Plasma Concentration Monitoring Research Articles

Simple and sensitive method for the analysis of 14 antituberculosis drugs using liquid chromatography/tandem mass spectrometry in human plasma.

Human plasma was precipitated by acetonitrile and was subsequently separated by an AQ-C18 column with a gradient elution. Drug concentrations were determined using multiple reaction monitoring in positive ion electrospray ionization mode. According to pharmacokinetic data of patients, the peak concentration ranges and the timing of blood collection were determined. Intra- and interday precision was < 14.8%. Linearity, accuracy, extraction recovery, and matrix effect were acceptable for each drug. The stability of the method satisfied different storage conditions. The method allowed the sensitive and reproducible determination of 14 frequently used anti-TB drugs which has already been of benefit for some TB patients.

A new validated HPLC-UV method for therapeutic monitoring of daptomycin in comparison with reference mass spectrometry

Daptomycin, a cyclic lipopeptide antibiotic with a broad spectrum of activity against Gram-positive bacteria, is also active against multi-resistant bacterial strains, as well as methicillin-resistant S. aureus, vancomycin-resistant enterococci or penicillin-resistant S. pneumoniae. For these reasons it is a viable alternative for the treatment of persisting infections. However, the therapeutic drug monitoring of daptomycin is recommended because the known variability in drug disposition and the severe clinical conditions of patients. Therefore, we developed a simple and fast UV-HPLC method according to FDA guidelines to monitor plasma concentrations of the drug. Briefly, after a liquid-liquid extraction, plasma calibration samples, quality controls and patients’ samples were injected in a HPLC instrument and peaks of daptomycin and gentamicin (internal standard) were resolved by a C18 250 × 4.6 mm, 5 μm stationary phase and peaks were monitored at UV = 262 nm. Mobile phase (isocratic flow of 1 mL/min) consisted of acetonitrile-buffer (KH2PO4 20 mM pH = 3.2) 46:54, vol/vol. Under these conditions, IS and daptomycin peaked at 4.1 and 5.8 min after injection. Values of limits of detection and quantitation accounted for 1.65 and 5.00 (μg/ml), respectively. Values of method linearity (r2) in range 5−100 mg/L were 0.9975 and 0.9956 plasma samples and solvent standard, respectively. Inter- and intra-day variability coefficients were lower than 15 %. The comparison with a reference, commercially-available LC–MS/MS method on 122 patient plasma samples returned excellent correlation (r2 = 0.9474). In conclusion, the present method demonstrated to be reliable and suitable for daptomycin TDM in clinical routine.

Quantitative determination of bilobetin in rat plasma by HPLC-MS/MS and its application to a pharmacokinetic study.

Although bilobetin, a biflavone isolated from the leaves of Ginkgo biloba, represents a variety of pharmacological activities, to date there have been no validated determination methods for bilobetin in biological samples. Thus, we developed a liquid chromatographic method using a tandem mass spectrometry for the determination of bilobetin in rat plasma. After protein precipitation with acetonitrile including diclofenac (internal standard), the analytes were chromatographed on a reversed-phased column with a mobile phase of purified water and acetonitrile (3:7, v/v, including 0.1% formic acid). The ion transitions of the precursor to the product ion were principally deprotonated ions [M - H]- at m/z 551.2 → 519.2 for bilobetin and 296.1 → 251.7 for the IS. The accuracy and precision of the assay were in accordance with US Food and Drug Administration regulations for the validation of bioanalytical methods. This analytical method was successfully applied to monitor plasma concentrations of bilobetin over time following intravenous administration in rats.

Population pharmacokinetics and pharmacodynamics of dobutamine in neonates on the first days of life.

AimsTo describe the pharmacokinetics (PK) and concentration‐related effects of https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=535 in critically ill neonates in the first days of life, using nonlinear mixed effects modelling.MethodsDosing, plasma concentration and haemodynamic monitoring data from a dose‐escalation study were analysed with a simultaneous population PK and pharmacodynamic model. Neonates receiving continuous infusion of dobutamine 5–20 μg kg−1 min−1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors.ResultsTwenty‐eight neonates with median (range) gestational age of 30.4 (22.7–41.0) weeks and birth weight (BW) of 1618 (465–4380) g were included. PK data were adequately described by 1‐compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) L h−1 for CL and 5.29 (0.821) L for volume of distribution, which shared a common between subject variability of 29% (17.2%). The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model.ConclusionIn the postnatal transitional period, PK of dobutamine was described by a 1‐compartmental linear model, CL related to BW and PMA. A concentration–response relationship with haemodynamic variables has been established.

Clinical evaluation of subcutaneous administration of cefepime

ObjectivesCefepime is a fourth-generation cephalosporin active against Pseudomonas aeruginosa and most Enterobacteriaceae. Intravenous (IV) administration is the standard route of prescription. However, subcutaneous administration (SC) may represent an interesting alternative. We aimed to evaluate SC administration of cefepime versus the IV route in geriatric patients. Patients and methodsMulticenter retrospective analysis in patients treated with cefepime by SC route who underwent plasma concentration monitoring. ResultsTwelve patients were included in the SC group and matched to 12 patients in the IV group. The median and mean Cmin levels were 29.05mg/L [14.2–48.2]; 33.4mg/L (±21.8) in the SC group and 31.9mg/L [26.5–51.7]; 39.6mg/L (±27) (P=NS) in the IV group. No local SC administration-related complications were reported. No relapse was observed over six months of follow up. ConclusionSubcutaneous use of cefepime seems to have the same clinical and microbiological effectiveness as parenteral administration.

FDA- and EMA-Approved Tyrosine Kinase Inhibitors in Advanced EGFR-Mutated Non-Small Cell Lung Cancer: Safety, Tolerability, Plasma Concentration Monitoring, and Management.

Non-small-cell lung cancer (NSCLC) is the most common form of primary lung cancer. The discovery of several oncogenic driver mutations in patients with NSCLC has allowed the development of personalized treatments based on these specific molecular alterations, in particular in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene. Gefitinib, erlotinib, afatinib, and osimertinib are TK inhibitors (TKIs) that specifically target EGFR and are currently approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as first line treatment for sensitive EGFR-mutant patients. However, these four drugs are associated with severe adverse events (AEs) that can significantly impact patient health-related quality of life and patient monitoring. EGFR-TKIs are commonly used together with other types of medication that can substantially interact. Here, we review approaches used for the management of TKI-AEs in patients with advanced NSCLC to promote the benefits of treatments and minimize the risk of TKI treatment discontinuation. We also consider potential TKI–drug interactions and discuss the usefulness of plasma concentration monitoring TKIs based on chromatographic and mass spectrometry approaches to guide clinical decision-making. Adjusting the most appropriate therapeutic strategies and drug doses may improve the performance therapy and prognosis of patients with advanced EGFR-mutated NSCLC.

Determination of total and free voriconazole in human plasma: Application to pharmacokinetic study and therapeutic monitoring

•Voriconazole (VCZ) is highly efficient in the treatment of invasive fungal infections. However, the therapy requires the monitoring of VCZ plasma concentration, due to a narrow therapeutic index and large inter-individual variability of pharmacokinetics of VCZ, which often exhibits nonlinearity. Total plasma concentration of VCZ does not always provide sufficient information, especially in hemato-oncology patients, who often show significant fluctuations in plasma protein concentration. Therefore, the monitoring of free drug seems crucial for a complete understanding of the ongoing antifungal therapy.•The study aimed to develop an HPLC-FLD method for the determination of total and free VCZ in clinical samples.•The analysis of total VCZ comprised the one-step samples preparation by plasma protein precipitation. The free drug was isolated from plasma by ultrafiltration. The non-specific bindings (NSB) between the drug and filter membranes were comprehensively evaluated.•The elaborated method fulfilled the validation requirements for bioanalytical methods. The ultrafiltration technique is recommended for the analysis of free VCZ, but requires a preconditioning step. Ultrafiltration was impacted with adsorption of the drug on the filter membrane, which was as high as 61–82% and was found to decrease after pretreatment of the membranes with 5% Tween 80. The method was applied for the quantification of plasma VCZ in patients undergoing antifungal therapy. Total and free VCZ concentrations ranged from 0.21 to 4.92 μg/mL and from 0.07 to 1.28 μg/mL, respectively; the mean protein binding was 47%.

Evaluation of Medication Adherence and Pharmacokinetics of Dasatinib for Earlier Molecular Response in Japanese Patients With Newly Diagnosed Chronic Myeloid Leukemia: A Pilot Study.

Tyrosine kinase inhibitors markedly improve the survival for patients with chronic myeloid leukemia (CML). However, a decrease in adherence leads to undesired therapeutic outcomes. In this study, the relationships among adherence, pharmacokinetics, response, and adverse effects for dasatinib treatment were prospectively investigated. This study was a prospective cohort study of patients with newly diagnosed CML at 4 general hospitals and 1 university hospital. Patients started to receive dasatinib 100 mg once daily. A Medication Event Monitoring System was used to assess medication adherence and the medication possession ratio during the 12 months. Plasma concentrations of dasatinib were measured using liquid chromatograph-tandem mass spectrometry (LC-MS/MS), and therapy responses were assessed at 3, 6, and 12 months after treatment. Ten patients were included. An extremely high medication adherence for dasatinib was observed; the median medication possession ratio was 99.4%. All 9 CML patients with breakpoints in the major BCR-ABL achieved major molecular response (MMR; major BCR-ABL transcript level below 0.1% on the International Scale) within 12 months, and 5 achieved MMR within 6 months. The receiver operating characteristic curve analysis revealed that the cutoff value for the dasatinib area under the concentration-time curve was 336.1 ng × h/mL (accuracy 88.9%, sensitivity 80.0%, specificity 100%, and receiver operating characteristic curve-area under the concentration-time curve 0.800) for achieving MMR within 6 months. Two patients had interrupted dasatinib treatment because of pleural effusion and diarrhea with intestinal edema, respectively. These edematous adverse events developed after plasma dasatinib Cmin surpassed 3.0 ng/mL. A Medication Event Monitoring System was applied for the direct evaluation of oral dasatinib adherence for the first time, and the clinical effect of dasatinib was investigated under the strict monitoring of patient adherence. Although this study had a small sample size, the plasma concentration monitoring of dasatinib is considered to be useful to predict an earlier molecular response with fewer edematous adverse events.

Application of imatinib plasma concentration monitoring in the whole process management of gastrointestinal stromal tumor patients

Objective: To investigate the significance of monitoring imatinib mesylate (IM) plasma concentrations in patients with gastrointestinal stromal tumor (GIST). Methods: A retrospective descriptive study was carried out. Inclusion criteria: (1) patients with GIST confirmed by postoperative pathology or puncture pathology receiving maintenance therapy of IM; (2) administration of same dose of IM for at least 4 weeks (achieving steady - state plasma concentration). Patients who had severe organ dysfunction, received IM generics, or received IM simultaneously with other drugs significantly affecting IM pharmacokinetic were excluded. A total of 185 patients at the GIST Clinic of Renji Hospital, Shanghai Jiaotong University School of Medicine from August 2018 to May 2019 were enrolled, including 114 males (61.6%) and 71 females (38.4%) with a median age of 60 years old (range, 30-89 years), and 63 advanced cases. Patients receiving preoperative or postoperative adjuvant therapy were given IM 400 mg QD; patients with KIT exon 9 mutation or with disease progression during IM 400 mg QD treatment were given IM 600 mg QD. If the patient had adverse reactions such as myelosuppression during the medication, IM would be reduced or given BID per day. The peripheral venous blood was collected (22 to 24 hours after the last dose for patients who took IM QD and 2 hours before the first dose per day for those who took IM BID). IM plasma concentration was measured through high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Correlation analysis between IM plasma concentration results and clinical data was performed using linear regression analysis. Results: A total of 241 stable blood samples of IM plasma concentration from 185 patients were finally collected. The IM plasma concentrations were significantly different between the doses of 300 mg/d and 400 mg/d [(942.4±433.5) μg/L vs. (1340.0±500.1) μg/L, t=6.317, P<0.001], and between 400 mg/d and 600 mg/d [(1340.0±500.1) μg/L vs. (2188.0±875.5) μg/L, t=3.557, P=0.004]. Among the blood samples of 57 patients receiving IM 300 mg/d, the IM plasma concentration of the advanced patients was significantly lower than that of the non-advanced patients [(795.6±225.8) μg/L vs. (992.2±484.4) μg/L, t=2.088, P=0.042]. Among the 137 blood samples of patients receiving IM 400 mg/d, the IM plasma concentration was higher in patients aged >60 years than those aged ≤60 years [(1461.0±595.3) μg/L vs. (1240.0±380.9) μg/L, t=2.528, P=0.013] and the IM plasma concentration of cases with diarrhea was significantly lower than that of those without diarrhea [(745.8±249.6) μg/L vs. (1382.0±486.9) μg/L, t=6.794, P<0.001]. Gender, primary location, surgical procedure, mutated gene, mutation type, or time of administration was associated with IM plasma concentration no matter in patients taking IM doses of 400 mg/d or 300 mg/d (all P>0.05). Regression analysis showed that body mass (P=0.004 and P=0.019), body mass index (P=0.016 and P=0.042), and body surface area (P=0.007 and P=0.028) were all negatively correlated with IM plasma concentrations in patients taking IM doses of 300 mg/d and 400 mg/d. Within the 137 patients who received a fixed oral dose of 400 mg/d IM, 17 patients received oral 200 mg BID, whose IM plasma drug concentration was not significantly different compared with that of 120 patients who received 400 mg IM QD [(1488.0±408.3) μg/L vs. (1319.0±509.7) μg/L, t=1.307, P=0.193]. Conclusions: Monitoring IM plasma concentration is significant throughout the whole process of management of GIST patients receiving IM treatment. In particular, regular monitoring IM plasma concentration and developing appropriate treatment strategies can bring better therapeutic benefits for patients with low doses, diarrhea, advanced condition and older age.

Effect of augmented renal clearance on plasma concentration of vancomycin and treatment outcome in children with methicillin-resistant Staphylococcus aureus infection

To investigate the effect of augmented renal clearance (ARC) on plasma concentration of vancomycin, bacteriological outcome, and clinical outcome in children with methicillin-resistant Staphylococcus aureus (MRSA) infection treated by vancomycin. A retrospective analysis was performed for the clinical data of 60 critically ill children who were treated with vancomycin due to MRSA infection from January 2013 to July 2017 and underwent plasma concentration monitoring. According to estimated glomerular filtration rate, these children were divided into an ARC group with 19 children and a normal renal function group with 41 children. The two groups were compared in terms of the use of vancomycin, plasma concentration of vancomycin, and treatment outcome. The children in the ARC group had an age of 1-12 years, and the ARC group had significantly higher body weight and body surface area than the normal renal function group (P<0.05). Compared with the normal renal function group, the ARC group had a significantly lower initial trough concentration of vancomycin and a significantly lower proportion of children who achieved the effective trough concentration of vancomycin (10-20 mg/L) (P<0.05). There were no significant differences in bacteriological outcome and clinical outcome between the two groups (P>0.05), but the ARC group had significantly longer length of stay in the pediatric intensive care unit (PICU) and length of hospital stay than the normal renal function group (P<0.05). ARC can significantly reduce the trough concentration of vancomycin and prolong the length of PICU stay and the length of hospital stay in children with MRSA infection. Idividualized medication should be administered to children with ARC.

Determination of ethanamizuril, a novel triazine coccidiostat, in rat plasma by ultra-performance liquid chromatography system-tandem mass spectrometry and its application in a toxicological study.

Ethanamizuril is a new triazine compound that has the potential to be a novel anticoccidial drug. Toxicological studies in experimental rats were performed to understand the safety profile of ethanamizuril for drug product development. In this study, a novel, selective and accurate ultra-performance liquid chromatography tandem mass spectrometry method has been developed for the determination of ethanamizuril concentrations in rat plasma. With 4-nitro-o-cresol as an internal standard, sample pretreatment involved a one-step extraction with acetonitrile of 100 μL plasma. The detection was carried out by electrospray ionization mass spectrometry in negative ion mode with selected ion recording. The standard curves were linear (r2 ≥ 0.999) over the concentration range of 0.1-100 μg/mL. The relative standard deviations of intra- and inter-day precisions were less than 8.4 and 8.87%, respectively. The mean extraction recovery of ethanamizuril from rat plasma was 97.68-102.57%. The method was fully validated and successfully applied to monitor plasma concentrations of ethanamizuril in a short-term toxicity study and two-generation reproduction toxicity study. The result of the study confirmed that the elimination of ethanamizuril in rats is slow.

Non-Invasive Extraction of Gabapentin for Therapeutic Drug Monitoring by Reverse Iontophoresis: Effect of pH, Ionic Strength, and Polyethylene Glycol 400 in the Receiving Medium

Background: Monitoring of plasma concentrations is a necessity for narrow therapeutic index potent drugs. Development of non-invasive methods can save the patients from the trauma of needles and hence is considered as a research priority. Introduction: Gabapentin, an anti-epileptic drug requires therapeutic monitoring because of its narrow therapeutic index. The objective of the study was to develop a suitable method for the non-invasive extraction of gabapentin for the same. Methods: Transdermal reverse iontophoresis was performed using pig ear skin as a barrier membrane. Three compartment iontophoretic cells were used for the extraction study. Extractions were carried out under low intensity electric field (current intensity- 0.5 mA/cm2, electrical field approximately 5 V). The donor compartment was charged with aqueous gabapentin (10 µg/ml in phosphate buffer of pH 7.4). For studying the effect of receiving vehicle (pH, ionic strength, and enhancer) on the extraction efficiency of gabapentin, the two receiver chambers were charged with media having varying concentration of these factors. Drug content was determined by HPLC. Results: Compared to other pHs, cumulative extraction of gabapentin at pH 5 was significantly higher at both anode and cathode (p&lt;0.001). At low ionic strength, extraction of gabapentin increased linearly with the increase in concentration of ions up to a certain value but at very high ionic strength the pattern reversed. Similar results were obtained with enhancer (polyethylene glycol 400). Extraction increased with increase in polyethylene glycol 400 up to 3% and then decreased. Conclusion: Extraction flux can be optimized by manipulation of the receiver media.

A retrospective analysis of plasma concentration monitoring of fluorouracil in patients with advanced colorectal cancer

ObjectivesTo analyse the results of fluorouracil (5-FU) plasma concentration monitoring in patients with advanced colorectal cancer after 5-FU treatment, and to provide a reference for the application prospect of 5-FU...

Population pharmacokinetics of continuous-infusion ceftazidime in febrile neutropenic children undergoing HSCT: implications for target attainment for empirical treatment against Pseudomonas aeruginosa.

To conduct a population pharmacokinetic analysis of continuous-infusion ceftazidime in a retrospective cohort of paediatric HSCT patients who were empirically treated for febrile neutropenia (FN) and who underwent therapeutic drug monitoring of ceftazidime steady-state plasma concentrations (Css) for optimization of drug exposure. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed to calculate the PTA of the pharmacodynamic determinant of efficacy (Css/MIC ≥4) against Pseudomonas aeruginosa with continuous-infusion ceftazidime dosages of 1-6 g daily. The Css safety threshold was arbitrarily placed at 100 mg/L and advisable dosages were used. A total of 46 patients with 70 ceftazidime Css values were included. Estimated glomerular filtration rate (eGFR) and body surface area were the covariates associated with drug clearance. At the EUCAST clinical breakpoint of 8 mg/L, simulations showed that continuous-infusion ceftazidime dosages of 4-6 g daily attained optimal PTAs (>90%) across most of 16 different clinical scenarios based on four classes of eGFR (50-145, 145.1-200, 200.1-286 and 286.1-422 mL/min/1.73 m2) and body surface area (0.30-0.64, 0.65-0.88, 0.89-1.34 and 1.35-1.84 m2). In patients with body surface area 0.30-0.64 m2 and eGFR ≤200 mL/min/1.73 m2 the advisable dose of 3 g daily allowed only suboptimal PTAs (<75%). The cumulative fraction of response against MIC distribution of P. aeruginosa was >87%. Continuous-infusion ceftazidime dosages ranging from 3 to 6 g daily according to different classes of eGFR and body surface area may allow optimized empirical treatment of P. aeruginosa infections in paediatric HSCT patients with FN.

A UHPLC-MS/MS method for the quantification of Δ9-tetrahydrocannabinol and cannabidiol in decoctions and in plasma samples for therapeutic monitoring of medical cannabis.

Aim: Monitoring of blood levels of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is necessary for optimization of administration of medical cannabis. We describe the validation of a ultra-HPLC-MS/MS method for quantifying THC and CBD from plasma and decoctions and its application for therapeutic drug monitoring.Materials& methods: Analyses were performed by using a TSQ Quantiva™ Triple Quadrupole coupled to a Ultimate 3000 UHPLC system with atmospheric pressure chemical ionization after sample preparation with a straightforward method with deuterated internal standards. Results:The method has been validated following EMA guidelines and is linear in plasma from 0.16 to 10ng/ml for both THC and CBD and in decoctions from 4.7 to 600ng/ml. Conclusion: Given the unpredictable pharmacokinetic behavior of THC and CBD in patients, monitoring of plasma concentrations is strongly recommended for patients under treatment with medical cannabis.

After standard dosage of piperacillin plasma concentrations of drug are subtherapeutic in burn patients.

Infections are a major problem in patients with burn diseases. Mortality is high despite antibiotic therapy as studies are controversial concerning drug underdosing. The aims of this prospective, observational study were to monitor plasma concentrations of piperacillin during standard piperacillin/tazobactam treatment in 20 burn patients and 16 controls from the intensive care unit (ICU) and to optimize doses by in silico analyses. Piperacillin/tazobactam (4/0.5g, tid) was administered over 0.5h. Blood samples were taken at 1, 4, and 7.5h after the end of the infusion. Free piperacillin plasma concentrations were determined. Pharmacokinetic parameters and in silico analysis results were calculated using the freeware TDMx. The primary target was defined as percentage of the day (fT>1xMIC; fT>4xMIC) when piperacillin concentrations exceeded 1xMIC/4xMIC (minimum inhibitory concentration), considering a MIC breakpoint of 16mg/L for Pseudomonas aeruginosa. In an off-label approach, two burn patients were treated with 8/1g piperacillin/tazobactam, 3h qid. fT>1xMIC (55 ± 22% vs. 77 ± 24%) and fT>4xMIC (17 ± 11% vs. 30 ± 11%) were lower in burn than in ICU patients after 4/0.5g, 0.5h, tid. In silico analyses indicated that fT>1xMIC (93 ± 12% burn, 97 ± 4% ICU) and fT>4xMIC (62 ± 23% burn, 84 ± 19% ICU) values increase by raising the piperacillin dosage to 8/1g qid and prolonging the infusion time to 3h. Off-label treatment results were similar to in silico data for burn patients (84%fT>1xMIC and 47%fT>4xMIC). Standard dosage regimens for piperacillin/tazobactam resulted in subtherapeutic piperacillin concentrations in burn and ICU patients. Dose adjustments via in silico analyses can help to optimize antibiotic therapy and to predict respective concentrations in vivo. Trial registration: NCT03335137, registered 07.11.2017, retrospectively.

Distribution characteristics of plasma concentration of vancomycin and clinical efficacy in pediatric patients with severe pneumonia and congenital heart disease

Objective To analyze the distribution characteristics of vancomycin blood concentration in children with severe pneumonia complicated with congenital heart disease(CHD) and children with simple severe pneumonia after using the same dose vancomycin, and observe the clinical efficacy at the same time. Methods Plasma concentrations in pediatric patients with severe pneumonia complicated with CHD(CHD group) who treated by vancomycin from November 2012 to September 2013 in Shengjing Hospital of China Medical University were collected.Plasma concentrations of children with simple severe pneumonia(control group) treated by vancomycin were also collected at the same period.The blood concentration values and therapeutic effects of the two groups were recorded into the database for statistical analysis.Peak, trough concentrations and efficacy were analyzed by receiver operating characteristic(ROC) curve. Results Twenty-five children with CHD were collected, the average peak concentration was (28.39±6.68)mg/L, the average trough concentration was (13.34±6.62)mg/L.Control group were also 25 cases, the average peak concentration was (16.23±2.50)mg/L and the average trough concentration was (2.77±1.01)mg/L.Both peak and trough concentrations of CHD children were significantly higher than those of the control group (tpeak=8.52, Ppeak<0.05; ttrough=7.89, Ptrough<0.05). In the ROC of peak, trough concentrations and efficacy, area under the curve were 0.74(95%CI 0.547-0.935, P=0.01) and 0.77(95%CI 0.605-0.935, P=0.004) respectively, and the difference was statistically significant. Conclusion Plasma concentrations of vancomycin in children with CHD are generally higher, it is necessery to monitor plasma concentration even under regular doses, to make the application of vancomycin more safe and effective in children with CHD.There is a correlation between plasma concentration of vancomycin and clinical efficacy in children, the higher the blood concentration, the more likely the clinical efficacy is to be effective. Key words: Severe pneumonia; Congenital heart disease; Vancomycin; Serum concentration; Peak concentration; Trough concentration

Levetiracetam circulating concentrations and response in status epilepticus

IntroductionIntravenous levetiracetam (LEV) is broadly used in the treatment of status epilepticus (SE). A loading dose is usually infused, aiming to reach quickly the range of plasma concentrations considered as therapeutic (12–46 mg/l). The aim of the study was to evaluate the response to LEV in SE, correlated exposure assessed by plasma concentration monitoring, as well as calculated exposure parameters. Materials & methodsWe retrospectively analyzed a SE registry, including patients since 2015 with at least one available LEV plasma level measured less than 36 h after loading. A Bayesian maximum likelihood approach based on a population pharmacokinetic model was used to estimate LEV exposure parameters. We compared plasma levels and pharmacokinetics parameter estimates between responders and nonresponders. Therapeutic response was defined as SE cessation within 24 h following LEV introduction without a need for additional antiepileptic drug (AED). ResultsWe included 29 patients (45 plasma levels). Variability was salient in LEV loading doses (ranging between 17 and 38 mg/kg) and monitoring practice. There was no difference in median plasma concentrations (19.5 versus 21.5 mg/l; p = 0.71), median estimated LEV exposure (25.8 versus 37.0 mg/l; p = 0.61), peak (30.4 versus 41.5 mg/l; p = 0.36), or residual levels after loading dose (14.4 versus 20.5 mg/l; p = 0.07) between responders and nonresponders. ConclusionsLevetiracetam exposure does not seem to differ significantly between responders and nonresponders; greater exposure was not associated with better outcome. Loading doses of 30 mg/kg seem, however, appropriate to quickly reach the target exposure level. The short LEV half-life makes standardized sampling measurement necessary to obtain directly interpretable LEV levels.

Clinical Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants in Patients with Renal Failure.

A recent survey on the use of direct oral anticoagulants (DOACs) revealed that 43% of patients with atrial fibrillation and renal impairment were potentially overdosed and had a hazard ratio for major bleeding of 2.19. In this review, we analyse and discuss the effect of renal failure on the pharmacokinetics and pharmacodynamics of DOACs and of strategies proposed to adjust doses according to the level of renal dysfunction. The pharmacokinetic characteristics of available DOACs (dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban) differ substantially as regards oral bioavailability, plasma protein binding and the relative involvement of renal and non-renal elimination. In this respect, 80% of dabigatran is excreted as an unchanged drug in urine, whereas edoxaban, rivaroxaban, apixaban and betrixiban are excreted unchanged by, respectively, 50, 33, 27 and 11% of the dose. Therefore, drug exposure (the area under the concentration-time curve, AUC) is expected to increase to differing extents, depending on the residual renal function and the contribution of the kidneys to the excretion of each drug. Our analysis found that the increased AUC in patients with severe renal dysfunction was greater than expected in the case of dabigatran, betrixaban and rivaroxaban, indicating that other pharmacokinetic parameters may be altered besides renal clearance. Although DAOC pharmacodynamics do not seem to be altered by renal diseases (the correlation between plasma levels and anticoagulant effects overlaps that of healthy subjects), renal failure per se is associated with an increased risk of bleeding and thromboembolism. Guidelines on dose adjustments in patients with renal dysfunction have been published by three National Drug Agencies (FDA, EMA, HC), but many of their items do not match one another, reflecting our substantial paucity of knowledge in advanced renal failure. Routine monitoring of DOAC anticoagulant effects or plasma concentrations is not recommended, since no validated therapeutic ranges have been established. However, this approach may be useful in emergency situations such as bleeding or thrombotic events, urgent surgery, pharmacokinetic interactions, etc. We conclude that more experimental work is needed to improve our knowledge of DOAC pharmacology in renal failure and to provide clinicians with valid tools to adjust therapy.

Quantification of Cefepime, Meropenem, Piperacillin, and Tazobactam in Human Plasma Using a Sensitive and Robust Liquid Chromatography-Tandem Mass Spectrometry Method, Part 1: Assay Development and Validation.

The highly variable pharmacokinetics of β-lactam antibiotics and β-lactamase inhibitors poses a significant challenge to clinicians in ensuring appropriate antibiotic doses in critically ill patients. Therefore, routine monitoring of plasma concentrations is important for individualization of antimicrobial therapy. Accordingly, a simple and robust analytical method for the simultaneous measurement of multiple β-lactam antibiotics and β-lactamase inhibitors is highly desirable to ensure quick decisions on dose adjustments. In this study, a sensitive, simple, and robust method for the simultaneous quantification of cefepime, meropenem, piperacillin, and tazobactam in human plasma was developed and rigorously validated according to FDA guidance. Sample extraction was accomplished by simple protein precipitation. Chromatographic separation of analytes was achieved using stepwise gradient elution. Analytes were monitored using tandem mass spectrometry (MS/MS) with a turbo ion spray source in positive multiple-reaction-monitoring mode. The calibration curve ranged from 0.5 to 150 μg/ml for cefepime, 0.1 to 150 μg/ml for meropenem and piperacillin, and 0.25 to 150 μg/ml for tazobactam. Inter- and intraday precision and accuracy, sensitivity, selectivity, dilution integrity, matrix effect, extraction recovery, and hemolysis effect were investigated for all four analytes, and the results met the acceptance criteria. Compared to other reported methods, our method is more robust because of the combination of the following features: (i) a simple sample extraction procedure, (ii) a short sample run time, (iii) a wide dynamic range, and (iv) the small plasma sample volume needed. Since our method already covers β-lactams and a β-lactamase inhibitor with highly heterogeneous physicochemical properties, further antibiotic candidates may easily be incorporated into this multianalyte method.