to a historical cohort (9.8 days). This was despite the poor performance of the DST in two children treated with continuous renal replacement therapy. These results demonstrate the clinical utility and benefit of the described DST, which is the first targeted to the pediatric heart transplant population. Rapid attainment of stable therapeutic tacrolimus dosing has benefits for the patient, clinician, and the healthcare system.

Melatonin is increasingly used to treat sleep disturbances, yet its overall efficacy remains unclear due to variability in existing evidence. This scoping review aimed to synthesize systematic reviews with meta-analyses assessing the effects of exogenously administered melatonin on sleep quality in humans. Seven databases were searched from inception to July 9, 2025. Eligible studies were systematic reviews containing at least one meta-analysis evaluating melatonin's effects on any domain of sleep quality compared to any comparator. Fifty-seven systematic reviews were included, comprising 227 meta-analyses. Overlap in primary studies was low (corrected covered area = 2.5%), suggesting that reviews drew on largely distinct evidence bases. Methodological quality was variable: only 8.8% of reviews met all seven predefined criteria for rigor, including protocol pre-registration, dual screening, and bias assessments. Vote counting based on the direction of effect was used to summarize efficacy. Of the 215 meta-analyses comparing melatonin to an inactive comparator, 80.9% favored melatonin, 7.9% favored the comparator, and 11.2% reported unclear results. Sleep quality was assessed using heterogeneous definitions and tools, with few reviews evaluating overall sleep quality directly. Adverse events were commonly reported and generally mild, with headaches, gastrointestinal problems, and dizziness most frequently observed. However, inconsistent terminology and reporting limited synthesis. Despite heterogeneity in review methods and outcome definitions, the direction of evidence consistently favored melatonin over placebo. These findings support the feasibility of a future quantitative umbrella review to estimate pooled effects and guide clinical practice.

Oxcarbazepine (OXC) is a second-generation antiseizure medication, effective through its active metabolite, 10-mono-hydroxy derivative (MHD). OXC is used as adjunctive therapy for focal-onset and primary generalized tonic-clonic seizures, with recommended dosing based on age and body weight. This study uses physiologically based pharmacokinetic (PBPK) modeling and leverages pharmacokinetic (PK) data acquired from children enrolled in pragmatic trials to understand dosing and subsequent exposure requirements in children with obesity. Drug concentrations of OXC and MHD (n = 148 each) from children with (n = 31) and without (n = 10) obesity, aged 2-20 years, were collected from two clinical trials (NCT01431326 and NCT02993861) and used for external evaluation of a previously developed PBPK model of OXC using PK-Sim. We used a previously published virtual population that accounts for the obesity-related changes in physiology (e.g., liver size and glomerular filtration rate) in children for PK simulations in children with obesity. Model evaluation showed that ≥80% of MHD concentrations contributed by about two thirds of study subjects (26 out of 41) fell within the 90% prediction interval. The PBPK model showed that children with obesity had lower median (interquartile range) simulated weight-normalized clearance (0.060 L/h/kg [0.048-0.076 L/h/kg]) than children without obesity (0.067 L/h/kg [0.060-0.077 L/h/kg]). Simulations revealed that the recommended pediatric dosing regimen produced comparable MHD exposure between children with and without obesity at steady state, supporting its applicability regardless of obesity status. This PBPK-based dosing aligns with product label recommendations and demonstrates the potential of PBPK modeling for dosing other drugs in children with obesity.

Bemnifosbuvir is a novel oral guanosine nucleotide prodrug candidate for the treatment of chronic hepatitis C virus infection. Potential drug-drug interactions (DDIs) of bemnifosbuvir as a substrate or perpetrator with regard to ATP-binding cassette (ABC) and solute carrier (SLC) transporters were evaluated in vitro and in clinical studies. Bemnifosbuvir was demonstrated in vitro as a substrate and inhibitor of the ABC transporters' P-glycoprotein (P-gp), as an inhibitor of the breast cancer resistance protein (BCRP), as well as a weak inhibitor of SLC transporters, including organic anion transporting polypeptide 1B1 (OATP1B1). Phase 1 studies in healthy participants were subsequently conducted to assess the clinical significance of transporter-mediated DDI potentials of bemnifosbuvir as a precipitant using digoxin and rosuvastatin as P-gp and BCRP/OATP1B1 index substrates, respectively. A single dose of 0.25 mg digoxin or 10 mg rosuvastatin was administered alone and with 1100 mg bemnifosbuvir, either simultaneously or staggered. Simultaneous administration of a single dose of 1100 mg bemnifosbuvir increased total plasma exposure of both drugs by less than 20%, and transiently increased the peak plasma exposure of digoxin and rosuvastatin by 78% and 40%, respectively. Staggered dosing reduced the magnitude of changes in peak exposure to digoxin and rosuvastatin. No serious adverse events or drug discontinuations were observed. Dose adjustments are therefore unlikely for drugs that are substrates of P-gp or BCRP/OAT1B1 when coadministered with bemnifosbuvir, and staggered dosing may further reduce any DDI risk.

The development of good-quality sleep is very important in early life. Sleep promotion programs aim to increase preterm infants' sleep quality because preterm infants in the neonatal intensive care unit (NICU) have poor sleep. Interestingly, the majority of preterm infants are treated with caffeine, a nervous system stimulant. The primary objective of this systematic review was therefore to appraise the current evidence concerning potentially sleep-disruptive effects of caffeine in preterm infants within the first month of life. We performed a search (PROSPERO protocol CRD42022273596) according to PRISMA guidelines in PubMed, Embase, Scopus, and PsycInfo (as well as CENTRAL). We looked for studies involving preterm infants (<37 weeks of gestational age) treated with caffeine in the NICU, with sleep measures acquired within the first month of life. Eight studies met the eligibility criteria. Underlying effect sizes for main outcomes are represented using albatross plots. Among studies reporting on wakefulness (N = 213), 83.33% detected significant disruptions (P <  .05). Among studies reporting on sensorimotor functioning (N = 80), 100% detected significant reductions (P <  .05). Moreover, significant reductions (P <  .05) in sleep states were detected. Available evidence suggests that caffeine exposure in preterm infants may produce alterations in sleep-wake and sensorimotor functioning, and related processes during the first month of life. The overall evidence is mixed, with some studies reporting no effect of caffeine exposure on neonatal sleep. Additional research is needed to understand how caffeine alters the quality of neonatal sleep in preterm infants and whether the effects may differ among infant subgroups. There is a continued need to investigate and support sleep quality in preterm infants during their NICU stay.