Plasma Concentration Monitoring Research Articles

Serum concentration threshold and risk factors of tigecycline-induced hypofibrinogenaemia in critically ill patients.

Hypofibrinogenaemia is a serious adverse reaction associated with tigecycline (TGC) therapy and may lead to the discontinuation of the treatment. This study aimed to explore the relevant factors of TGC-induced hypofibrinogenaemia and determine the thresholds of serum concentration as a predictive indicator of TGC-induced hypofibrinogenaemia. A retrospective single-centre study was conducted on patients with severe infection who were treated with TGC. Clinical data and serum concentration parameters were extracted from the electronic medical records of these patients. Patients were divided into the hypofibrinogenaemia group (< 2.0 g/L) and the normal fibrinogen group (≥ 2.0 g/L) in order to evaluate risk factors associated with TGC-induced hypofibrinogenaemia. Logistic regression analysis and receiver operating characteristic curves were utilized to identify the risk factors associated with TGC-induced hypofibrinogenaemia and to establish plasma concentration thresholds as predictive indicators. A total of 114 patients were enrolled in this study, with 59.6% experiencing hypofibrinogenaemia. The multivariate regression analysis indicated that baseline fibrinogen level, trough concentration (Cmin), peak concentration (Cmax), the concentration at 6 h after the dosing (C6h) and the area under the concentration-time curve over a 24-h period (AUC0-24) were significantly associated with hypofibrinogenaemia (P < 0.05). Furthermore, it was found that AUC0-24 is the optimal predictor of TGC-induced hypofibrinogenaemia. The optimal cut-off for the AUC0-24 of TGC in ICU patients was determined to be 17.03 mg h/L. TGC exposure is highly predictive of TGC-induced hypofibrinogenaemia. We recommend closely monitoring plasma concentrations of TGC in patients to ensure patient efficacy and safety.

Triple broadly neutralizing antibody (bnAb) combination therapy: a cure for pediatric HIV?

Abstract Background In 2022, UNAIDS estimated out of the 1.7 million children living with HIV, only 57.1% had access to antiretroviral therapy (ART). Though ART has significantly decreased HIV-associated morbidity and mortality, it cannot eliminate the latent viral reservoir. Consequently, most people living with HIV demonstrate viral rebound when ART is interrupted. There is therefore a critical need for alternative therapeutic to achieve long term ART free viral control. Broadly neutralizing antibodies (bnAb) have shown promising results in preclinical and clinical studies, but their potential efficacy is limited by the emergence of escape variants, especially with monotherapy. We previously tested the neutralizing and non-neutralizing functions of different bnAb combinations and identified a triple bnAb combination that showed robust neutralization potency and breadth, as well as non-neutralizing functions. In this project, we investigated the impact of combination bnAb therapy on viral rebound in SHIV infected infant rhesus macaques (RMs). Methods Ten infant rhesus macaques were orally challenged with SHIV.C.CH505 at 4 weeks of age. Oral challenge is a well-established method that is used to mimic breastmilk transmission of HIV, which contributes to almost 50% of pediatric HIV infections every year. A triple bnAb combination of simianized 3BNC117 (CD4 binding site), PGDM1400 (V2 glycan dependent), and PGT151 (interface) was subcutaneously administered twice at 40 mg/kg of each antibody. The initial infusion was administered at ART initiation (8 weeks post-infection) while the second infusion with administered at the time of analytical treatment interruption (ATI) (49 weeks post-infection). RMs were monitored weekly from the beginning of infection until 12 weeks post-ATI. Enzyme-linked Immunosorbent Assay (ELISA) was used to monitor plasma concentrations of each bNab and Env-specific IgG binding responses. Results Env-specific antibody binding levels against HIV envelope proteins gp120 and gp41 peaked in plasma 8 weeks after infection. The antibody levels then slightly decreased during ART and increased again after viral rebound following ATI. BnAb plasma concentrations peaked 1-2 weeks after each bnAb infusion, then slowly declined. After the initial infusion, all RMs had undetectable levels of 3BNC117 and PGT151 by 8 weeks post initial infusion, and only 2/10 RMs had detectable PGDM1400 levels. All animals experienced viral rebound following ATI.). Importantly, the average time to virus rebound (7 weeks, range 3-10 weeks) was significantly longer than a s control group of RMs without any immune-based intervention (~2.5 weeks). By the time of viral rebound, most animals had undetectable plasma levels of 3BNC117, PGDM1400 or PGT151. However, in some animals, rebound occurs when passively administered antibodies were still detectable, suggesting the emergence of bnAb resistant variants. Conclusion Passive immunization with a triple-bnAb combination of 3BNC117, PGT151 and PGDM1400 was associated with delayed viral rebound, but more investigation is needed to understand the potential role of this strategy in the HIV therapeutic portfolio. Future work will investigate the sensitivity of the rebound viruses to the bnAb combination to evaluate the contribution of bnAb escape to viral rebound.

Plasma apixaban concentrations and thrombin generation assay parameters in response to dose reduction for atrial fibrillation.

To investigate plasma apixaban concentrations and thrombin generation assay (TGA) parameters across different apixaban doses in atrial fibrillation patients who had dose-reduction criteria for apixaban. This observational study included 374 patients (mean age 75.6 ± 7.7 years, 54.8% female) with dose-reduction criteria for apixaban. The patients were divided into 3 groups: (i) on-label standard dose (5 mg twice daily, n =166); (ii) on-label reduced dose (2.5 mg twice daily, n =55); and (iii) off-label underdose (2.5 mg twice daily, n =153). Apixaban concentrations determined via the anti-Xa assay and TGA parameters were compared at trough levels. The off-label underdose group exhibited significantly lower apixaban trough concentrations than the on-label reduced-dose and standard-dose groups (56.7 ± 42.9 vs. 83.7 ± 70.4 vs. 129.9 ± 101.8 ng/mL, all P <.001). Less than 70% of all patients fell within the expected range of apixaban concentrations. Proportions exceeding the upper limit of the expected range were significantly lower in the off-label underdose group (1.3%) than in the on-label reduced-dose (9.1%, P =.005) and standard-dose (12.7%, P <.001) groups. The TGA parameters showed the on-label standard-dose group displaying the lowest thrombogenic profiles. Lower creatinine clearance was the most significant predictor of higher apixaban concentrations. Off-label underdosed apixaban resulted in lower apixaban concentrations than both on-label standard and reduced-dose regimens. A considerable proportion of the patients exhibited apixaban concentrations outside the expected range, suggesting the potential benefits of plasma concentration monitoring. Further studies are needed to compare dosages directly, investigate the impact of plasma apixaban concentration monitoring and validate the current dose-reduction criteria.

Determination of metformin from micro-liter plasma and blood glucose test strip using eco-friendly micro-extraction procedures for point-of-care diagnostics

Metformin is commonly used in the treatment of type 2 diabetes and polycystic ovary syndrome. Beyond these common applications, it also holds promise in treating chronic pain, and as an antiaging and anticancer agent. In addition, it has cardiovascular protective and neuroprotective effects. However, elevated concentrations of metformin in the plasma, such as in patients with renal impairment or with conditions that can disrupt lactate clearance, could cause metformin-associated lactic acidosis. Moreover, metformin can cause a deficiency of vitamin-B12 and folic acid and impact one-carbon metabolism negatively. This study employs micro-extraction procedures to extract metformin from the human plasma and blood glucose test strips followed by detection using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Under the optimized micro-extraction procedures and by using an eco-friendly base and solvent, the proposed method required only 10 µL of the human plasma and a small piece of the blood glucose test strip for metformin analysis. The method exhibits a linear range of 0.05–5 μg mL−1 with a coefficient of determination (r2) of 0.999 and a limit of detection of 0.01 μg mL−1. The relative standard deviation (RSD) and relative error (RE) were both below 6.7 %. The test strip is a disposable product; its reuse before disposal could increase its additional applicability. Furthermore, major blood proteins and their modifications could be identified using this tiny volume of blood by mass spectrometry after protein digestion. The proposed technique could be invaluable in point-of-care diagnostics, enabling rapid monitoring of metformin plasma concentration and major plasma proteins to help patients mitigate the risk of metformin-associated lactic acidosis. To reduce organic waste in clinical applications, micro-extraction is a simple and efficient protocol for sample preparation using minute volumes of blood samples.

Apixaban plasma concentrations before and after catheter ablation for atrial fibrillation.

Catheter ablation in patients with atrial fibrillation is associated with a transient increase in thromboembolic risk and adequate anticoagulation is highly important. When patients are anticoagulated with apixaban, monitoring of plasma concentrations of the drug is not routinely performed. This study aimed to assess the influence of clinical patient characteristics, concomitant drug treatment and self-reported adherence on apixaban concentrations, and to describe the intra- and inter-individual variability in apixaban concentrations in this group of patients. Method Apixaban concentrations from 141 patients were measured in plasma one week before ablation and two, six and ten weeks after ablation, employing ultra-high performance liquid chromatography coupled with tandem mass spectrometry. In samples not obtained at trough, apixaban concentrations were adjusted to trough levels. Self-reported adherence was registered by means of the 8-item Morisky Medication Adherence Scale before and after ablation. There were statistically significant, positive correlations between apixaban concentrations and increased age, female sex, lower glomerular filtration rate, higher CHA2DS2-VASc score, use of cytochrome P450 3A4 and/or p-glycoprotein inhibitors, and use of amiodarone. Self-reported adherence was generally high. The mean intra-individual and inter-individual coefficients of variation were 29% and 49%, respectively. In patients undergoing catheter ablation for atrial fibrillation, age, sex, renal function, interacting drugs and cerebrovascular risk profile were all associated with altered plasma apixaban concentration. In this group of patients with a generally high self-reported adherence, intra-individual variability was modest, but the inter-individual variability was substantial, and similar to those previously reported in other patient apixaban-treated populations. If a therapeutic concentration range is established, there might be a need for a more flexible approach to apixaban dosing, guided by therapeutic drug monitoring.

Posaconazole gastro-resistant tablets for preventing invasive fungal disease after haematopoietic stem cell transplantation: a propensity-matched cohort study

ObjectivesTo evaluate posaconazole (POS) gastro-resistant tablets for preventing invasive fungal disease (IFD) in haematopoietic stem cell transplantation (HSCT) patients and analyse POS plasma concentrations. MethodsA single-arm trial was designed with a historical cohort as a control. Patients aged 13 years and older undergoing HSCT at the HSCT Center of Blood Diseases Hospital, Chinese Academy of Medical Sciences between December 2020 and May 2022 were enrolled, prospectively taking POS gastro-resistant tablets orally from day 1 to day 90 post-transplant and monitoring plasma concentrations. We also identified a retrospective cohort treated with alternative antifungal prophylaxis between January 2018 and December 2020, matched using propensity score methods. The primary outcome was the cumulative incidence of IFD at day 90 post-transplant. ResultsThe prospective study involved 144 patients receiving POS gastro-resistant tablets for IFD prevention, contrasting with 287 patients receiving non-POS tablets. By day 90 post-transplant, the POS tablet group exhibited a significantly lower cumulative incidence of IFD (2.81%; 95% CI, 0.09–5.50% vs. 7.69%; 95% CI, 4.60–10.78%; p 0.044). Adverse events were comparable between the groups with liver changes in 33/144 (22.92%) vs. 84/287 (29.27%) (p 0.162), and renal injuries in 15/144 (10.41%) vs. 37/287 (12.89%) (p 0.457). Mean POS plasma concentrations on days 4, 8, 15, and 22 post-administration were 930.97 ng/mL, 1143.97 ng/mL, 1569.8 ng/mL, and 1652.57 ng/mL, respectively. DiscussionPatients administered POS gastro-resistant tablets for antifungal prophylaxis experienced a lower cumulative incidence of IFD. POS plasma concentrations in HSCT patients stabilized by day 15 of medication.

Standard atezolizumab leads to severe overexposure in real-world patients with lung cancer: How far could we go in extending dosing intervals and saving money?

3085 Background: Immune checkpoint inhibitors are given as fixed doses, which may lead to drug exposure exceeding the plasma concentrations required for target engagement. If confirmed, this could pave the way for de-escalating treatments without compromising efficacy while reducing drug-costs. Methods: We monitored plasma concentrations of Atezolizumab in 40 real-world patients. A final set of 33 patients with SCLC or NSCLC were available for full PK/PD analysis. Individual PK parameters were derived using a population pharmacokinetics approach. Individual PK parameters allowed to simulate the full concentration-time profiles and to further simulate for each patient the time to reach the target threshold after the first dose of Atezolizumab. In addition, efficacy (RECIST criteria) and immune-related adverse events, (IRAEs, CTCAE grading) were monitored and statistical analysis was performed to search for possible exposure-response relationships. Results: Overall Response Rate was 55% and no severe IRAEs were observed. All patients had Cmin levels significantly above the target threshold on the first cycle of Atezolizumab. The mean Cmax after the first dose on cycle 1 was 426.1 µg/ml and the mean Cmin was 68.5 µg/ml, i.e. 11-time higher than the target threshold associated with target engagement (i.e., 6 µg/ml). The mean AUC at the first cycle was 4763 µg.d/ml. Exposure metrics and PK parameters at baseline and simulated prior RECIST evaluation were tested together with other covariates (i.e. age, sex, smoking, NLR, number of metastatic sites, line of treatment) as possible predictive markers of response or toxicity. None of the parameters related to Atezolizumab pharmacokinetics or exposure levels were associated with efficacy or toxicity, most likely because all patients had plasma levels well above pharmacologically active concentrations. First-line therapy was associated with better response on univariate analysis, but this effect was lost on multivariate analysis. Further simulations based on time required to fall below the efficacy threshold suggest that dosing intervals could be extended from Q7W to Q19W (mean: Q12W). Considering the annual budget for Atezolizumab at our institution, further simulations showed that the annual drug cost could thus be reduced from 2.5 M€ to 0.6 M€ while ensuring that all patients remain above active concentrations. Conclusions: Our study demonstrates in a real-world setting that standard Atezolizumab given as 1200 mg Q3W infusion leads to severe overexposure of the drug. This strong overexposure was not associated with more severe treatment-related toxicities. Finally, our study suggests that PK-guided dosing with Atezolizumab could help customizing the dosing interval while maintaining efficacious trough levels and that Q12W could be an alternate scheduling leading to significant cut in drug costs.

Development and Validation of a Capillary Zone Electrophoresis-Tandem Mass Spectrometry Method for Simultaneous Quantification of Eight β-Lactam Antibiotics and Two β-Lactamase Inhibitors in Plasma Samples.

Monitoring plasma concentrations of β-lactam antibiotics is crucial, particularly in critically ill patients, where variations in concentrations can lead to treatment failure or adverse events. Standardized antimicrobial regimens may not be effective for all patients, especially in special groups with altered physiological parameters. Pharmacokinetic/pharmacodynamic (PK/PD) studies highlight the time-dependent antibacterial activity of these antibiotics, emphasizing the need for personalized dosing. Therapeutic drug monitoring (TDM) is essential, requiring rapid and accurate analytical methods for precise determination of drugs in biological material (typically plasma or serum). This study presents a novel capillary zone electrophoresis-tandem mass spectrometry (CZE-MS/MS) method designed for the simultaneous quantification of five penicillin antibiotics, two cephalosporins, one carbapenem, and two β-lactamase inhibitors in a single run. The method involves a simple sample pretreatment-precipitation with organic solvent-and has a run time of 20 min. Optimization of CZE separation conditions revealed that 20 mM ammonium hydrogen carbonate (NH4HCO3) serves as the optimal background electrolyte (BGE). Positive electrospray ionization (ESI) mode, with isopropyl alcohol (IP)/10 mM ammonium formate water solution (50/50, v/v) as the sheath liquid, was identified as the optimal condition for MS detection. Method validation according to the Food and Drug Administration (FDA) guideline for development of bioanalytical methods demonstrated satisfactory selectivity, linearity, recovery, robustness, and stability. The method's practicality was evaluated using the Blue Applicability Grade Index (BAGI), yielding a score of 77.5. Moreover, the greenness of the proposed method was evaluated by two commonly used metric tools-Analytical GREEnness (AGREE) and Green Analytical Procedure Index (GAPI). The developed CZE-MS/MS method offers a practical and reliable approach for quantifying a broad spectrum of β-lactam antibiotics in plasma. Its ability to simultaneously quantify multiple analytes in a single run, coupled with a straightforward sample pretreatment, positions it as a valuable and prospective tool for TDM in critically ill patients.

Effect of continuous renal replacement therapy on the clinical efficacy and pharmacokinetics of polymyxin B in the treatment of severe pulmonary infection

ObjectiveThis study aimed to evaluate the pharmacokinetics of polymyxin B in patients with ventilator-associated pneumonia caused by multi-drug resistant bacteria, and to analyze the effect of continuous renal replacement therapy (CRRT) on pharmacokinetics of polymyxin B. MethodsThirty-five patients with ventilator-associated pneumonia caused by multi-drug resistant bacteria admitted to our hospital from June 2021 to January 2022 were selected as the subjects. The patients were divided into the standard group (n = 20) and the non-standard group (n = 15) based on the factors affecting the compliance of polymyxin B plasma concentration. The patients received with polymyxin B and the plasma concentration was monitored. According to the monitoring results, they were divided into the standard group and the non-standard group, to analyze the influencing factors of polymyxin B on the blood concentration. Besides, the patients were then divided into the control group (n = 28) and the observation group (n = 7) according to whether the patients received CRRT treatment. Patients in the control group treated with polymyxin B alone, while patients in the observation group received with polymyxin B and CRRT. The general data of patients in the two groups were compared. The levels of plasma concentration of polymyxin B measured before the next administration (Cmin), peak plasma concentration of polymyxin B measured immediately after end of infusion (Cmax) and intermediate plasma concentration measured 6 h after administration (midpoint of the dosing interval) (C1/2t) were detected and compared between the two groups. Correlation between pharmacokinetics and efficacy was analyzed by Spearman correlation. The incidence of complications and the 28-day mortality rate of the two groups were recorded. ResultsThe age, body mass index (BMI) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores in the non-standard group were higher than these in the standard group (p < 0.05). BMI and APACHE II scores were independent risk factors affecting the pharmacokinetics of polymyxin B in patients with severe pulmonary infection (p < 0.05). There were no significant differences in age, BMI, APACHEII score, alanine aminotransferase level, aspartate aminotransferase level, albumin level, gender and diabetes ratio between the control group and the observation group (p > 0.05). The levels of Cmin, Cmax, and C1/2t in the observation group were lower than these in the control group (p < 0.001). The response rate was 50.00% in the control group and 36.36% in the observation group (p > 0.05). The levels of Cmin, Cmax, and C1/2t in the observation group were no significant correlation with the clinical efficacy (p > 0.05), while these in the control group were positive correlation with the clinical efficacy (r = 0.485, p < 0.05). There was no significant difference in the incidence of skin pigmentation, nephrotoxicity and 28-day mortality between the two groups (p > 0.05). ConclusionIn patients with ventilator-associated pneumonia not receiving multidrug-resistant bacteria, the rate of achieving blood drug concentration with the usual recommended dose of polymyxin B was satisfactory. However, the proportion of patients with a 6-h plasma concentration exceeding the maximum plasma concentration was high. BMI and APACHE II scores were important factors affecting the pharmacokinetics of polymyxin B. In patients undergoing CRRT, the plasma concentration of polymyxin B was significantly reduced, suggesting that in patients with severe disease, plasma concentration monitoring played an important role in drug efficacy and patient safety. In patients treated with CRRT, the dose of polymyxin B may need to be increased.

Simultaneous determination of oxacillin and cloxacillin in plasma and CSF using turbulent flow liquid chromatography coupled to high-resolution mass spectrometry: Application in therapeutic drug monitoring

Cloxacillin and oxacillin are group M penicillins. The therapeutic monitoring of plasma concentrations of these antibiotics and those of their hydroxymethylated metabolites is of great clinical interest, especially in the choice of an adequate dosage allowing an effective treatment while limiting the occurrence of undesirable effects and the development of bacterial resistance. In this context, we conducted this work aiming at developing and validating a method allowing the determination of cloxacillin and oxacillin as well as the identification of their active metabolites in different biological matrices (CSF and plasma) using turbulent flow liquid chromatography coupled to high-resolution mass spectrometry. To do this, we carried out several optimisation tests. Subsequently, we validated our method according to the latest bioanalytical validation recommendations of the European Medicines Agency. The validation results showed that our method is specific and sensitive. We obtained good linearity in the range 0.5 to 100 µg/mL with correlation coefficients above 0.995. The lower limit of quantification was 0.5 µg/mL for each analyte. The method was found to be accurate with repeatability and reproducibility coefficients of variation below 15 %. Our method is also accurate with bias values below 15 %. Recovery values ranged from 87 % to 95 %. Finally, we were able to apply our method to the therapeutic monitoring of the analysed molecules and to identify their active metabolites. Our results suggest that LC-MS shows superiority in the therapeutic monitoring of these antibiotics due to the superiority of specificity shown by this method. This assay method can be routinely used for the daily plasma assays of patients treated with these antibiotics in the context of therapeutic monitoring.

The extent of cytochrome P450 3A induction by antiseizure medications: A systematic review and network meta-analysis.

Antiseizure medications (ASMs) are commonly categorized as enzyme-inducers and non-enzyme-inducers based on their propensity to enhance the metabolism of concomitantly administered drugs. This systematic review and network meta-analysis aimed to rank ASMs as cytochrome P450 3A (CYP3A)-inducers based on a comparative assessment of ASM-induced reduction in the concentrations of sensitive substrate drugs. The protocol was registered with PROSPERO (International Prospective Register of Systematic Reviews; CRD42022335846), and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) standards were followed. We searched MEDLINE, Embase, and Cochrane until March 14, 2023 without an initial date restriction. Data were additionally obtained via the US Food and Drug Administration database. Studies had to be prospective, with ASM monotherapy for ≥5 days. The primary parameter was the magnitude of change in the area under the concentration-time curve of CYP3A substrates following treatment with the ASM. The standardized mean difference (SMD) was used as the point estimate for the indirect comparisons between ASMs using the pairwise method. Bias risk was assessed using the PKclin tool. We identified 14 open-label, fixed-sequence studies with 370 participants. The effect size of 600 mg/day carbamazepine did not differ from those of 300 mg/day phenytoin (SMD = -.06, 95% confidence interval [CI] = -.18 to .07) and 200 mg/day cenobamate (SMD = -.11, 95% CI = -.26 to .04). Carbamazepine at 600 mg/day was the strongest CYP3A-inducer (P-score = .88), followed by carbamazepine 400 mg/day (.83), phenytoin 300 mg/day (.79), and cenobamate 200 mg/day (.73). Eslicarbazepine (800 mg/day) ranked higher than cenobamate 100 mg/day and oxcarbazepine 900 mg/day (.60, .39, and .37, respectively). Despite the limited number of studies, our network meta-analysis emphasizes that the magnitude of ASM effects on CYP3A substrate metabolism is a dose-dependent continuum. When possible, ASM classification as inducers should apply cutoff values tailored to the outcome. Prescribers should monitor plasma concentrations or clinical effects of CYP3A substrates and consider selecting concomitant medications accordingly.

Liquid Chromatography-Tandem Mass Spectrometry Method for the Quantification of Plasma Busulfan.

Busulfan is an alkylating agent and functions as a myeloablative and anti-leukemic chemotherapy drug. It is widely used with cyclophosphamide for conditioning patients undergoing bone marrow transplantation for myeloid leukemia. Studies have shown that the busulfan plasma concentration correlates better with clinical efficacy and toxicity than the patient's administered dosage. Low concentrations predispose to disease recurrence and even graft rejection, and higher concentrations can increase the risk of hepatic toxicity. As a result, dosing levels can vary significantly from patient to patient. Therapeutic drug monitoring (TDM) of busulfan plasma concentration guides the dosage adjustment to optimally achieve complete bone marrow ablation while minimizing the dosage-dependent toxicity. The quick and precise (precision <10%) UPLC-MS/MS method described here for monitoring plasma busulfan levels between 50ng/mL and 5000ng/mL involves the addition of an organic solvent and deuterated internal standard (busulfan d-8) followed by a liquid-liquid extraction, injection of the extract onto a C18 column, and analysis by multiple reaction monitoring (MRM) in ESI-positive mode.

Intoxicación por vancomicina en un paciente con síndrome de secreción inadecuada de hormona antidiurética y diarrea

Vancomycin is an antibiotic used for infections by gram-positive bacteria with a two-compartment pharmacokinetic model. Its monitoring has an established therapeutic range (10-20 mg/L) to prevent nephrotoxicity and ototoxicity due to supra-therapeutic levels, and inefficiency and development of resistance by subtherapeutic levels.Nephrotoxicity for vancomycin monotherapy at standard doses according to pathogen and typical regimens (usual dose: 15-20 mg/kg/12 h) is rare and usually reversible. Moreover, monitoring plasma concentrations allows to achieve concentrations within therapeutic range to allow safe and effective drug use. The renal hypoperfusion can cause pre-renal damage, resulting in elevated levels of serum creatinine, resulting in decreased antibiotic elimination and nephrotoxicity.We report a case of unexpected vancomycin nephrotoxicity in a patient with syndrome Inappropriate antidiuretic hormone secretion associated paraneoplastic.

Tolerability of Chronic Extremely High-dose Use of Methylphenidate. Description of A Clinical Case

Methylphenidate (MPH) is frequently employed off-label and at high uncontrolled dosages, even beyond the scope of attention deficit hyperactivity disorder (ADHD) treatment. Intoxications appear to be infrequent and are documented in only a few case reports, with monitoring of plasma concentrations not consistently conducted. In the literature, there are no case reports or studies on the tolerability of high-normal doses of MPH. Here we present a case of prolonged and excessive use of MPH without side effects before the patient was admitted to our psychiatric facility, following the consumption of illegal substances and a brief episode of acute confusion. Surprisingly, after admission, the patient's symptoms improved rapidly, before we substantially reduced the dose.

A fully validated method for simultaneous determination of icotinib, osimertinib, gefitinib and O-desmethyl gefitinib in human plasma using UPLC-MS/MS for therapeutic drug monitoring

Background and aimsA few researches have reported the exposure-efficacy/toxicity relationships of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). On account of the large interpatient pharmacokinetic variability, therapeutic drug monitoring (TDM) seems promising for optimizing dosage regimen and improving treatment efficacy and safety. Therefore, a rapid and convenient ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of icotinib, osimertinib, gefitinib and O-demesthyl gefitinib in human plasma for TDM. Materials and methodsIcotinib-D4 and osimertinib-13CD3 were used as the internal standards (ISs). The samples were prepared by protein precipitation using acetonitrile. Chromatographic separation was achieved on a 40 ℃ Shimadzu Shim-pack Scepter C18–120 column (2.1 ×50 mm, 3.0 µm, Japan) by a Shimadzu 30 A solvent management system. Detection was carried out using a Shimadzu LC-MS 8050CL triple quadrupole mass spectrometer coupled with an electrospray ionization source in positive mode. ResultsThis analytical method was fully validated with selectivity, carry-over, linearity, lower limit of quantification, accuracy (from 92.68% to 106.62%) and precision (intra- and inter-day coefficients of variation ranged from 0.92% to 9.85%), matrix effect, extraction recovery, stability and dilution integrity. The calibration curves were developed to be within the concentration ranges of 200–4000 ng/mL for icotinib, 50–1000 ng/mL for osimertinib, gefitinib and O-desmethyl gefitinib in human plasma which meet the needs of routine TDM. ConclusionsThe proposed method was used in 100 patients with non-small cell lung cancer for monitoring plasma concentration of the mentioned EGFR-TKIs. The trough concentrations of ICO were distributed between 226.42 ng/mL and 3853.36 ng/mL, peak concentrations were between 609.20 ng/mL and 2191.54 ng/mL. The trough concentrations of OSI were distributed between 110.48 ng/mL and 1183.13 ng/mL. The trough concentrations of GEF were distributed between 117.71 ng/mL and 582.74 ng/mL, while DeGEF was distributed from 76.21 ng/mL to 1939.83 ng/mL with two less than 20 ng/mL. The results of therapeutic drug monitoring aimed to investigate exposure-efficacy/toxicity relationship and improve the efficacy and safety of targeted therapies.

Therapeutic drug monitoring and the therapeutic reference range of levetiracetam for Chinese patients: Problems and issues

BackgroundLevetiracetam (LEV) is widely used in the clinical monotherapy or multi-drug combination treatment of seizures due to its good tolerability and efficacy. Due to a lack of large-scale clinical studies, the relationship between levetiracetam concentrations, disease activity and adverse is unclear, limiting the usefulness of therapeutic drug monitoring (TDM) based LEV plasma levels. This study was intended to investigate factors influencing the pharmacokinetics of and the appropriate reference range of LEV concentration using available LEV TDM data. MethodsA rapid, accurate and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) method was established to determine LEV plasma concentrations. In this study, the levetiracetam plasma concentration monitoring data from 352 samples (taken from 248 patients) were used to explore the relationship between levetiracetam dose, age, combined administration with other antiseizure medications in patients with epilepsy. ResultsAge and combined administration emerged as important affecting factors for the correlation of LEV concentration and dose. The correlation between concentration and dose was better in monotherapy. Combined administration may affect LEV concentration, especially when LEV is combined with oxcarbazepine, which might decrease the LEV concentration. ConclusionThese findings emphasize the need to monitor LEV routinely LEV, especially among children and older adults when other antiseizure comedications are prescribed in the treatment regimen. LEV TDM is a well-established tool for the management of patients with epilepsy.

Fluorescent Immunochromatography of Vancomycin in Plasma: A Rapid and Sensitive Quantitative Analysis.

Vancomycin (VAN) has a narrow therapeutic window and variable pharmacokinetic properties, which require timely monitoring of plasma concentration to adjust the dosage for better effectiveness. A sensitive and quantitative immunochromatographic method was developed to detect vancomycin in plasma. The linear response range of the method to detect plasma vancomycin was 1.25-50 μg/mL. The intra-assay and inter-assay coefficients were 4.68% and 8.81%, respectively, while the recovery was 89.10-98.32%. The clinical comparative experiment results demonstrated a good correlation (r>0.90) between the fluorescent immunochromatographic strip test and the mass spectrum. In this study, a simple, rapid, and high-sensitivity immunochromatographic method was established for detecting vancomycin, which helped establish the basis for further application of monitoring plasma concentration.

Norvancomycin plasma concentration monitoring in hemodialysis patients with end stage kidney disease: A retrospective cohort study

Blood concentration monitoring plays an important role in the rational use of norvancomycin. However, the reference interval for the norvancomycin plasma concentration in the treatment of infections in hemodialysis patients with end stage kidney disease is undefined. To determine the safe and effective interval for the norvancomycin plasma trough concentration, 39 patients treated with hemodialysis and norvancomycin were analyzed retrospectively. The norvancomycin plasma concentration before hemodialysis was tested as the trough concentration. The associations of the norvancomycin trough concentration with efficacy and adverse reactions were evaluated. No norvancomycin concentration above 20μg/mL was detected. The trough concentration, but not the dose, had a significant effect on the anti-infectious efficacy. Compared with the low norvancomycin trough concentration group (<9.30μg/mL), the high concentration group (9.30-20.0μg/mL) had improved efficacy (OR=15.45, p<0.01) with similar side effects (OR=0.5417, p=0.4069). It is beneficial to maintain the norvancomycin trough concentration at 9.30-20.0μg/mL to achieve a good anti-infectious effect in hemodialysis patients with end stage kidney disease. Plasma concentration monitoring provides a data basis for the individual treatment of infections with norvancomycin in hemodialysis patients.

Safety and Efficacy Re-Evaluation of Edoxaban and Rivaroxaban Dosing With Plasma Concentration Monitoring in Non-Valvular Atrial Fibrillation: With Observations of On-Label and Off-Label Dosing.

Background: Off-label dosing of direct oral anticoagulants (DOAC) as a treatment for non-valvular atrial fibrillation (NVAF) is problematic. Here, we investigated the status of rivaroxaban and edoxaban dosing by monitoring plasma concentrations (PCs). Methods and Results: We monitored drug PCs in 391 and 333 outpatients receiving rivaroxaban and edoxaban, respectively, for NVAF. Drug doses were adjusted if the PC was above the cut-off value (rivaroxaban: 404 ng/mL; edoxaban: 402 ng/mL), determined from receiver operating characteristic curves for predicting bleeding events. On-label standard dosing was reduced to off-label underdosing due to high PCs above the cut-off more often for rivaroxaban (28.1%) than edoxaban (12.6%; P<0.001). Over a median follow-up of 13 months for rivaroxaban and 10 months for edoxaban, the annual incidence of bleeding events was higher with rivaroxaban than with edoxaban (4.88 vs. 3.73 patient-years; P<0.05), although no thromboembolic events occurred in either group. Furthermore, for patients with creatinine clearance >50 mL/min and body weight ≤60 kg, there was a greater incidence of bleeding events with rivaroxaban on-label 15 mg dosing than with edoxaban on-label 30 mg dosing (22.2% vs 2.9%; P<0.01). Conclusions: Monitoring the PCs of rivaroxaban and edoxaban in NVAF patients enables dose adjustments to reduce bleeding risk. The incidence of bleeding under drug PC monitoring was less in the edoxaban than rivaroxaban group.

Interactions Between Direct Oral Anticoagulants (DOACs) and Antiseizure Medications: Potential Implications on DOAC Treatment.

The use of direct oral anticoagulants (DOACs) is increasing because of their superior efficacy and safety compared with vitamin K antagonists. Pharmacokinetic drug interactions, particularly those involving cytochrome P450- mediated metabolism andP-glycoprotein transport, significantly affect the efficacy and safety of DOACs. In this article, we assess the effects of cytochrome P450- and P-glycoprotein-inducing antiseizure medications on DOAC pharmacokinetics in comparison to rifampicin. Rifampicin decreases to a varying extent the plasma exposure (area under the concentration-time curve) and peak concentration of each DOAC, consistent with its specific absorption and elimination pathways. For apixaban and rivaroxaban, rifampicin had a greater effect on the area under the concentration-time curve than on peak concentration. Therefore, using peak concentration to monitor DOAC concentrations may underestimate the effect of rifampicin on DOAC exposure. Antiseizure medications that are cytochrome P450 and P-glycoprotein inducers are commonly used with DOACs. Several studies have observed a correlation between the concomitant use of DOACs and enzyme-inducing antiseizure medications and DOAC treatment failure, for example, ischemic and thrombotic events. The European Society of Cardiology recommends avoiding this combination, as well as the combination of DOACs with levetiracetam and valproic acid, owing to a risk of low DOAC concentrations. However, levetiracetam and valproic acid are not cytochrome P450 or P-glycoprotein inducers, and the implications of their use with DOACs remain to be elucidated. Our comparative analysis suggests DOAC plasma concentration monitoring as a possible strategy to guide dosing owing to the predictable correlation between DOACs' plasma concentration and effect. Patients taking concomitant enzyme-inducing antiseizure medications are at risk for low DOAC concentrations and subsequently, treatment failure and thus can benefit from DOAC concentration monitoring to prophylactically identify this risk.