Clinical Pharmacology And Therapeutics[JOURNAL]
Sun
200 papers
Safety, Tolerability, and Pharmacokinetics of GMDTC for Cadmium Poisoning: A Randomized Phase 1a/1b Trial.
Ren X, Hu W, Deng X … +19 more , Ma R, Pei F, Chen X, Wang X, Tang J, Lai Y, Pan S, Zhong Z, Fu S, Yuan H, Yuan J, Huang C, Zeng Y, Ying X, Dong G, Zhang J, Zhao J, Lin K, Tang X
Clin Pharmacol Ther · 2026 Jul · PMID 41915445 · Full text
Cadmium exposure causes serious health consequences; however, there is no clinically approved antidote for cadmium poisoning. This Phase 1a/1b trial aimed to investigate safety, tolerability, and pharmacokinetics of Sodi...
Cadmium exposure causes serious health consequences; however, there is no clinically approved antidote for cadmium poisoning. This Phase 1a/1b trial aimed to investigate safety, tolerability, and pharmacokinetics of Sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl) amino)-4-(methylthio) butanoate (GMDTC), a novel chelating agent proved to eliminate cadmium through renal glucose transporters. This first-in-human study included two phases. Phase 1a was a randomized, double-blind, single-center, single-dose, dose escalation trial, in which 78 eligible healthy participants aged 18-65 years were assigned to cohorts receiving GMDTC (250, 500, 850, 1200, 1600, or 2000 mg) or placebo. Thereafter, Phase 1b randomized 30 participants with elevated urinary cadmium into three groups (500, 1000, or 2000 mg GMDTC), who received daily injections for 3 consecutive days, with placebo controls included in each group. During the trial, safety and tolerability were monitored for 72 hour following administration. The primary endpoints included dose-limiting toxicity, urinary cadmium excretion, pharmacokinetic parameters, and efficacy of GMDTC. In Phase 1a, 76 participants completed the study. No dose-limiting toxicities were observed, and 169 adverse events were recorded across all cohorts, with no apparent dose-related pattern or serious safety concerns. GMDTC exhibited dose-proportional pharmacokinetics, with a half-life of 1.25-2.63 hour, and urinary cadmium excretion increased dose-dependently within 24 hour after treatment. In Phase 1b, GMDTC significantly increased 24-hour urinary cadmium excretion, which positively correlated with the administered dose. GMDTC was well tolerated at doses up to 2000 mg, with no serious adverse events or dose-limiting toxicities. These findings support GMDTC as a novel therapeutic agent to enhance cadmium elimination in humans.
Prediction of paclitaxel-induced myelosuppression: Validation of a regression model using creatinine clearance and other risk factors obtained retrospectively in hospitalized cancer patients.
Hai Y, Liu Y
Int J Clin Pharmacol Ther · 2026 May · PMID 41914614 · Publisher ↗
OBJECTIVE: To develop a predictive model for paclitaxel (PTX)-induced moderate-to-severe myelosuppression in hospitalized cancer patients and to evaluate its accuracy through cross-validation. MATERIALS AND METHODS: A to...
OBJECTIVE: To develop a predictive model for paclitaxel (PTX)-induced moderate-to-severe myelosuppression in hospitalized cancer patients and to evaluate its accuracy through cross-validation. MATERIALS AND METHODS: A total of 348 cancer patients treated with PTX at Yingshang County People's Hospital between January 2022 and August 2025 were retrospectively reviewed. Clinical data from 278 patients were used to develop the model, including sex, age, underlying diseases, and baseline laboratory parameters at admission. Multivariate logistic regression was used to identify independent risk factors for moderate-to-severe myelosuppression and to construct the predictive model. The model was evaluated using receiver operating characteristic (ROC) curve analysis. An additional 70 patients were used for cross-validation to assess the model's accuracy. RESULTS: The incidence of PTX-induced moderate-to-severe myelosuppression was 32.37% in the 278-patient cohort. Multivariate analysis identified the following independent predictors: creatinine clearance rate (OR = 3.81, 95% CI: 1.853 - 7.836, p < 0.001), red blood cell count (OR = 2.69, 95% CI: 1.263 - 5.726, p = 0.01), hemoglobin (OR = 6.49, 95% CI: 2.431 - 17.328, p < 0.001), neutrophil count (OR = 3.196, 95% CI: 1.077 - 9.485, p = 0.036), and nutritional status (OR = 2.373, 95% CI: 1.008 - 5.586, p = 0.048). The predictive model incorporating these five factors demonstrated strong performance, achieving an AUC of 0.845, a sensitivity of 75.56%, and a specificity of 78.19%. Furthermore, cross-validation on an independent cohort of 70 patients confirmed a prediction accuracy of 84.29%. CONCLUSION: The developed predictive model demonstrates strong performance in assessing the risk of PTX-induced moderate-to-severe myelosuppression and may serve as a useful tool for early identification of high-risk patients, supporting clinical decision-making and personalized treatment strategies.
Postoperative infusion of dexmedetomidine for the prevention of postoperative delirium in elderly patients undergoing lung surgery: A randomized controlled trial.
Li F, Zhang W, Huo J … +2 more , Cheng L, Zhao R
Int J Clin Pharmacol Ther · 2026 Jun · PMID 41914613 · Publisher ↗
OBJECTIVE: This study aimed to investigate the effect of intravenous (IV) patient-controlled anesthesia (PCA) combined with dexmedetomidine (DEX) injections on reducing the risk of postoperative delirium (POD) in elderly...
OBJECTIVE: This study aimed to investigate the effect of intravenous (IV) patient-controlled anesthesia (PCA) combined with dexmedetomidine (DEX) injections on reducing the risk of postoperative delirium (POD) in elderly patients undergoing thoracoscopic lung surgery, hypothesizing a potential risk reduction. MATERIALS AND METHODS: Patients aged 65 years and older who underwent thoracoscopic lung surgery were assessed for eligibility. The participants were randomly assigned to either the test or control group. The test group received DEX through an IV PCA pump, consisting of 3 μg×kg sufentanil and 3 μg×kg DEX, while the control group received 3 μg×kg sufentanil. PCA parameters were standardized, including a total volume of 150 mL, a 2-mL bolus dose with a 15-minute lock-out period, and a background infusion rate of 2 mL/h. The primary outcome was the incidence of POD, which was evaluated twice daily for 7 days after surgery. The secondary outcomes included duration of POD, incidence of postoperative nausea and vomiting (PONV), postoperative hospitalization duration, pain assessment, and adverse events. RESULTS: A total of 287 patients were recruited. The incidence of POD in the control group was significantly higher (15.28 vs. 4.9%, p = 0.006). There were no significant differences in POD duration, PONV, or the length of hospital stay after operation between the two groups. The incidence of hypertension in the test group was significantly lower (p < 0.001), and no differences were found for other adverse events. CONCLUSION: IV patient-controlled DEX injections after major thoracoscopic lung surgery can reduce postoperative delirium.
Community Partnerships in Clinical Research: A Framework for Sustainability and Resilience.
Killam SR, Azure B, Bodnar CB … +5 more , Finley V, Grant MR, Kelly P, Brown KE, Woodahl EL
Clin Pharmacol Ther · 2026 May · PMID 41913066 · Publisher ↗
Variable health outcomes across populations remain chronic challenges in modern healthcare, due in part to an imbalance in participation in clinical research. Rather than base novel therapeutics on narrow cohorts that li...
Variable health outcomes across populations remain chronic challenges in modern healthcare, due in part to an imbalance in participation in clinical research. Rather than base novel therapeutics on narrow cohorts that limit validity and generalizability, we should broaden our commitments to developing solutions that benefit all populations. Many participants remain hesitant due to mistrust in research and medical institutions; however, novel approaches are necessary to bridge the gap in research representation. These concerns are particularly prominent in Indigenous communities, which have faced a long history of unethical research practices. Community-based participatory research methods can aid researchers in improving research access by centering community engagement at the core of the research partnership and enabling co-creation of research priorities. We have created a community-academic partnership with an Indigenous community in Montana over almost two decades, built on mutual respect and learning. Drawing on our partnership, we present community-engaged strategies that together form a framework for building meaningful, enduring community partnerships that foster trust in research. This framework can help to ensure that clinical research opportunities are more broadly available, supporting the diffusion of health innovations to every patient.
Peripheral nerve regeneration and synergistic pharmacology using , lithium, and vitamin B12: The triple neuromodulatory axis hypothesis.
Radanović D, Rasulić L, Savić A … +4 more , Matić S, Micić D, Petrović P, Divac N
Int J Clin Pharmacol Ther · 2026 Mar · PMID 41878942 · Publisher ↗
BACKGROUND: Peripheral nerve injuries (PNI) frequently result in incomplete functional recovery, creating a significant translational gap despite advances in surgical techniques. While (), lithium, and vitamin B12 have...
BACKGROUND: Peripheral nerve injuries (PNI) frequently result in incomplete functional recovery, creating a significant translational gap despite advances in surgical techniques. While (), lithium, and vitamin B12 have individually demonstrated promising neuromodulatory and neurotrophic properties -targeting axonal growth, myelination, and neuroprotection - no existing experimental model has investigated their combined synergistic potential. This lack of integrated approach represents a major barrier to developing effective multimodal therapies. HYPOTHESIS: We propose a "triple neuromodulatory axis" hypothesis: that the combined administration of , lithium, and vitamin B12 will exert a synergistic effect on peripheral nerve regeneration. This synergy is mechanistically driven by the agents' convergence on three vital pathways: neurotrophic signaling (TrkA/ERK), glial modulation (GSK-3β/β-catenin), and metabolic/methylation support. The coordinated action of this axis is hypothesized to ensure simultaneous initiation of axonal growth, rapid Schwann cell proliferation, and sustained myelination. Translational rationale: The convergence of these mechanisms suggests that the triple axis, when tested in appropriate in vivo models of nerve injury, will yield superior functional outcomes (e.g., Sciatic Functional Index) and histological repair (e.g., myelin density and axon count) compared to standard treatments or mono-treatments. CONCLUSION: The triple neuromodulatory axis provides a testable translational framework for designing future multi-arm studies aimed at validating a novel, synergistic pharmacological strategy for enhancing neurorepair in diabetic and post-traumatic neuropathies.
Beneficial effects of dexmedetomidine with sevoflurane inhalation in abdominal surgery: Quality of anesthesia, intestinal flora, and serum pain mediators.
Pan Q, Mao L, Lv Q
Int J Clin Pharmacol Ther · 2026 Jul · PMID 41878941 · Publisher ↗
OBJECTIVE: To evaluate the effects of anesthesia with dexmedetomidine (DEX) and closed-loop target-controlled inhalation of sevoflurane on the intestinal flora and levels of serum pain mediators in patients undergoing ab...
OBJECTIVE: To evaluate the effects of anesthesia with dexmedetomidine (DEX) and closed-loop target-controlled inhalation of sevoflurane on the intestinal flora and levels of serum pain mediators in patients undergoing abdominal surgery. MATERIALS AND METHODS: A cohort of 100 patients who had received abdominal surgery in the period February 2022 to March 2024 were recruited in this retrospective study. The observational group (n = 50) received anesthesia with DEX plus closed-loop target-controlled inhalation of sevoflurane, and the control group (n = 50) received anesthesia with DEX alone. Inter-group comparisons were made for sex, age, etiology, and educational level and for the quality of anesthesia (anesthesia recovery time and induction time), changes in the intestinal flora (Shannon index and Simpson index) and levels of serum pain mediators (prostaglandin E (PGE), tumor necrosis factor-α (TNF-α), and 5-hydroxytryptamine (5-HT)) before anesthesia and 5 minutes after anesthesia induction. RESULTS: The anesthesia recovery and induction time were significantly shorter in the observational group than in the control group (p < 0.05). At 5 minutes after anesthesia induction, both the Shannon index and Simpson index were significantly lower in the control group than in the observation group (p < 0.05), and the levels of PGE, TNF-α, and 5-HT were also significantly lower in the observation group (p < 0.05). CONCLUSION: Evidence was provided showing that anesthesia with DEX plus closed-loop target-controlled inhalation with sevoflurane improves the quality of the anesthesia, reduces the levels of serum pain mediators, and has potentially beneficial effects on the intestinal flora in patients undergoing abdominal surgery.
Systemic bismuth absorption and safety of the gastric mucosal protective bismuth potassium citrate, administered as granules and tablets in healthy Chinese and validation of a new, ICP-MS bismuth assay.
Lv X, Wu J, Ye S … +5 more , Wang Q, Gan S, Pi J, Xiong Y, Zhang N
Int J Clin Pharmacol Ther · 2026 Jun · PMID 41878940 · Publisher ↗
BACKGROUND: The mucosal protective agent, bismuth potassium citrate, is used for treatment of chronic gastritis and gastric stress conditions, including heartburn and acid reflux. OBJECTIVES: 1) To establish and validate...
BACKGROUND: The mucosal protective agent, bismuth potassium citrate, is used for treatment of chronic gastritis and gastric stress conditions, including heartburn and acid reflux. OBJECTIVES: 1) To establish and validate a new inductively coupled mass spectrometry (ICP-MS) analytical method for the determination of bismuth metal in human plasma; and 2) to determine the systemic absorption and safety characteristics of bismuth following the administration of bismuth potassium citrate granules (test drug) and bismuth potassium citrate tablets (reference drug) in healthy Chinese subjects. MATERIALS AND METHODS: A single-center, randomized, open-label, two-drug, single-dose, two-cycle, double-crossover pharmacokinetics study was carried out in a cohort of 24 healthy adult subjects in the fasting state. Subjects meeting the inclusion criteria were randomly assigned to the first cycle in ascending order of screening number obtained prior to dosing. The randomization table assigned subject either to the TR-group (test-reference cycle) or the RT group (reference-test cycle) where each group contained a total of 12 subjects. Subjects recruited but not completing the study, or in whom the data sets were incomplete, were not replaced. Using this study design, all subjects received a single dose of both preparations in the fasting state whereby 12 subjects received the drugs in the order RT and 12 subjects in the order TR, with a washout period of 7 days between each drug administration cycle, respectively. RESULTS: Pharmacokinetic parameters (concentration maximum (C), AUC, and area under the concentration-time curve to infinity (AUC) were analyzed using a linear mixed-effects model after natural log transformation. The lower limit of the 90% confidence intervals for the geometric mean ratio (test preparation/reference preparation) were below 100%, and the bioavailability of the test formulation (granules) was markedly superior to that for the reference formulation (tablets) where values for C, AUC, and AUC after natural log transformation were 5.44, 12.82, 10.86, 22.44, and 13.79%, 27.42%, respectively. The systemic absorption of bismuth metal from the granules was not greater than that for the tablets. CONCLUSION: Although the bioavailability of the granules was markedly superior to tablets, the systemic absorption of bismuth metal from the two formulations was similar, and there was no evidence for a difference in the safety characteristics.
Serious Infection in Crohn's Disease Patients Treated With Ustekinumab: US Food and Drug Administration Active Postmarket Risk Identification and Analysis in the Sentinel Initiative.
Weissfeld JL, Iyer GS, Seo SC … +7 more , Giffin A, Simon AL, Kluberg SA, Hoffman ER, Jones JT, Dutcher SK, Korvick JA
Clin Pharmacol Ther · 2026 Jun · PMID 41874438 · Full text
The U.S. Food and Drug Administration (FDA) used an Active Postmarket Risk Identification and Analysis (ARIA) system to address a safety issue (serious infection) identified during clinical review of an application to ma...
The U.S. Food and Drug Administration (FDA) used an Active Postmarket Risk Identification and Analysis (ARIA) system to address a safety issue (serious infection) identified during clinical review of an application to market ustekinumab as a treatment for Crohn's disease (CD). FDA used an active-comparator new-user cohort design, data from six Sentinel Data Partners, a method developed in Sentinel for identifying serious infection, and ARIA analytic tools to estimate serious infection incidence in adult CD patients during treatment with ustekinumab or an active comparator (infliximab, adalimumab, or vedolizumab). Inverse probability of treatment weighting (IPTW) was used to control for baseline differences between treatment groups. Analyses compared ustekinumab and comparator cohorts with 15,490 and 51,503 patients, respectively. The primary composite outcome of serious infection or COVID-19 occurred in 747 ustekinumab patients (4.82 %; 44.1 per 1000 patient-years) during mean 400-day follow-up. IPTW proportional hazard (Cox) regression estimated risk in the ustekinumab cohort vs. active comparator with hazard ratio 0.88 (95% confidence interval 0.80-0.96). Findings were similar (a) according to line of therapy (use or non-use of an advanced inflammatory bowel disease therapy during a 183-day baseline period) and (b) before and after the start of the COVID-19 pandemic. Additional analyses excluded large magnitude risks from ustekinumab for major types of serious infection. In conclusion, IPTW analyses excluded large magnitude risks from ustekinumab for serious infection. This report describes the first ARIA study to use complex confounding adjustment to help resolve a safety issue identified during FDA review of a marketing application.
TMDD Modeling for Antibodies Directed Against Soluble Targets: Parameter Values for De Novo Modeling and Simulation From Experimental Data.
Nasim A, Fairman D, Nixon E … +4 more , Jagdale P, Cui Z, Mohan K, Yates JWT
Clin Pharmacol Ther · 2026 Jun · PMID 41874430 · Publisher ↗
The Target-Mediated Drug Disposition (TMDD) model is an important framework in pharmacokinetics (PK) and pharmacodynamics (PD), providing insights into drug interactions with soluble and membrane-bound targets, particula...
The Target-Mediated Drug Disposition (TMDD) model is an important framework in pharmacokinetics (PK) and pharmacodynamics (PD), providing insights into drug interactions with soluble and membrane-bound targets, particularly for monoclonal antibodies. This paper reviews TMDD modeling specifically focused on monoclonal antibodies targeting soluble ligands, synthesizing existing research and highlighting current advancements. By doing so, we aim to enhance understanding of the application and potential of TMDD modeling in predicting drug behavior and optimizing therapeutic outcomes for soluble targets.
Advances in Human Mass Balance Studies: An IQ Consortium Perspective on Current Practices and Emerging Trends.
Boer J, Cannady E, Cuyckens F … +22 more , Glaenzel U, Granvil C, Huth F, James AD, Li W, Veau C, Young G, Yue Q, Walker GS, Argikar UA, Bauman JN, Cantalloube C, Chen YL, Kang P, Moliner P, Pedersen ML, Piel I, Schadt S, Schieferstein H, Suchomel J, Wang S, Khojasteh SC
Clin Pharmacol Ther · 2026 Jul · PMID 41860591 · Full text
Human radiolabeled mass balance studies are crucial for comprehensively characterizing the absorption, distribution, metabolism, and excretion (ADME) of investigational drugs, providing essential data for drug developmen...
Human radiolabeled mass balance studies are crucial for comprehensively characterizing the absorption, distribution, metabolism, and excretion (ADME) of investigational drugs, providing essential data for drug development, regulatory evaluation, and product labeling. The IQ Consortium's Human Mass Balance Radiolabeled ADME (hADME) Working Group developed this perspective to address key considerations and highlight opportunities for these studies. This is particularly relevant as regulatory guidance, such as the 2024 US Food and Drug Administration (FDA) and China's National Medical Products Administration (NMPA), have finalized dedicated guidance documents, along with recommendations from other global regulatory bodies (including European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (of Japan; PMDA)); still, there are some regional differences. This review outlines current practices and emerging trends in hADME study design. It details seven clinical designs, from conventional radiolabeled approaches to microtracer studies that employ analytical techniques, such as accelerator mass spectrometry (AMS). It further highlights alternative non-radioactive approaches, including the use of Fluorine-19 nuclear magnetic resonance (F-NMR) spectroscopy. The manuscript also explores the integration of hADME studies with absolute bioavailability (ABA) assessments and highlights their impact on early drug development with case studies. This collective effort by the IQ working group highlights fit-for-purpose study designs to ensure comprehensive ADME characterization supporting drug registration and patient well-being.
Correction to "Promise of Quantitative Proteomics in the Qualification of New Approach Methodologies".
Clin Pharmacol Ther · 2026 May · PMID 41860590 · Publisher ↗
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Model-Based Patient Selection and Dosing Strategies for HRAS and PIK3CA Dysregulated HNSCC: A QSP Model for Alpelisib and Tipifarnib Combination.
Shim J, Chung D, Smith A … +5 more , Malik S, Balsara B, Burrows F, van der Graaf PH, Mitra A
Clin Pharmacol Ther · 2026 Mar · PMID 41851057 · Publisher ↗
Identifying ideal candidates for cancer therapies is challenging, especially with multiple oncogenic variants involved. In head and neck squamous cell carcinoma, the PI3Kα-AKT-mTOR and HRAS-MAPK pathways are frequently d...
Identifying ideal candidates for cancer therapies is challenging, especially with multiple oncogenic variants involved. In head and neck squamous cell carcinoma, the PI3Kα-AKT-mTOR and HRAS-MAPK pathways are frequently dysregulated. This study demonstrates how a quantitative systems pharmacology (QSP) model can help optimize clinical trial design by guiding patient selection and dosing strategies based on oncogenic genotypes. A QSP model was developed to capture the experimentally observed dynamics of the HRAS and PI3K pathways across five molecularly defined patient cohorts in the KURRENT-HN Phase I/II trial (NCT04997902). The model assessed which genotypes would benefit the most from combination therapy with tipifarnib (farnesyl transferase inhibitor) and alpelisib (PIK3CA inhibitor). Simulation results identified the PIK3CA gain of function (GOF) as the genotype most likely to benefit. Virtual population analysis of PIK3CA GOF with dose escalation to 600 mg b.i.d. tipifarnib and 250 mg q.d. alpelisib suggested that a higher tipifarnib dose could enhance tumor response, potentially due to significant dependency of the PIK3CA-mutant cells on mTORC1 signaling. These simulations were consistent with the clinical data. This key dependency can be targeted by tipifarnib by blocking farnsylation of RHEB, an essential activator of mTORC1. Vpop responders showed that reduced intracellular mTOR activity in simulations increased the likelihood of tumor volume reduction. Global sensitivity analysis identified compensatory feedback, tumor proliferation rate, and PI3K-mTOR crosstalk as key determinants of tumor response. This novel QSP application exemplifies an innovative bottom-up modeling approach to support patient selection and dosing strategies for future clinical studies.
Optimal Dose and Safety of Intravenous Favipiravir in Hospitalized Patients With COVID-19: A Dose-Escalating, Randomized Controlled Phase Ib Study.
Rowland T, FitzGerald R, Challenger E … +30 more , Dickinson L, Else LJ, Walker L, Hale C, Shaw V, Kelly C, Lyon R, Gibney J, Dhamani K, Irwin M, Enever Y, Tetlow M, Wood W, Reynolds H, Chiong J, Osanlou O, Pertinez H, Bullock K, Greenhalf W, Owen A, Lalloo DG, Jacobs M, Hiscox JA, Jaki T, Mozgunov P, Saunders G, Griffiths G, Khoo SH, Fletcher TE, AGILE CST‐6 Study Group
Clin Pharmacol Ther · 2026 Jun · PMID 41848748 · Full text
AGILE (NCT04746183) is a Phase Ib/IIa platform, evaluating candidates to treat COVID-19. Candidate Specific Trial 6 evaluated the safety and optimal dose of a novel intravenous formulation of favipiravir in a dose-escala...
AGILE (NCT04746183) is a Phase Ib/IIa platform, evaluating candidates to treat COVID-19. Candidate Specific Trial 6 evaluated the safety and optimal dose of a novel intravenous formulation of favipiravir in a dose-escalating, open-label, randomized, controlled, Bayesian adaptive Phase Ib trial. Hospitalized adults with PCR-confirmed SARS-CoV-2 infection, within 14 days of symptomatic COVID-19 were randomized 2:1 in groups of 6 (n = 4 favipiravir, n = 2 standard of care) to ascending doses of intravenous favipiravir twice daily (b.i.d.) for 7 days or standard of care. Clinical data, safety evaluations, virology and pharmacokinetic samples were collected. The primary outcome was safety. Secondary outcomes included clinical, pharmacokinetic and virological endpoints. Twenty-four participants enrolled between September 10, 2022 and November 1, 2023 [10/24 female; median age 74 years (range 52-93)]. Favipiravir was well tolerated despite a high background rate of unrelated adverse events. No dose limiting toxicities were observed, with a model-predicted dose limiting toxicity risk of 16.8% and probability of unacceptable toxicity of 2.7% at the highest dose level. No serious adverse events were deemed related to favipiravir but an expected association with asymptomatic, transient hyperuricemia was observed. Favipiravir exposures increased disproportionally to dose with significant accumulation in plasma, but with marked variability between participants within each cohort. This novel formulation of favipiravir was safe at sustained high doses that reached pre-specified pharmacokinetic targets in a study group with frailty and complex health profiles. We consider doses up to 2,400 mg b.i.d. to be safe for further evaluation.
Pharmacogenetics-Not Just Low-Hanging Fruit.
Cascorbi I, Minichmayr IK
Clin Pharmacol Ther · 2026 Apr · PMID 41848157 · Publisher ↗
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Can tiotropium add-on inhalation revolutionize therapy in elderly asthmatic patients? A treatable traits approach towards successful aging.
Ishiura Y, Nomura S, Ohkura N … +3 more , Hara J, Fujimura M, Ito T
Int J Clin Pharmacol Ther · 2026 Jun · PMID 41841282 · Publisher ↗
BACKGROUND: The population of elderly patients with asthma is increasing, resulting in serious health problems because of hospitalization and high mortality rate. Furthermore, several recent studies have shown that progr...
BACKGROUND: The population of elderly patients with asthma is increasing, resulting in serious health problems because of hospitalization and high mortality rate. Furthermore, several recent studies have shown that progressive airflow limitation may worsen cognitive dysfunction and contribute to poor asthma control. Maintaining good respiratory function is therefore important in the elderly in order to achieve a satisfactory quality of life. MATERIALS AND METHODS: A 12-week, open-label, cross-over study was conducted in elderly patients with asthma to investigate the effect of 5 μg/day tiotropium bromide (TIO) add-on therapy administered using a soft mist inhaler (SMI), in addition to a dosage of 500/20 µg/day fluticasone propionate/formoterol fumarate (FP/FM) treatment and to compare the effects of treatment with those following the administration of 500/20 µg/day FP/FM alone. The trial design thus entailed a 4-week run-in period and two 4-week treatment periods. RESULTS: A total of 21 patients aged over 65 years with stable bronchial asthma were recruited in the study. Forced expiratory volume in 1 second values after the treatment period with FP/FM and TIO add-on therapy were significantly higher than those after the run-in period (p < 0.01). CONCLUSION: TIO add-on therapy FP/FM treatment using an SMI in elderly patients with asthma improved lung function parameters demonstrating, the value of TIO add-on therapy as a treatable traits option for improving quality of life and achieving successful aging in this population.
Acute arsenic poisoning from realgar water: Case series from Guilin, China.
Fu YF, Xu HZ, Long X … +8 more , Liao QQ, Huang HL, Deng K, Jiang YJ, Tang GR, Tang SP, Tang J, Qin D
Int J Clin Pharmacol Ther · 2026 Jun · PMID 41841281 · Publisher ↗
BACKGROUND: The inappropriate use of Traditional Chinese Medicine (TCM) poses significant health risks. Realgar (AsS), an arsenic-containing mineral traditionally consumed during China's Dragon Boat Festival, may induce...
BACKGROUND: The inappropriate use of Traditional Chinese Medicine (TCM) poses significant health risks. Realgar (AsS), an arsenic-containing mineral traditionally consumed during China's Dragon Boat Festival, may induce acute toxicity following ingestion. MATERIALS AND METHODS: This case series describes 8 patients (age: 1 - 80 years), including 2 children, with clinically confirmed acute arsenic poisoning subsequent to Dragon Boat Festival ingestion of realgar-containing water. We systematically evaluated clinical manifestations, laboratory parameters, and environmental arsenic concentrations. Urinary arsenic quantification was performed in all cases, with intravenous 2,3-dimercaptopropane sulfonic acid (DMPS) sodium salt initiated as chelation therapy. RESULTS: All patients developed gastrointestinal manifestations (nausea, vomiting, and diarrhea) within 5 - 14 days post exposure, accompanied by biochemical evidence of hepatic dysfunction. Laboratory analyses confirmed elevated urinary arsenic concentrations (> 0.032 mg/L) and identified arsenic contamination in drinking water (> 0.01 mg/L), with both measures exceeding established safety thresholds. Multi-organ dysfunction syndrome (MODS) was observed in 3 patients. All cases demonstrated a favorable clinical response to intravenous DMPS sodium salt chelation therapy, achieving clinical improvements and subsequent discharge. CONCLUSION: This case series documented acute arsenic toxicity secondary to realgar consumption in both adults and children. The findings underscore the critical need for targeted public health education initiatives and enhanced regulatory oversight regarding traditional medicinal practices, particularly during cultural festivals. Furthermore, they emphasize the necessity for heightened clinical vigilance in the prompt diagnosis and management of arsenic poisoning associated with traditional cultural practices.
Network pharmacology and bioinformatics analysis of the multi-target immune-inflammatory mechanisms of Shengma Gegen decoction in chronic urticaria.
Hu M, Ma Y, Li J … +1 more , Wu J
Int J Clin Pharmacol Ther · 2026 Jul · PMID 41841280 · Publisher ↗
BACKGROUND: Chronic urticaria (CU) is a refractory, long-course skin disorder involving multifactorial and complex pathophysiology. Although Shengma Gegen decoction (SMGG) shows clinical benefit, its mechanistic basis re...
BACKGROUND: Chronic urticaria (CU) is a refractory, long-course skin disorder involving multifactorial and complex pathophysiology. Although Shengma Gegen decoction (SMGG) shows clinical benefit, its mechanistic basis remains unclear. AIMS: To elucidate the multitarget, multipathway mechanisms of SMGG in CU and to prioritize key targets and pathways for subsequent experimental validation. MATERIALS AND METHODS: We integrated network pharmacology and bioinformatics using TCMSP, UniProt, GeneCards, and OMIM. A total of 126 bioactive compounds and 216 putative targets were identified. Enrichment analyses (including KEGG) were performed, immune-infiltration patterns were assessed, and molecular docking plus molecular-dynamics simulations evaluated ligand-target interactions. RESULTS: Key regulatory targets were highlighted - MMP9, IL6, AKT1, IL1B and TNF - with strong associations to inflammatory and immune regulation. KEGG analysis prioritized AGE-RAGE, TNF, and IL-17 pathways. Immune-infiltration analysis suggested that SMGG may modulate the Th1/Th2 balance. Docking and dynamics demonstrated stable binding and plausible dynamic interactions between representative active components and the prioritized targets. DISCUSSION: These findings support a multi-target, multi-pathway mode of action for SMGG in CU, aligning inflammatory signaling and immune modulation. As an in-silico study, the results provide hypotheses that warrant rigorous in-vitro and in-vivo validation. CONCLUSION: SMGG may ameliorate CU by coordinately regulating inflammatory pathways (AGE-RAGE, TNF, IL-17) and immune balance via core targets (MMP9, IL6, AKT1, IL1B, TNF). The study offers a mechanistic basis and target/pathway prioritization to guide future experimental work and the modernization of traditional formulations.
Real-World Safety of JAK Inhibitors in Skin Immune-Mediated Inflammatory Diseases: Boxed Warning Outcomes from a Multinational Cohort Study.
Lin TL, Fan YH, Fan KS … +3 more , Juan CK, Chen YJ, Wu CY
Clin Pharmacol Ther · 2026 Jun · PMID 41830903 · Publisher ↗
Janus kinase inhibitors (JAKis) have emerged as effective treatments for several skin immune-mediated inflammatory diseases (IMIDs). However, safety concerns have been raised due to boxed warnings from rheumatoid arthrit...
Janus kinase inhibitors (JAKis) have emerged as effective treatments for several skin immune-mediated inflammatory diseases (IMIDs). However, safety concerns have been raised due to boxed warnings from rheumatoid arthritis trials, and whether these risks apply to skin IMIDs remains uncertain. This multinational retrospective cohort study used the TriNetX database to compare the real-world safety of JAKis and conventional immunomodulators (cIMs) in patients aged 12 years or older with skin IMIDs (psoriatic disease, atopic dermatitis, or alopecia areata). Patients newly prescribed JAKis (tofacitinib, upadacitinib, deucravacitinib, baricitinib, abrocitinib, or ritlecitinib) were propensity score-matched (1:1) with those prescribed cIMs (methotrexate or cyclosporine) based on demographics, baseline skin IMIDs, and comorbidities, yielding 17,068 matched patients. Over 2 years, the JAKi cohort showed lower incidences of all-cause mortality (0.28% vs. 0.62%; P = 0.015) and major adverse cardiovascular events (MACE; 1.15% vs. 1.95%; P = 0.005) than the cIM cohort, corresponding to reduced risks (mortality: HR, 0.47; 95% CI, 0.25-0.88; MACE: HR, 0.63; 95% CI, 0.46-0.88). Risks of venous thromboembolism (HR, 0.80; 95% CI, 0.43-1.48) and malignancy (HR, 0.85; 95% CI, 0.63-1.16) were not increased. Subgroup analyses, including older adults and those with cardiometabolic risk factors, showed no signal of increased risk, with consistent findings across available agent-level and sensitivity analyses. These results suggest that, over 2 years, JAKis are not associated with increased risks of mortality, MACE, venous thromboembolism, or malignancy compared with conventional systemic agents in patients with skin IMIDs.
Safety, Pharmacokinetics, and Dose Recommendations for Nirmatrelvir/Ritonavir in Individuals with Mild to Moderate COVID-19 and Severe Renal Impairment.
Gerhart J, Bramson CR, Goulding M … +5 more , Shi H, Oladoyinbo O, Chan PLS, Chime S, Hammond J
Clin Pharmacol Ther · 2026 Jun · PMID 41823072 · Full text
Patients with severe renal impairment and COVID-19 are at high risk for severe disease and death. Nirmatrelvir/ritonavir, an antiviral therapy for COVID-19, is eliminated by renal excretion and can accumulate in patients...
Patients with severe renal impairment and COVID-19 are at high risk for severe disease and death. Nirmatrelvir/ritonavir, an antiviral therapy for COVID-19, is eliminated by renal excretion and can accumulate in patients with severe renal impairment. The phase 1 Evaluation of Protease Inhibition for COVID-19 in Patients with Severe Renal Impairment (EPIC-SRI) study evaluated the safety and pharmacokinetics of nirmatrelvir/ritonavir for this population. Fifteen participants (3 not requiring hemodialysis, 12 requiring intermittent hemodialysis) received oral nirmatrelvir/ritonavir 300/100 mg on Day 1, followed by nirmatrelvir/ritonavir 150/100 mg once daily on Days 2-5. No treatment-related adverse events were reported. Geometric mean (coefficient of variation) maximum plasma concentration, plasma trough concentration, and area under the concentration-time curve from 0 to 24 hours for daily dosing of nirmatrelvir for participants from the Intermittent Hemodialysis Cohort were 3280 ng/mL (48%), 2188 ng/mL (81%), and 65,700 ng*h/mL (59%), respectively. Geometric mean (coefficient of variation) nirmatrelvir hemodialysis clearance and fraction removed from the body by hemodialysis were 30.5 mL/min (35%) and 6.9% (138%), respectively. Population pharmacokinetic modeling demonstrated that simulated distributions of nirmatrelvir maximum plasma concentration, minimum trough concentration, and area under the concentration-time curve from 0 to 24 hours for daily dosing at the studied regimen were similar to those for virtual subjects with normal to moderate renal function receiving the approved dose of nirmatrelvir/ritonavir. SARS-CoV-2 RNA levels were substantially reduced across both cohorts. Findings suggest that the studied regimen is well tolerated, achieves and maintains adequate exposure, and is suitable for patients with COVID-19 and severe renal impairment. NCT05487040.
Periconceptional Use of Analgesics and Severity of Structural Birth Defects.
Ekenze SO, Huezo-Garcia M, Kerr SM … +4 more , Fisher SC, Nestoridi E, Werler MM, National Birth Defects Prevention Study
Clin Pharmacol Ther · 2026 Jul · PMID 41821430 · Publisher ↗
Reports of associations between use of specific analgesic medications and specific structural birth defects are inconsistent and difficult to translate for clinical guidelines and informed decision-making. To overcome th...
Reports of associations between use of specific analgesic medications and specific structural birth defects are inconsistent and difficult to translate for clinical guidelines and informed decision-making. To overcome this challenge, this study examines associations between use of specific analgesics and severity of structural birth defects, using a novel approach based on survival rates. We recorded average 12-month survival rates reported in the literature for specific birth defects and applied those rates to birth defects in the National Birth Defects Prevention Study (1997-2011) to create severity groups: < 95% survival (n = 20,229), < 70% survival (n = 2936), and ≥ 95% survival (6911). Maternal uses of specific analgesic medications during the month before through the first 3 months of pregnancy (periconception) were compared between non-malformed controls (n = 11,614) and severity groups with odds ratios (aOR) and 95% confidence intervals (CI) adjusted for race/ethnicity, maternal education, pre-pregnancy body mass index, maternal periconceptional alcohol use, exposure to known teratogens, infant sex, and study site. Use of acetaminophen as a single component product or in combination with cough/cold agents was not associated with any of the birth defect severity groups. Elevated aORs in relation to risks of < 70% survival birth defects were observed for use of acetaminophen in combination with aspirin and caffeine, hydrocodone, codeine, or propoxyphene (aOR range: 1.46-2.00) and for hydrocodone alone (OR: 2.45). aORs remained elevated for the < 95% group except for acetaminophen plus codeine (OR 1.07). aORs for each severity group in association with use of acetaminophen combined with oxycodone approximated the null and those for ibuprofen, naproxen, and aspirin ranged between 1.15 and 1.28. In consideration of severity of birth defects, our findings indicate both safer and riskier analgesic medication options are available.
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