Therapeutic Drug Monitoring最新文献

Background: A versatile ultra-high performance liquid chromatography method with diode array detection was developed to quantify a wide range of antibiotics in human serum. This method addresses the need for rapid and accurate determination of antibiotic levels to ensure effective patient treatment and support the fight against antibiotic resistance.

Methods: This method assesses 31 different compounds covering β-lactams, fluoroquinolones, antifungals, antituberculars, and more. Proteins were precipitated using methanol or acetonitrile, and drugs were extracted by liquid-liquid extraction with dichloromethane. Separation of the antimicrobials was achieved on a pentafluorophenyl column, using a mobile phase of phosphoric acid (0.01 mol/L) and acetonitrile in a gradient elution mode, with a flow rate of 500 μL/min.

Results: Almost all compounds were detected at 200 nm. The total analysis time for this method was kept under 18 minutes, including equilibration time.

Conclusions: This efficient method enables fast determination of numerous antimicrobial classes, providing clinicians with an essential tool for ensuring effective patient treatment and combating antimicrobial resistance.

Abstract: Low-dose methotrexate has been proposed as therapy for patients with severely disabling psoriasis and psoriatic arthritis. However, it can be associated with severe toxicity, such as pancytopenia, characterized by anemia (hemoglobin level <13 g/dL in men), thrombocytopenia (platelet count <150 × 109/L), and neutropenia or agranulocytosis (neutrophil count <1.5 × 109/L and 0.5 × 109/L, respectively). Here, we report a challenging clinical scenario characterized by pancytopenia and acute renal failure to inform clinicians about potential drug-drug interactions and subclinical renal insufficiency.

Background: The aim of this study was to determine the therapeutic reference range of lurasidone, and to analyze the factors influencing the dose-corrected concentration of lurasidone in Chinese psychiatric patients, thereby providing a basis for the development of individualized dosing of lurasidone.

Methods: A retrospective analysis was conducted for hospitalized patients who had received lurasidone and undergone blood concentration monitoring from May 2022 to September 2023 at the Affiliated Brain Hospital of Guangzhou Medical University. Analyses were based on patient demographic data, treatment regimens, and administered drug concentrations.

Results: Data for a total of 123 lurasidone steady-state trough concentrations were collected from 120 hospitalized patients. It was found that 85.56% of lurasidone steady-state trough concentrations were below the lower limit of the lurasidone therapeutic reference range (15 ng·mL-1), and that the median steady-state trough concentration was 7.09 ng·mL-1 (IQ1-IQ3 = 4.12-11.82 ng·mL-1). Gender, age, and co-medication with valproic acid were found to be significant factors influencing lurasidone steady-state trough concentration/daily dose (C/D) values. C/D values for females were 14% higher than those obtained for males. Among patients who did not receive concomitant administration of valproic acid, the C/D values were 55% higher than those who had received co-administered valproic acid. Furthermore, C/D values obtained for elderly patients (≥60 years) were 140% higher than those recorded for adolescents (<18 years) and 157% higher than those in younger adults (18-60 years).

Conclusions: The findings of this study indicated that the guideline-recommended therapeutic reference range (15-40 ng·mL-1) for lurasidone may not be appropriate, at least for the Chinese population. More extensive therapeutic drug monitoring is recommended for elderly female patients and those receiving co-medication with lurasidone and valproic acid.

Objective: To monitor total trough concentration (Cmin_total) and unbound trough concentration (Cmin_free) of vancomycin in clinical samples and analyze the factors influencing them, and to assess their correlation with clinical efficacy and acute kidney injury (AKI).

Methods: Plasma samples were processed by protein precipitation, followed by hollow-fiber centrifugal ultrafiltration to separate unbound vancomycin from plasma. Thereafter, Cmin_total and Cmin_free were determined using high-performance liquid chromatography. Clinical data of patients were collected. Factors affecting vancomycin Cmin_total, Cmin_free, and their correlation with clinical efficacy and nephrotoxicity were investigated.

Results: A total of 146 samples from 105 included patients were collected. Cmin_total and Cmin_free of vancomycin ranged from 0.62 to 56.08 mcg·mL-1 and 0.61-38.51 mcg·mL-1, respectively. Cmin_total and Cmin_free were correlated (r = 0.8899), influenced by basal creatinine and cystatin C. Higher level of Cmin_free (˃8.6 mcg·mL-1) and nephrotoxic drugs concomitant were risk factors of vancomycin-associated AKI (P < 0.05); Cmin_total and Cmin_free thresholds of vancomycin-associated AKI were 15.35 and 6.83 mcg·mL-1, respectively.

Conclusions: vancomycin Cmin_total and Cmin_free, higher Cmin_total and Cmin_free were correlated and higher concentrations of both may increase the risk of AKI.

Background: Ceftriaxone is a first-line beta-lactam antibiotic used in diverse clinical settings. Owing to pharmacokinetic alterations, ceftriaxone therapeutic drug monitoring is currently recommended for patients in the intensive care unit. Ultrafiltration is typically used to measure unbound ceftriaxone concentrations, as it is less costly and time-consuming compared with equilibrium dialysis. However, the reference method, equilibrium dialysis, has not been compared with equilibrium dialysis for ceftriaxone to measure the unbound ceftriaxone concentrations. Therefore, unbound ceftriaxone fractions measured by ultrafiltration versus equilibrium dialysis were compared in patients in the intensive care unit.

Methods: Total and unbound ceftriaxone plasma fractions were measured by ultrafiltration (9500g at 37°C for 30 minutes) and equilibrium dialysis (12 kDa, 37°C for 4 hours) in 32 plasma samples from 28 patients who were critically ill collected during a previous prospective pharmacokinetic study. Passing-Bablok regression and Bland-Altman analyses were performed to evaluate the agreements between both methods.

Results: The median (range) total ceftriaxone plasma concentration was 108.6 (5.2-233) mg/L. The median unbound concentration measured by equilibrium dialysis and ultrafiltration was 14.5 (0.7-52.9) and 23.3 (0.9-79.2) mg/L, respectively, showing a significant difference. Passing-Bablok regression analysis revealed significant proportional and systematic bias. This result was confirmed by Bland-Altman analysis, with a mean relative bias of 43.3% and wide agreement limits (-21% to 108%).

Conclusions: Ultrafiltration substantially overestimates the unbound ceftriaxone fraction compared with equilibrium dialysis at 37°C. It is important to report methodological details and consider this information when interpreting unbound fractions of ceftriaxone and other drugs. These findings may impact the therapeutic drug monitoring of ceftriaxone.

Background: In adult patients with sepsis or septic shock admitted to the emergency department, a single intravenous 15 mg/kg amikacin dose provides inadequate pharmacokinetic-pharmacodynamic target attainment at the locally reported minimum inhibitory concentration (MIC) of 2 mg/L and the European Committee on Antimicrobial Susceptibility Testing clinical breakpoint for Enterobacterales of 8 mg/L.

Objectives: To provide an amikacin dosing strategy with a clinically acceptable probability of target attainment (PTA) for all patients.

Methods: Stochastic simulations were performed using a two-compartment population pharmacokinetics model of amikacin (NONMEM 7.5). PTA was evaluated for various dosing strategies across a range of virtual patients' body weight, body mass index, serum total protein, serum sodium, fluid balance, and estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI), at the locally reported MIC of 2 mg/L and the clinical breakpoint of 8 mg/L. The pharmacokinetic-pharmacodynamic targets were a 24-hour area under the concentration-time curve (AUC24h)/MIC of ≥80 and a 24-hour postdose concentration (C24h) of < 3 mg/L for efficacy and safety, respectively.

Results: The PTA for the clinical breakpoint of 8 mg/L was <90% with standard 15 mg/kg dosing, across all patient characteristics. A flat 1500-mg dose achieved ≥90% PTA for the entire population at a MIC of 2 mg/L. However, at the clinical breakpoint of 8 mg/L, a flat 3500-mg dose provided ≥90% PTA only when the eGFRCKD-EPI was <96 mL/min/1.73 m2. The C24h was similar for 1500 mg and 15 mg/kg dosing, whereas 3500 mg resulted in a higher C24h.

Conclusions: A flat dose is recommended over weight-based dosing. However, selecting a 1500-mg or 3500-mg dose may compromise either efficacy (MIC 2 mg/L) or safety (clinical breakpoint 8 mg/L), posing a dilemma. Clinical validation is warranted.

Background: Paxlovid is a combination of the antiviral agents nirmatrelvir and ritonavir indicated for the oral treatment of high-risk, symptomatic patients with coronavirus disease 2019 (COVID-19). As real-world data on the plasma concentrations of nirmatrelvir/ritonavir (Paxlovid) are limited, the aim of this study was to investigate nirmatrelvir/ritonavir plasma trough levels in a clinical setting using therapeutic drug monitoring.

Methods: A prospective, noninterventional, multicenter, observational clinical study was conducted in which the plasma trough levels of nirmatrelvir/ritonavir were simultaneously determined by using liquid chromatography tandem mass spectrometry in patients with symptomatic COVID-19. The blood samples were collected on days 1, 3, and 5 after the first full-dose day (day 0), and patient data such as sex, height, weight, renal function, liver enzymes, and concomitant (co-) medications were obtained to describe the plasma levels with respect to potential influencing factors.

Results: A total of 46 blood samples from 21 patients were analyzed. The geometric mean Cmin was 4997 ng/mL for nirmatrelvir and 529.4 ng/mL for ritonavir. The plasma concentrations covered a wide range, the highest being observed in patients with advanced age and renally excreted comedications. Patients older than 65 years had a significantly higher risk of achieving excessive plasma trough concentrations above 8840 ng/mL for nirmatrelvir and 1440 ng/mL for ritonavir compared with younger patients (odds ratio 11.2, 95% confidence interval 1.04-120.4).

Conclusions: The plasma trough concentrations of nirmatrelvir and ritonavir in patients treated for symptomatic COVID-19 were higher than the reference values of 2210 ng/mL for nirmatrelvir and 360 ng/mL for ritonavir stated in the product characteristics. Advanced age and renally eliminated comedication were identified as possible influencing factors that warrant further investigation.

Background: Therapeutic drug monitoring of infliximab is commonly performed based on trough concentration. However, doses and dosing intervals may be adapted to patient outcomes, and this trough concentration target may correspond to a large range of exposures in terms of the area under the concentration-time curve (AUC). The objectives of this study were to assess the real-life exposure to intravenous infliximab in patients with Crohn disease in remission at year 1 and to assess the evolution of exposure in patients who switched to subcutaneous infliximab.

Methods: The authors conducted a retrospective observational pharmacokinetic study in patients with Crohn disease who had available infliximab concentrations during intravenous and subcutaneous infliximab maintenance therapy as per the standard of care. Infliximab exposure parameters (AUCs and trough concentrations, C0) were compared for different dosing regimens of intravenous infliximab before (intravenous) and after (subcutaneous) the switch.

Results: A total of 113 patients had 383 intravenous infliximab concentrations. Dosing intervals ranged from 4 to 12 weeks. The median/range/CV% C0, AUC0-t, and AUC0-8weeks were 5.3 mcg/mL [

Conclusions: In this study, the authors suggested that in patients treated with IV IFX, different targets of C0 should be proposed according to treatment schemes and that AUC0-t might be a relevant determinant of clinical remission. Moreover, exposure did not remain stable throughout the switch from IV to SC IFX in any patient. These variations may depend on the intravenous dosing interval before switching.

Background: Geriatric depression is challenging to treat owing to age-related changes in pharmacokinetics and comorbidities. Although renal insufficiency and multimorbidity are typical geriatric complications that cannot be completely separated from each other, no study has examined the influence of these factors on the serum concentrations of antidepressants. For the first time, we evaluated the effects of these factors in combination on the dose-corrected serum concentration (C/D) of antidepressants in geriatric patients.

Methods: In this retrospective study, data from 123 geriatric patients in a gerontopsychiatric day care unit at the University Hospital of Würzburg were analyzed. Multiple linear regression analysis and analysis of variance with confounders were used to examine the associations between glomerular filtration rate (GFR) and stages of renal impairment and the C/D of venlafaxine, mirtazapine, sertraline, and escitalopram corrected for multimorbidity, sex, lithium intake, and the number of triple whammy drugs.

Results: GFR (P < 0.001, ß = -0.070) was associated with the C/D of the active moiety of venlafaxine (N = 32). GFR, multimorbidity, and sex were not associated with the C/D of mirtazapine, escitalopram, or sertraline.

Conclusions: As the influence of sex may be less pronounced than that of decreasing GFR in terms of the C/D of the active moiety of venlafaxine in geriatric patients, we recommend considering the GFR for dose adjustment rather than sex. In conclusion, even in patients with mild renal impairment, serum venlafaxine concentration should be monitored to prevent overdosing. Mirtazapine, sertraline, and escitalopram may be well-suited antidepressants for geriatric patients with renal function impairment stage 2-3 as well as multimorbidity.

Background: This report presents the case of a patient with drug-resistant epilepsy. Despite treatment with 4 antiepileptic drugs, the patient experienced an increasing frequency of focal seizures, necessitating hospitalization, and continuous intravenous midazolam infusion.

Methods: Cobicistat was introduced as a pharmacokinetic booster to decrease the metabolic clearance of midazolam, leading to increased exposure and an extended half-life.

Results: Cobicistat boosting allowed the switch from intravenous to oral midazolam, and the patient was discharged on an oral midazolam regimen.

Conclusions: Cobicistat can be effectively used to boost midazolam exposure pharmacokinetically in patients with drug-resistant epilepsy who require stable midazolam blood concentrations.