International journal of clinical pharmacology and therapeutics最新文献

Hematologic responses (< 1%) to piperacillin/tazobactam were uncommon, and mostly reported in non-pregnant adults. The use of piperacillin/tazobactam during pregnancy is considered to be moderately safe for the human embryo-fetus (pregnancy grade B). However, changes in pharmacokinetics during pregnancy (such as an increase in plasma volume and an increase in renal clearance rate) may alter the toxicity threshold of the drug. This is a case of a pregnant woman (26 weeks of gestation) treated with piperacillin/tazobactam for psoas abscess (Proteus mirabilis). After 22 days, the patient developed low-grade fever, leukopenia, neutropenia, and thrombocytopenia. Three days after discontinuation of piperacillin/tazobactam, the above adverse reactions were all reversed. The Naranjo scale yielded a score of 7, which indicates a definite result for this adverse drug reaction. This was the first report of piperacillin-tazobactam-induced pancytopenia in pregnancy.

Background: Linezolid is classified under the reserve group of antibiotics, and it exerts its antibacterial activity by disrupting protein synthesis. Clinically, linezolid is used for treatment of severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). It is eliminated through both renal and hepatic routes. Being a narrow therapeutic index drug, linezolid needs special dosing considerations for safe and effective treatment.

Materials and methods: A plasma concentration dataset of 94 patients with 347 samples was used for development of a population pharmacokinetic model on NONMEM software. The influence of significant covariates on pharmacokinetic parameters was analyzed by stepwise covariate modeling, and dosing simulations were performed on the basis of significant covariates.

Results: The data was best analyzed using a one-compartment model with first-order elimination. The clearance (CL) of linezolid was estimated as 3.38 L/h, while volume of distribution (Vd) was 36 L. The between-subject variability on linezolid CL was 29.8%, and that of Vd was 39.6%. Creatinine clearance (CrCl) and age of the patients were proven to be significant covariates on CL, while no significant covariate was observed for Vd during stepwise covariate modeling. The dosing simulations revealed that a different dose should be administered based on the CrCl of patients.

Conclusion: The renal status and age of the patients are significant covariates responsible for linezolid CL, and a dose of 200, 300, 400, and 600 mg is appropriate for patients with CrCl of 20, 40, 80, and 120 mL/min, respectively.

Objective: This study evaluated and compared the safety, pharmacokinetics, and pharmacodynamics of regadenoson injection (test) and regadenoson original injection (Lexiscan, reference) in healthy Chinese subjects.

Materials and methods: In a randomized, positive-control, single-center, single-dose study, 24 healthy Chinese subjects were divided into test and reference groups (12 subjects each). Subjects in the test group received a single bolus of test drug (0.4 mg/5 mL), while the reference group received the same dose of reference drug. Blood and urine samples were collected before and after drug administration, and regadenoson concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results: No serious adverse events (AEs) occurred. There was no significant difference in the incidence of adverse reactions between the two preparations. The pharmacokinetic parameters, including maximum concentration (C_max), the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC_0-t), and the area under the concentration-time curve from time 0 to infinity (AUC_0-∞), were assessed to compare the pharmacokinetic of two regadenoson preparations. The test/reference geometric mean ratios of C_max, AUC_0-t, and AUC_0-∞ were 102.84, 99.16, and 99.77%, respectively. The 90% confidence intervals (CIs) of AUC_0-t and AUC_0-∞ fell within 0.8 - 1.25, but the 90% CIs of C_max did not. Blood pressure (BP) and heart rate (HR) were measured to compare the pharmacodynamics of the two preparations. The test and reference drugs had similar HR responses (63.22 ± 38.45% vs. 37.50 ± 16.96%), systolic BP response (4.81 ± 13.73% vs. -3.83 ± 12.29%), and diastolic BP response (-7.75 ± 12.84% vs. -16.13 ± 9.85%), p > 0.05. After adjusting the weight of males and females, there were significant differences in C_max, AUC_0-t, AUC_0-∞, T_1/2, V_ss, λ_z, Ae%, p < 0.05.

Conclusion: The test drug demonstrated similar pharmacokinetic and pharmacodynamic characteristics as the reference drug. Additionally, it was well-tolerated and safe in healthy Chinese participants. Sex may influence regadenoson pharmacokinetics.

Objective: The aim of this study was to analyze the cardiotoxicity associated with antifungal agents based on data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).

Materials and methods: We extracted and evaluated cardiac adverse events (CAEs) linked to antifungals in the FAERS database (2004 - 2023). Signal strength for five antifungal classes was assessed using the reporting odds ratio (ROR) and information component (IC).

Results: Among 50,603 cases, triazoles, polyenes, and imidazoles showed significant associations with Torsade de Pointes (TdP)/QT prolongation (QTP), with fluconazole exhibiting the strongest link (ROR: 11.96, 95% CI: 10.62 - 13.46; IC: 2.19, 95% CI: 1.92 - 2.44). Triazoles were notably connected to arrhythmias, particularly itraconazole (ROR: 3.31, 95% CI: 2.88 - 3.79; IC: 1.67, 95% CI: 1.20 - 2.11). Fluconazole also demonstrated strong associations with conduction defects (ROR 6.44, 95% CI 5.60 - 7.39; IC 2.65, 95% CI 2.16 - 3.08) and ventricular tachyarrhythmias (ROR 9.09, 95% CI 7.84 - 10.54; IC 3.15, 95% CI 2.60 - 3.58). Notably, only itraconazole showed significant signals for cardiac failure (ROR 4.04, 95% CI 3.52 - 4.64; IC 1.96, 95% CI 1.48 - 2.40) and cardiomyopathy (ROR 6.34, 95% CI 5.04 - 7.96; IC 2.64, 95% CI 1.79 - 3.30). In contrast, echinocandins did not exhibit significant CAE signals.

Conclusion: These findings highlight that azoles and polyenes show substantial associations with CAEs, particularly for TdP/QTP and arrhythmias. Itraconazole showed a significant association with cardiac failure and cardiomyopathy, while the signal for isavuconazole was weaker than for other triazoles. No significant cardiotoxicity signals were detected for echinocandins.

Background: The misuse of antibiotics leads to antimicrobial resistance, particularly concerning infections related to orthopedic implants. The aim of this study was to determine the sensitivity pattern of bacterial isolates in patients with orthopedic implants having infections.

Materials and methods: A retrospective cross-sectional study was conducted at Ghurki Trust Teaching Hospital, Lahore. Culture sensitivity reports from 548 patients were collected between January 2020 and March 2023. Patient demographics, including age, sex, culture specimens (blood, wound, etc.), and antibiotic sensitivity were recorded.

Results: Seven types of implants were analyzed, with Ilizarov (25.5%) being the most infected external implant and nails (24.7%) the most infected internal implant. The study included 10 clinically significant bacteria, with Staphylococcus aureus (n = 195, 35.5%) being the most common Gram-positive pathogen, and Escherichia coli (n = 99, 18.0%) being the most prevalent Gram-negative pathogen. A total of 40 antibiotics were tested; amoxicillin was the least effective, whereas linezolid, vancomycin, and fosfomycin showed the highest efficacy against all implant-related infections included in this study.

Conclusion: The critical challenges of antimicrobial resistance in orthopedic implant-related infections have been highlighted. Urgent institutional and policy level interventions are required for implementation of stringent infection control protocols and robust antibiotic stewardship programs to prevent a post-antibiotic crisis.

Objective: In this study, we aimed to develop a method for predicting the response of patients to three commonly used anti-epileptic drugs (AEDs), namely, carbamazepine, phenytoin, and valproate, using machine learning models, based on the patients' peripheral blood RNA profiles.

Materials and methods: A data set from the Gene Expression Omnibus Series database (GSE143272) was utilized that included the peripheral blood RNA information and some clinical features (age, weight, sex, epilepsy type, drug response) of 57 epilepsy patients. 22 classification models were constructed and trained, in which the peripheral blood RNA information, age, weight, sex, and epilepsy type served as predictors, and the patient' response to anti-epileptic drug as the outcome. The predicting capacity was evaluated by utilizing the sensitivity, the specificity, and the receiver operating characteristic curve of the models.

Results: Among the 22 trained models, the model of a quadratic support vector machine with a pretreatment of principal component analysis displayed the highest accuracy at 0.75, and the highest value of area under ROC curve at 0.81.

Conclusion: The model of a quadratic support vector machine with a pretreatment of principal component analysis is a potential tool for predicting the response of patients with epilepsy to drug treatment.

Objective: To characterize tofacitinib pharmacokinetics (PK) in patients with active ankylosing spondylitis (AS) and estimate the effects of covariates on variability of PK parameters.

Materials and methods: Pooled data from two studies in patients with AS who received tofacitinib were analyzed using nonlinear mixed-effects modeling. Tofacitinib PK was described by a one-compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution (V/F), and a first-order absorption rate constant (k_a). Covariates evaluated: baseline age, sex, race, creatinine clearance (BCCL), and C-reactive protein for CL/F; baseline age/body weight for V/F.

Results: Analysis included 279 patients. The point estimates for CL/F, V/F, and k_a were 27.1 L/hour, 126 L, and 3.07 hour^-1, respectively, in a reference patient. Excluding BCCL, point estimates of area under the concentration-time curve (AUC) over a dosing interval at steady-state and maximum steady-state tofacitinib concentration (C_max) change vs. the reference patient ranged from 98 - 112% and 89 - 115%, respectively. Estimated AUC was 24% higher in a patient with BCCL = 50 mL/min vs. the reference patient (BCCL = 126 mL/min). Point estimates and 90% confidence intervals of the AUC and C_max ratios indicated no major differences in tofacitinib exposure over the range of baseline age/body weight studied, and sex/race.

Conclusion: Tofacitinib does not require dose adjustment/restriction for age, body weight, sex, or race based on the differences (< 20%) in exposure relative to a reference patient with AS. The tofacitinib CL/F and BCCL relationship was consistent with known contribution of renal excretion to total tofacitinib clearance.

Objective: This study aimed to characterize adverse drug reactions (ADRs) associated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors in cancer immunotherapy, identifying demographic, pharmacological, and clinical determinants of toxicity severity using real-world pharmacovigilance data.

Materials and methods: We analyzed 93,925 ADR reports from the FDA Adverse Event Reporting System (FAERS, 2023-2024). Data preprocessing included deduplication, terminology standardization, and severity classification. Multivariate logistic regression and machine learning models were employed to assess predictors of serious ADRs, integrating demographic variables (age, sex), drug agents, and organ-specific toxicities.

Results: Pembrolizumab (38.4%), atezolizumab (26.5%), and nivolumab (25.0%) accounted for 89.9% of ADR cases. Frequent ADRs included death (7.9%), off-label use (7.5%), and malignant progression (6.9%). Immune-related toxicities (diarrhea, hypothyroidism, pneumonitis) comprised 6.1 - 2.4% of cases. Severe ADRs (grade 3 - 4) predominantly affected hepatic (68%), cardiac (65%), and neurological systems (62%). Octogenarians exhibited a 42% increased risk of serious ADRs (p < 0.001), with males representing 51.1% of severe cases (p < 0.001).

Conclusion: Age, sex, and drug-specific profiles critically influence PD-1/PD-L1 inhibitor toxicity. The findings support personalized risk stratification and time-dependent monitoring protocols to mitigate immune-related adverse events, particularly in elderly and male patients. These insights enhance evidence-based management strategies for optimizing immunotherapy safety.

Background: Septic shock is a critical condition requiring vasopressor support and mechanical ventilation. The sequence of vasopressor weaning may affect clinical outcomes, such as mechanical ventilation duration and patient survival.

Objectives: This study assesses how vasopressor weaning order affects hemodynamic stability, clinical outcomes, and the length of mechanical ventilation in critically ill septic shock patients.

Materials and methods: A retrospective cohort study was conducted at Prince Sultan Military Medical City, Riyadh, Saudi Arabia, from January 2022 to December 2023. Critically ill adult patients receiving intravenous norepinephrine and vasopressin for septic shock and requiring mechanical ventilation were included. Patients were classified into two groups: vasopressin weaned first or norepinephrine weaned first. The duration of mechanical ventilation was the main outcome. These were secondary outcomes: mean arterial pressure (MAP) stability, 30-day and in-hospital mortality, length of stay (LOS) in the intensive care unit and hospital, and rates of reintubation.

Results: Among 100 patients (mean age: 65.1 ± 19.7 years; 58% male), vasopressin was weaned first in 47 patients (47%) and norepinephrine first in 53 (53%). Patients extubated while on vasopressors (vasopressin weaned first) had a shorter median duration of mechanical ventilation (4 days) and lower odds of mortality (adjusted OR = 0.30, 95% CI: 0.09 - 0.98; p = 0.046) compared to those weaned off norepinephrine first. No significant differences were observed in reintubation rates or LOS.

Conclusion: Weaning vasopressin before norepinephrine may be associated with improved survival and reduced mechanical ventilation duration in septic shock patients, although further research is needed to validate these findings and optimize vasopressor weaning strategies.

Objective: We aimed to evaluate the effect of extracorporeal anticoagulation with nafamostat mesilate (NM) and continuous renal replacement therapy (CRRT) on sepsis complicated with acute kidney injury (AKI).

Materials and methods: The clinical data of 106 sepsis patients complicated with AKI admitted from January 2023 to December 2024 were retrospectively analyzed. According to different treatment protocols, the patients were assigned into a control group (n = 53, regional citrate anticoagulation (RCA) plus CRRT) and a study group (n = 53, NM extracorporeal anticoagulation plus CRRT). The use of extracorporeal circulation circuit was compared.

Results: After 3 days of treatment, the levels of procalcitonin, interleukin-6, and tumor necrosis factor-α decreased in the two groups compared to those before treatment (p < 0.05), and they were lower in the study group than in the control group (p < 0.05). After 3 days of treatment, both groups had lowered levels of serum creatinine (Scr), cystatin C (Cys-C), and blood urea nitrogen (BUN), together with increased mean transit time (MTT), peak intensity (PI), and area under the curve (AUC) compared with those before treatment. In the study group, the levels of Scr, Cys-C, and BUN declined, while MTT, PI, and AUC rose compared with those in the control group (p < 0.05). The incidence of adverse reactions in the study group was lower than that in the control group (3.77 vs. 16.98%) (p < 0.05).

Conclusion: NM outperforms RCA in prolonging the hemofilter lifespan, reducing hemofilter replacement frequency, improving renal perfusion and renal function, and eliminating inflammatory mediators.