Therapeutic Drug Monitoring最新文献

Background: Tocilizumab targets the interleukin-6 receptor, and dosing is complex owing to its nonlinear clearance related to target binding. Therefore, tapering tocilizumab requires a different approach than that of tumor necrosis factor inhibitors (TNFi). This study aimed to identify these differences and enable personalized treatment of rheumatoid arthritis (RA) beyond TNFi therapy.

Methods: A population pharmacokinetic model of intravenous tocilizumab was developed using data from a randomized controlled trial of dose tapering in patients with RA. Subsequent population-level Monte Carlo and individual Bayesian simulations were performed to create tapering strategies involving dose reduction and interval extension. The target trough concentration of tocilizumab was 5 mg/L. Finally, the drug savings were compared between the 2 methods.

Results: The pharmacokinetic of tocilizumab was described with a 2-compartment model with parallel linear (CL 0.20 L/d) and nonlinear (VM 5.2 mg/d, KM 0.19 mg/L) elimination. The linear clearance rate and central volume of distribution increased with lean body mass, and men exhibited higher clearance rates than women. The simulated concentration-time profiles demonstrated that, owing to nonlinear clearance, drug concentrations decreased more than dose-proportionally with lower doses. Tapering based on an individual Bayesian approach emerged as the most promising strategy, yielding a 39% reduction in drug use across virtual populations.

Conclusions: Tapering strategies were developed for intravenous tocilizumab, offering potential application in patients with RA who have reached low disease activity or remission, pending clinical validation. The developed strategies demonstrate that the tapering of tocilizumab should be approached more carefully and in smaller steps than that of TNFi.

Background: Therapeutic monitoring is routinely performed to ensure tacrolimus whole-blood concentrations fall within a predefined target. Despite this, patients still experience inefficacy and toxicity that could be related to variability in free (unbound) tacrolimus exposure. Therefore, the aim of this study was to compare tacrolimus-free plasma (Cu), total plasma (Cp), and whole-blood (Cwb) concentrations in adult kidney transplant recipients and to characterize tacrolimus disposition across different matrices.

Methods: Twelve-hour concentration-time profiling was performed in 15 recipients, allowing simultaneous measurement of Cu, Cp, and Cwb. Pharmacokinetic parameters were estimated using noncompartmental analysis. The relationship between Cwb and Cp were examined using a capacity-limited binding model, incorporating the hematocrit fraction (fHCT) to estimate maximum binding concentration (Bmax) and dissociation constant (Kd). The relationship between Cp and Cu was evaluated using a linear binding model to estimate the nonspecific binding parameter (Nplasma). Nonlinear regression analysis was used to obtain estimates of Bmax, Kd, and Nplasma.

Results: A total of 195 paired Cwb, Cp, and Cu values were collected. The median ratios of Cwb:Cp, Cp:Cu, and Cwb:Cu were 9:1, 20:1, and 138:1, respectively. Variability in free plasma exposure was large; free trough values ranged from 8 to 51 ng/L and free area-under-the-concentration-time-curve values ranged from 424 to 7160 ng·h/L. Median (range) estimates of Bmax, Kd, and Nplasma were 90.4 µg/L (22.4-752.5 µg/L), 2.36 µg/L (0-69.2 µg/L), and 0.05 (0.035-0.085), respectively. The interindividual variability (CV%) in binding parameters was considerable (Bmax 117.2%; Nplasma 32.5%).

Conclusions: Large variability was observed in tacrolimus-free plasma exposure and binding parameters. Future research to characterize the relationship between tacrolimus Cu and patient outcomes may be of benefit.

Background: Allopurinol dose reduction proportional to creatinine clearance (CLcr) results in suboptimal urate lowering in patients with gout. Similarly, diuretic therapy reduces oxypurinol clearance but is unexpectedly associated with the need for higher allopurinol doses to achieve the serum urate target (<0.36 mmol/L). The authors aimed to clarify the relationship between oxypurinol exposure and urate-lowering response in patients with gout at different stages of chronic kidney disease and those taking diuretics to determine the implications for maintenance dose selection.

Methods: Oxypurinol and urate data from 5 clinical studies were available. Model-derived steady-state oxypurinol areas under the concentration-time curves (AUCss0-tau) were estimated using a Bayesian methodology. The observed response metrics included the percentage reduction in urate from baseline and achievement of the target urate level. Exposure-response was explored graphically and using logistic regression. In addition, the influence of chronic kidney disease and diuretic use on the allopurinol dose and oxypurinol AUCss0-tau requirements to achieve the serum urate target were explored.

Results: Data from 258 patients with gout taking allopurinol representing 1288 paired steady-state oxypurinol and serum urate measurements were available. Higher oxypurinol exposure seems to be required for urate-lowering response normalization and achieve the serum urate target in individuals with reduced kidney function and those taking diuretics. However, allopurinol dose requirements were reduced by 2-fold at the extremes of kidney function and unchanged in those taking or not taking diuretics.

Conclusions: A lower allopurinol maintenance dose was required in patients with reduced kidney function (CLcr <30 mL/min), but this was not proportional to CLcr. Diuretic therapy did not influence allopurinol dose requirements.

Background: Voriconazole is the first-line therapy for invasive aspergillosis (IA). To determine the minimum inhibitory concentration of Aspergillus, a voriconazole pharmacokinetic-pharmacodynamic (PK-PD) model linked to galactomannan response was developed and evaluated, and its clinical correlation for IA treatment was elucidated.

Methods: Adult patients with probable or definite IA and at least one serum voriconazole measurement were included. A two-compartment voriconazole PK model was linked to a previously described PD model of galactomannan response. PK and PD parameters were estimated using a nonparametric adaptive grid technique. The relationship between the ratio of voriconazole exposure that induced half-maximum galactomannan response (EC50) and the observed terminal galactomannan concentration was evaluated. The factors associated with the PK-PD parameters and mortality were also determined.

Results: Between January 2013 and December 2022, 41 patients were prescribed voriconazole for IA. The 30-day mortality rate was 17%. A high correlation was found for the observed-predicted Bayesian posterior estimates of voriconazole and galactomannan levels. Moreover, a nonlinear relationship was identified between AUC:EC50 and terminal galactomannan. The factors associated with higher AUC:EC50 were intravenous administration and intubation. In the survival analysis, higher EC50 tended to be associated with mortality, higher AUC was significantly associated with increased mortality, and higher AUC:EC50 tended to be associated with higher mortality. After adjusting for the intravenous route, higher AUC and AUC:EC50 were not associated with mortality.

Conclusions: Individual EC50 estimation can provide insights into in vivo host and organism responses. Elevated EC50 showed comparable and unfavorable trends to higher minimum inhibitory concentration. Thus, determining EC50 might help guide individualized target serum voriconazole levels.

Background: Dalbavancin, an antimicrobial lipoglycopeptide, is authorized in Europe for treating acute bacterial infections of the skin and skin structures in adults and pediatric patients aged 3 months and older. However, off-label dosing regimens have been proposed for various indications beyond acute bacterial infections of the skin and skin structures. This study presents a novel bioanalytical method using liquid chromatography-tandem mass spectrometry to quantify dalbavancin in low-volume plasma samples (50 μL).

Methods: The method underwent validation in accordance with international guidelines for bioanalytical method validation and was applied to 9 clinical samples obtained from pediatric and young adult patients undergoing dalbavancin therapy. Liquid chromatography-tandem mass spectrometry analyses were conducted at the G. Gaslini Institute in Genoa, Italy, utilizing an Ultimate 3000 ultra high performance liquid chromatography system coupled to a TSQ Quantiva Triple Quadrupole system (Thermo Fisher Scientific, Milan, Italy). The analytical procedure involved the addition of deuterated dalbavancin as internal standard and a rapid extraction from 50 µL of human plasma, followed by chromatographic separation on a Thermo Scientific Accucore Polar Premium column. Accurate quantification of the analyte was achieved through multiple reaction monitoring detection.

Results: The assay exhibited linearity within the concentration range of 0.66-400 mcg/mL in plasma, demonstrating accuracy and reproducibility in the absence of matrix effects. Stability testing was conducted on both quality controls and real samples to establish a robust protocol under real-life conditions.

Conclusions: This fast and reliable dalbavancin quantitation method could improve current pediatric clinical practice by enabling data collection for future dose recommendations in special patient populations.

Background: This study was conducted to evaluate the cost-benefit indicators of a vancomycin monitoring protocol based on area under the curve estimation using commercial Bayesian software.

Methods: This quasi-experimental study included patients who were aged >18 years with a vancomycin prescription for >24 hours. Patients who were terminally ill or those with acute kidney injury (AKI) ≤24 hours were excluded. During the preintervention period, doses were adjusted based on the trough concentration target of 15-20 mg/L, whereas the postintervention period target was 400-500 mg × h/L for the area under the curve. The medical team was responsible for deciding to stop the antimicrobial prescription without influence from the therapeutic drug monitoring team. The main outcomes were the incidence of AKI and length of stay. Cost-benefit simulation was performed after statistical analysis.

Results: There were 96 patients in the preintervention group and 110 in the postintervention group. The AKI rate decreased from 20% (n = 19) to 6% (n = 6; P = 0.003), whereas the number of vancomycin serum samples decreased from 5 (interquartile range: 2-7) to 2 (interquartile range: 1-3) examinations per patient ( P < 0.001). The mean length of hospital stay for patients was 26.19 days after vancomycin prescription, compared with 17.13 days for those without AKI ( P = 0.003). At our institution, the decrease in AKI rate and reduced length of stay boosted yearly savings of up to US$ 369,000 for 300 patients receiving vancomycin therapy.

Conclusions: Even in resource-limited settings, a commercial Bayesian forecasting-based protocol for vancomycin is important for determining cost-benefit outcomes.

Background: The case study discusses a complex scenario involving the use of amoxicillin in a critically ill patient undergoing intermittent renal replacement therapy.Severe infections are complicated by septic shock and organ failure, requiring urgent and effective antibiotic treatment.

Methods: The patient's comorbidities, including obesity and acute kidney injury, required careful consideration of the amoxicillin dosing strategies.

Results: Therapeutic drug monitoring is critical for dose adjustment during treatment.

Conclusions: This case highlights the importance of a collaborative approach between clinicians and therapeutic drug monitoring consultants to optimize antibiotic therapy for critically ill patients with renal impairment.

Background: Ibrutinib and zanubrutinib are Bruton tyrosine kinase inhibitors used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Dihydroxydiol ibrutinib (DHI) is an active metabolite of the drug. A liquid chromatography-tandem mass spectrometry method was developed to detect ibrutinib, DHI, and zanubrutinib in human plasma.

Methods: The method involved a protein precipitation step, followed by chromatographic separation using a gradient of 10 mM ammonium acetate (containing 0.1% formic acid)-acetonitrile. Ibrutinib-d5 was used as an internal standard. Analytes were separated within 6.5 minutes. The optimized multiple reaction monitoring transitions of m/z 441.1 → 304.2, 475.2 → 304.2, 472.2 → 455.2, and 446.2 → 309.2 were selected to inspect ibrutinib, DHI, zanubrutinib, and the internal standards in positive ion mode.

Results: The validated curve ranges included 0.200-800, 0.500-500, and 1.00-1000 ng/mL for ibrutinib, DHI, and zanubrutinib, respectively. The precisions of the lower limit of quantification of samples were below 15.5%, the precisions of the other level samples were below 11.4%, and the accuracies were between -8.6% and 8.4%. The matrix effect and extraction recovery of all compounds ranged between 97.6%-109.0% and 93.9%-105.2%, respectively. The selectivity, accuracy, precision, matrix effect, and extraction recovery results were acceptable according to international method validation guidelines.

Conclusions: A simple and rapid method was developed and validated in this study. This method was used to analyze plasma concentrations of ibrutinib and zanubrutinib in patients with mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, or diffuse large B-cell lymphoma. The selected patients were aged between 44 and 74 years.