International journal of clinical pharmacology and therapeutics最新文献

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.

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: To investigate the epidemiological characteristics of severe cutaneous adverse reactions (cirAEs) induced by immune checkpoint inhibitors (ICIs) and to provide evidence for the rational clinical use of ICIs and pharmacovigilance for cutaneous toxicities.

Materials and methods: We systematically searched the PubMed, MEDLINE, EMBASE, CNKI, and Wanfang databases using keywords including "immune checkpoint inhibitors," "cutaneous adverse reactions," "cutaneous toxicity," "induced," and "case," and their combinations to identify detailed case reports on cirAEs. Data on patient demographics (sex and age), primary cancer type, ICI use, time to cirAE onset, cirAE severity grading, and reaction classification were extracted. Descriptive statistics, co-occurrence analysis of clinical manifestations, and the Apriori algorithm were employed to analyze cirAE patterns.

Results: The analysis included a total of 120 articles involving 126 patients (male: 80; female: 46) with a mean age of 63.05 ± 11.85 years. The highest incidence was observed in patients aged 60 - 69 years. The primary cancers were predominantly non-small cell lung cancer and melanoma. Programmed death 1 (PD-1) inhibitors were the most commonly used therapeutic agents. The median time to onset was 15 - 28 days. Most cases were classified as severe Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).

Conclusion: Healthcare professionals must remain vigilant for severe cirAEs and ensure timely diagnosis and management to safeguard patient safety during ICI therapy.

Objective: Oral semaglutide contains salcaprozate sodium, which promotes the opening of epithelial tight junctions and increases gastric pH to prevent its degradation; these actions together improve absorption. Proton pump inhibitors (PPIs) increase gastric pH. However, it is unclear whether PPIs affect the absorption of semaglutide and may therefore enhance the blood glucose lowering effect of semaglutide or affect the reduction of hemoglobin A1c (HbA1c). Therefore, this study investigated differences in HbA1c changes and adverse events between those with and without PPI co-administration.

Materials and methods: This single-center retrospective study included patients with type 2 diabetes who received oral semaglutide. Patients were categorized into two groups: those on treatment with PPI (w/PPI) and those not on treatment with PPI (without PPI (w/o PPI)). The primary outcome was the change in HbA1c levels at 52 weeks, while the secondary outcomes included changes at 26 weeks and the incidence of adverse events.

Results: A total of 66 patients were included. HbA1c reduction at 52 weeks was significantly greater in the w/PPI group (-1.56 ± 0.37%) than in the w/o PPI group (-1.08 ± 0.76%, p = 0.024). The incidences of adverse events were 24.0% and 31.7% in the w/PPI and w/o PPI groups, respectively (p = 0.502).

Conclusion: HbA1c reduction at 52 weeks was significantly greater in the PPI co-administration group than in the group without PPI. Future research should include larger sample sizes and pharmacokinetic studies to clarify the clinical implications and interactions between oral semaglutide and PPIs.

Background: Tegoprazan is a potassium channel inhibitor with an anti-acid secretion effect. It is metabolized by CYP3A4, a cytochrome enzyme the occurrence of which in the Mexican population, differs from that in some other populations. Since the efficacy and safety studies on tegoprazan have been conducted in Koreans, it is of considerable clinical importance to establish whether differences exist in CYP3A4 metabolism between the two populations.

Aims: To evaluate the oral pharmacokinetics of tegoprazan and to compare the pharmacokinetic data with those reported in the literature for Koreans.

Materials and methods: The investigation was carried out in a cohort of 20 healthy Mexican volunteers (11 women and 9 men), who were administered a dose of 50 mg after fasting for at least 10 hours. Blood samples were taken at selected time points over 24 hours, and tegoprazan plasma concentrations measured using high-performance liquid chromatography. Pharmacokinetic parameters were compared to those in Koreans reported in the literature.

Results: Tegoprazan is rapidly absorbed from the gastrointestinal tract reaching C_max at ~ 1 hour post dose (t_max) and is removed from the circulation with an average half-life of ~ 4 hours. The pharmacokinetic parameters obtained were similar to those obtained in Koreans including elimination half-life, maximum tegoprazan concentrations, and oral bioavailability.

Discussion and conclusion: Since no clinically relevant pharmacokinetic differences were observed in the pharmacokinetics of tegoprazan, a substrate for CYP3A4, between Mexicans and Koreans, it is concluded that the efficacy and safety data for tegoprazan obtained in Koreans will be valid in the Mexican population.

Objective: This study was conducted to compare the single-dose pharmacokinetic and safety profiles of JLP-1401 (fixed-dose combination (FDC) of telmisartan/amlodipine/rosuvastatin) to those of each constituent co-administered in healthy Korean male volunteers.

Materials and methods: A total of 40 healthy Korean subjects participated in an open-label, randomized, single-dose, 4-period crossover study. During each treatment period, the subjects received the test drug (FDC tablet of telmisartan/amlodipine/rosuvastatin 80 mg/10 mg/20 mg) or reference drug (co-administration of telmisartan/amlodipine FDC tablet and rosuvastatin tablet). Plasma samples were collected pre dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours post dose to evaluate pharmacokinetic profiles. Safety was assessed by the evaluation of adverse events (AEs), laboratory assessments, 12-lead electrocardiograms, physical examinations, and vital sign measurements.

Results: The geometric least-square mean ratios and their 90% confidence intervals of AUC_last and C_max were 1.01 (0.94 - 1.07) and 0.83 (0.72 - 0.95) for telmisartan, 1.01 (0.99 - 1.04) and 1.03 (1.01 - 1.06) for amlodipine, and 1.03 (0.98 - 1.08) and 0.94 (0.85 - 1.04) for rosuvastatin, respectively. All AEs were of mild or moderate intensity, and there were no significant differences in the incidence of AEs between the treatments.

Discussion and conclusion: The pharmacokinetic profiles of the test and reference drugs were within the bioequivalent criteria, and both drugs were safe and well tolerated.

Objective: To examine the effects of the oral uremic toxin absorbent AST-120 on the concentration of free and protein-bound indoxyl sulphate (IS) and to assess the effects of serum albumin in end-stage kidney disease (ESKD) patients undergoing hemodialysis.

Materials and methods: The study enrolled 37 ESKD patients who initiated hemodialysis at the Shirasagi Hospital. Serum free and bound IS concentrations were measured before the first of 4 hemodialysis sessions and after the last hemodialysis 7 days later. The cohort contained a subgroup of patients in whom AST-120 treatment (6 g/day) was discontinued immediately prior to the first hemodialysis and a subgroup not treated with AST-120. Clinical characteristics were obtained from electronic medical records.

Results: Discontinuation in AST-120 treatment prior to dialysis resulted in marked but highly variable increases in IS concentrations, measured 7 days later, where the efficiency of dialysis of IS was dependent on the serum albumin concentration.

Discussion: The observation that the percentage change in IS concentration was significantly higher after discontinuation of AST-120 compared to those not receiving AST-120 was unexpected as was the finding of a high inter-patient variability in IS concentrations before and after hemodialysis. The effects of a discontinuation in AST-120 administration can be interpreted as a rebound in the systemic absorption of indole precursors, but the source of variability in IS concentrations was unclear. Although there are important limitations in this investigation, the report presents valid and valuable data on free and albumin-bound IS concentrations during hemodialysis and AST-120 treatment as well as measurements of serum albumin concentrations in the group of largely elderly subjects.

Conclusion: AST-120 in ESKD patients has profound effects on the disposition of IS. There are important sources of variability having a possible marked effect on the concentration of IS in patients with chronic kidney disease. Discontinuing AST-120 treatment before hemodialysis, a practice in Japan to avoid the "off-label" administrations of the agent, will result in high and variable concentrations of uremic toxins such as IS. The consequences of this effect will include progression of the disease and the occurrence of cardiovascular and neurological degeneration.

Objective: To present a case of suspected colistin-induced neurotoxicity, likely resulting from drug accumulation during treatment of multidrug-resistant Pseudomonas aeruginosa (PA) bacteremia.

Case report: An 18-year-old female with no prior medical history was admitted to the coronary care unit with fulminant myocarditis, requiring mechanical circulatory support and ultimately left-ventricular assist device implantation. Three weeks later, she developed PA bacteremia. Despite multiple targeted antibiotic regimens, PA persisted in subsequent blood cultures. Colistimethate sodium (CMS) was initiated at 2 × 4.5 MIU, the recommended dose according to serum creatinine-based renal function (eGFR ~ 133 mL/min/1.73m²). On day 4, the patient developed an acute confusional state with hallucinations. While serum creatinine remained stable, cystatin C and 24-hour urine clearance indicated impaired renal function (eGFR ~ 32 mL/min/1.73m²). As therapeutic drug monitoring (TDM) was unavailable, the CMS dose was reduced to 2 × 2.5 MIU based on cystatin C-estimated renal function, leading to resolution of neurological symptoms within 3 days. CMS was continued for 10 days, leading to improved inflammatory markers and clinical stabilization.

Conclusion: Colistin-induced neurotoxicity should be considered in patients with new-onset neuropsychiatric symptoms, particularly in the setting of renal dysfunction or high cumulative exposure. Reliance on serum creatinine alone may misrepresent renal function; incorporation of cystatin C or urine clearance can improve dosing accuracy and reduce toxicity risk. When therapeutic alternatives are limited, dose reduction rather than discontinuation may be an appropriate strategy. Broader implementation of TDM is essential to optimize dosing and minimize adverse outcomes in clinical practice.

Background: Extracorporeal membrane oxygenation (ECMO) provides life support for critically ill tuberculosis (TB) patients. However, during ECMO therapy, significant fluctuations in the plasma concentration of anti-TB drugs occur due to drug adsorption in the ECMO circuit, hemodilution, and metabolic disturbances.

Materials and methods: This single-case study monitored the plasma concentration of anti-TB drugs in a TB patient supported by ECMO.

Results: The differences in peak plasma concentrations (C_max) measured at the end of ECMO support vs. 7 days after ECMO withdrawal were as follows: isoniazid (66%), linezolid (63%), ethambutol (56%), and levofloxacin (12%).

Conclusion: We analyzed ECMO's impact on drug concentrations and implemented therapeutic drug monitoring to optimize therapy. However, this single-case study has inherent limitations; future multi-center studies are warranted to validate these findings.