Therapeutic Drug Monitoring最新文献

Background: Data on the effect of extracorporeal membrane oxygenation (ECMO) on cefepime concentration and protein binding are limited. This study aimed to describe the pharmacokinetics of cefepime in patients receiving ECMO, with or without renal replacement therapy.

Methods: Participants receiving ECMO were prospectively enrolled in the thoracic and lung transplant intensive care unit at the University of Florida Health-Shands Hospital in Gainesville, FL. Serum samples for drug quantification were collected at 1, 2, 4, 6, and 8 hours after the completion of cefepime infusion, pre- and post-ECMO oxygenator. The total and free drug concentrations in the ultrafiltrate were measured using liquid chromatography-tandem mass spectrometry at the University of Florida Infectious Disease Pharmacokinetics Laboratory.

Results: Six patients who underwent venovenous ECMO were enrolled in the study. The median [interquartile range (IQR)] age and weight were 56.5 years (48-61.8) and 80.6 kg (75.4-90.6), respectively, and 67% were female. All patients received 2 g of cefepime infused over 30 minutes, with dosing intervals per renal function. The median (IQR) time between ECMO initiation and pharmacokinetic sampling was 3.5 days (2.5-24.7). None of the patients underwent renal replacement therapy during sampling. Minimal differences in cefepime concentrations pre- and postoxygenator were observed (<20% difference for all paired samples; median 3.5%). The median (IQR) protein-binding rates for cefepime both pre- [6.2% (2.6-10.8)] and post- [8.7% (2.5-13.4)] oxygenator were lower than previously published estimates of 20%.

Conclusions: No differences in pre- or post-ECMO oxygenator cefepime concentrations were observed. The median protein-binding values were less than previously published values.

Background: Reports regarding the relationship between tacrolimus exposure and the risk of acute kidney allograft rejection are conflicting. This may be explained by the previous use of methodological approaches that disregarded important factors in the analysis of longitudinal measurements and time-to-event data. Therefore, in this study, joint models were used to investigate the relationship between repeated measurements of tacrolimus predose concentrations (C 0 ) and time to acute biopsy-proven acute rejection (BPAR).

Methods: This was a post hoc analysis of a randomized controlled trial in which living-donor kidney transplant recipients (KTR) received either a standard, bodyweight-based or CYP3A5 genotype-based tacrolimus starting dose. Joint modeling was performed by coupling a mixed-effects model for tacrolimus C 0 with a Cox proportional hazards model for the risk of rejection. Only the first episode of rejection was considered.

Results: A total of 229 KTRs were included, of whom the incidence of BPAR was 10.5% (n = 24 KTRs) in the first 3 months posttransplant. A total of 3069 tacrolimus measurements were available for the analysis. A joint model adjusted for recipient age and peak panel reactive antibodies demonstrated that tacrolimus C 0 was associated with risk of rejection. A 1-unit increase in the time-normalized area under the curve for logarithmically (log)-transformed C 0 represented a change of -2.65 in the log of the relative hazard (95% credible interval: -5.05 to -0.36, P = 0.022).

Conclusions: A negative association between the cumulative effect of tacrolimus C 0 and BPAR was observed using joint modeling. This demonstrated that KTRs with lower tacrolimus exposure were at a higher risk of rejection.

Background: Cyclosporine (CsA), an immunosuppressant widely used in solid-organ transplantation, requires precise therapeutic drug monitoring to balance its efficacy and toxicity. The interdose area under the concentration-time curve (AUC 0-12 h ) is considered to be a superior metric of drug exposure compared with single concentration measurements but is, nevertheless, resource-intensive. Machine learning (ML) offers a novel approach for AUC prediction by leveraging patient-specific data without relying on traditional pharmacokinetic assumptions. This study intended to develop and evaluate XGBoost ML models for predicting CsA AUC 0-12 h using either two or three blood concentrations and to compare their performance against maximum a posteriori Bayesian estimation (MAP-BE) based on population pharmacokinetic models.

Methods: Using data from 2009 patients and 6360 dose-adjustment requests on the Immunosuppressant Bayesian Dose Adjustment website ( https://abis.chu-limoges.fr/ ), supervised ML models were trained with predictors including CsA concentrations at predefined time points (C0, C1, and C3), dose, age, and sampling time deviations. External validation was performed using rich pharmacokinetic profiles of kidney, heart, lung, and bone marrow transplant recipients.

Results: The three-sample XGBoost model achieved high accuracy in kidney transplant recipients (root mean square error [RMSE] <3%, RMSE<8.2%), closely matching the MAP-BE performance (rMPE <3%, RMSE <8.7%). The two-sample ML model demonstrated lower precision and higher variability but remained applicable in constrained sampling scenarios. The performance was reduced in heart and lung recipients for both ML and MAP-BE, reflecting the limited representation of these populations in the data set.

Conclusions: ML-based AUC prediction is a promising alternative to MAP-BE, particularly for kidney transplantation. Future studies should focus on expanding datasets, incorporating additional transplant types, and refining ML models for broader applicability.

Background: The Cockcroft-Gault (CG) formula is more likely to overestimate renal function and carboplatin dosing in patients who are overweight. In this prospective pharmacokinetic study, the use of an adjusted Cockcroft-Gault formula (aCG) was evaluated to correct for overweight status.

Methods: aCG was adjusted in patients with body mass index (BMI) >25 kg/m 2 using adjusted ideal body weight, capping low serum creatinine values at 60 μmol/L, and high creatinine clearance values at 125 mL/min. Patients were categorized as follows: BMI <25.0 (normal weight), 25.0-29.9 (overweight), and ≥30.0 kg/m 2 (obese). To assess the pharmacokinetics, blood samples were collected and carboplatin ultrafiltrate concentrations were analyzed. Exposure was estimated using a population pharmacokinetic model and compared with the target area under the curve (AUC) regarding bias mean prediction error (MPE%) and imprecision mean absolute prediction error (MAPE%). In addition, substitutes for renal function, including weight descriptors, cystatin C, 24-hour creatinine clearance, and glomerular filtration rate estimators, were compared.

Results: Eighteen patients were included in this study. aCG slightly underestimated individual carboplatin clearance across all weight groups, with the highest deviation in patients who had obesity (MPE%: -10.5%) versus +8.8% using CG. aCG underestimated -5.7% in patients with a normal weight and overestimated by +1.1% in those who were overweight, compared with -4.2% and +2.8%, respectively, using CG. The most accurate predictor of the target AUC for all weight categories was cystatin C (MPE%: +0.2%, -2.0%, and -0.1% for patients with a normal weight, those who were overweight, and those who had obesity, respectively) with low imprecision (MAPE%: 9.8%, 9.5%, and 13.3%, respectively).

Conclusions: This study did not find evidence to support using aCG to predict carboplatin clearance better than CG. However, cystatin C was found to be the most precise and accurate biomarker for carboplatin clearance.

Background: The use of direct oral anticoagulants, such as rivaroxaban, is preferred over vitamin K antagonists. Several clinical scenarios highlighting potential benefits of measuring plasma concentrations have been reported. This study aimed to describe the clinical experience with rivaroxaban in adult patients and develop a mathematical model to predict rivaroxaban concentrations using routine coagulation screening assays.

Methods: Data were prospectively collected over a 4-year-period, including clinical patient characteristics, total plasma rivaroxaban concentrations, and screening coagulation assays, if available. Prothrombin time, activated partial thromboplastin time (aPTT), and thrombin clotting time were included in the model to predict rivaroxaban concentrations.

Results: There were 403 rivaroxaban concentrations with a median of 66 mcg/L. The most common indications for measuring rivaroxaban concentration were routine postinitiation (78/403, 19%), breakthrough thromboembolic or bleeding events (98/403, 24%), and post-dose adjustments (42/403, 10%). Dose adjustments were made after measuring rivaroxaban concentrations in 85 patients (85/403, 21%). A statistically significant relationship existed between PT and aPTT against rivaroxaban concentrations; however, attempts to construct an accurate mathematical model using linear regression to determine rivaroxaban concentrations based on these coagulation assays were unsuccessful.

Conclusions: There was a wide range of measured rivaroxaban concentrations, reflecting the diversity of indications for measurement, with a significant minority associated with subsequent changes in rivaroxaban dosing. Given the frequency of altering dosing regimens based on the results, future efforts should focus on the correlation of concentration data with clinical endpoints to determine reference ranges. An accurate mathematical model to determine rivaroxaban concentrations based on coagulation screening assays could not be developed.

Background: Osimertinib, the first-line treatment for nonsmall cell lung cancer, has 2 main active metabolites, AZ5104 and AZ7550, which demonstrate potency against wild-type epidermal growth factor receptor mutations. In this study, a simple and sensitive analytical method using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/mass spectrometry) was developed and validated to simultaneously quantify osimertinib and its active metabolites in human plasma.

Methods: Plasma samples were subjected to protein precipitation with zinc sulfate solution and acetonitrile using osimertinib- 13 C, d 3 as an internal standard. The separation was performed on a ThermoScientific Hypersil GOLD C18 column (4.6 × 50 mm, 5 μm) with a mobile phase composed of 0.1% formic acid water-acetonitrile through gradient elution. The compounds were monitored using electrospray ionization in the positive mode with multiple reaction monitoring.

Results: Excellent linearity of calibration curves was observed over the ranges of 10-1000 ng·mL -1 for osimertinib, and 1.5-120 ng·mL -1 for AZ7550 and AZ5104 in human plasma. Both within-run and between-run accuracies were within ±15%, with the coefficient of variation <15%.

Conclusions: The method met all the validation criteria and was successfully applied to clinical samples from patients with nonsmall cell lung cancer. Furthermore, the correlation between steady-state trough concentrations of osimertinib, AZ5104, and AZ7550 and patients' baseline characteristics were explored. Women exhibited a significantly higher C min, ss for AZ7550 ( P = 0.023). In addition, body mass index was associated with the C min, ss of both AZ5104 ( P = 0.047) and AZ7550 ( P = 0.001).

Background: The emergence of a linezolid minimum inhibitory concentration creep (2-4 mg/L) necessitates higher trough concentrations (C min ), which may increase the risk of hematological side effects. Evaluating the effects of different linezolid C min levels on hematological indices and determining a new target C min range are essential.

Methods: Elderly patients receiving linezolid at 4 tertiary hospitals between May 2021 and March 2024 were grouped according to their C min levels. Linezolid C min and hematological indices were monitored dynamically.

Results: A total of 320 patients were enrolled, and 128 patients were included in the analysis of hematological side effects following propensity score matching between C min >16 mg/L and C min ≤16 mg/L. The incidence of thrombocytopenia and the reduction in platelet count were significantly greater in patients with C min >16 mg/L compared with those with C min ≤16 mg/L. However, no significant differences were observed in the incidence of anemia or changes in hemoglobin levels. Among the 96 patients with C min ≤16 mg/L, multivariate analysis identified C min as an independent risk factor for thrombocytopenia but not for anemia. Furthermore, no significant difference in thrombocytopenia risk was found between patients with C min levels of 8-14.5 mg/L and those with C min of <8 mg/L (odds ratio, 1.183; 95% confidence interval, 0.428-3.275; P = 0.746).

Conclusions: In elderly patients, hematological side effects did not increase with increasing C min levels up to 14.5 mg/L. These findings suggest that a target C min range of 2-14.5 mg/L may be appropriate for the elderly population receiving linezolid.

Clinical trial registration number: ChiCTR2100045707; April 23, 2021.

Background: Acute lymphoblastic leukemia (ALL) is the predominant malignancy in pediatric patients. As a crucial constituent of ALL chemotherapy, l -asparaginase is recognized as an integral element of treatment with a threshold concentration of 0.1 IU/mL used in treatment protocols. This study presents a novel liquid chromatography-tandem mass spectrometry method for evaluating plasma l -asparaginase activity in pediatric patients with ALL undergoing pegaspargase therapy.

Methods: Initially, an enzyme incubation was conducted using 20 μL of plasma and 100 μL of l -asparagine (0.1 mol/L) at 37°C for 15 minutes. The reaction was stopped by adding sulfosalicylic acid and methanol. After the addition of isotope internal standard l -aspartic 13 C 4 acid, subsequent centrifugation, and dilution, the plasma samples underwent analysis by liquid chromatography-tandem mass spectrometry on a hydrophilic interaction liquid chromatography analytical column. A flow rate of 0.3 mL/min was used during isocratic elution using a mobile phase consisting of methanol-water (95:5, vol/vol) with 0.2% formic acid within a 5-minute run.

Results: The calibration curves exhibited excellent linearity ranging from 0.1 to 15 IU/mL, with determination coefficients ( r2 ) exceeding 0.99. The precision and accuracy ranged from 1% to 7% and from 93% to 110%, respectively. The relative recovery fell within the range of 98%-100%, and the internal standard-normalized matrix effect ranged from 95% to 101%. The stability was satisfactory across various conditions.

Conclusions: This method was fully validated and successfully applied to quantify l -asparaginase activity in plasma samples of 15 children with ALL, enabling the monitoring of l -asparaginase activity with mass spectrometry.

Background: Therapeutic drug monitoring of methadone for opioid replacement therapy in the management of opioid dependence is well-described. However, only a few studies have described the correlation between serum methadone concentration and cancer pain during palliative care.

Methods: Patients were recruited from an exploratory randomized controlled trial (RCT) comparing methadone rotation with other opioid rotations for refractory cancer-induced bone pain. Serum methadone trough levels and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) levels on day 14 of the rotation were analyzed using validated liquid chromatography-mass spectrometry. The average and worst pain intensities were rated at baseline and on day 14, preceding the recorded methadone levels. The Common Terminology Criteria for Adverse Events composite score was used to determine the adverse effects of methadone. The Spearman ρ was used to examine the correlation between methadone trough levels and pain reduction.

Results: Among the 20 patients who were randomized to receive methadone in the RCT, eight consented to this substudy. The mean (SD) steady-state 24-hour methadone dose was 11.6 (2.6) mg, whereas the mean (SD) serum methadone trough concentration was 93.7 (45.6) ng/mL with an acceptable adverse effect profile. All patients had an EDDP concentration of <0.01 mg/L, suggesting good metabolite clearance.

Conclusions: The reported methadone concentration required for therapeutic benefit was significantly lower than that reported previously. The study highlights that further appropriately powered studies are required to establish the role of routine trough methadone monitoring in patients newly rotated for the management of refractory cancer pain.