Monitoring Of Blood Concentrations Research Articles

CCQM-K159 free amino acids in plasma

Main textInherited metabolic disorders affect approximately 1 in 1000 babies; amino acid disorders are less frequent, at approximately 1 in 6000. Babies diagnosed with amino acid disorders require constant monitoring of amino acid blood concentration, especially for disease states such as phenylketonuria. In addition, amino acid measurement may aid in the evaluation of several other disorders such as neurological and nutritional disorders. Free amino acids in healthy patients are typically in the low mg/kg range but, for example, elevated phenylalanine indicates phenylketonuria disease state. Evidence of successful participation in formal, relevant international comparisons is needed to document calibration and measurement capability claims (CMCs) made by national metrology institutes (NMIs) and designated institutes (DIs).This Track A study is being used to assess the core competencies of the National Metrology Institutes/Designated Institutes (NMIs/DIs) for provision of measurement services. The aim of this study is to assess the performance of the NMIs/DIs for a matrix material for clinical analytes. This follows and builds on the successful CCQM-K109 study on urea and uric acid in human serum.Eleven NMIs participated in the Track A Key Comparison CCQM-K159 Free amino acids in plasma. NMIs/DIs were given the option of taking part in a parallel pilot study CCQM-P202, however all participants opted for the Track A key comparison and there were no participants for CCQM-P202. Participants were requested to evaluate the mass fractions, expressed in mg/kg, of DL-phenylalanine and DL-leucine in pooled frozen human plasma with lithium heparin added as an anticoagulant.Successful participation in CCQM-K159 demonstrates the following measurement capabilities in determining mass fraction of organic compounds, with molecular mass of 50 g/mol to 500 g/mol, having high to mid polarity pKow > -4, in mass fraction range from 1 mg/kg to 1000 mg/kg in a biological matrix such as human plasma, serum and urine.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Determination of sacubitril and seven sartan drugs in serum samples by online solid phase extraction-liquid chromatography-tandem mass spectrometry

An online solid phase extraction–ultra performance liquid chromatography–tandem mass spectrometry detection method was developed for the simultaneous determination of sacubitril and seven sartan drugs in blood serum in this study. The compounds were separated through a C18 column. Mass spectrometry of the samples was performed using a jet stream electrospray ion source (AJS, ESI+). The samples were detected via a multiple reaction monitoring (MRM) mode and quantified via a stable isotope internal standard method. 900 μL of prepared sample was injected and a run time of 12.5 minutes was obtained in this proposed method. The eight examined target compounds showed good linearity (r2＞0.994) in the corresponding mass concentration range and a lower limit of quantitation (LLOQ) was in the range of 0.05–0.1 μg/L. The recovery of the spiked serum samples ranged from 90.90 % to 106.20 % with relative standard deviations (RSDs) of 4.57 %–9.27 %. Five target compounds were detected in the actual serum samples using this method. The proposed method is simple to use, sensitive, accurate, and suitable for the trace detection of sacubitril and seven sartan drugs present in serum samples. The method can meet the needs for clinical monitoring of blood concentrations of this type of drug, while providing detection technology support for the development of compound preparations of sacubitril and other sartan drugs.

Construction of an electrochemical aptamer-based sensors for rapid quantification of the anticancer drug imatinib in blood to improve drug bioavailability at microdoses

Imatinib (Ima), as a commonly used anticancer drug for the clinical treatment of leukemia and gastrointestinal mesenchymal stromal tumour, requires timely monitoring of patients' blood concentration to ensure efficacy while reducing complications and achieving precision medicine due to its narrow therapeutic window (1–5 μM) and the varying sensitivity and resistance of different patients to Ima. However, traditional assays are slow and cumbersome, so improved and innovative platforms for monitoring Ima in the clinic are necessary. In this work, a nanoporous electrochemical aptamer-based (E-AB) sensor was designed for the detection of Ima and imatinib mesylate (Ima-Mes) in blood. Apt-37, a high-affinity and conformationally variable aptamer, was screened by molecular docking simulation calculations and circular dichroism (CD) for the construction of the E-AB sensor. The sensor detected Ima and Ima-Mes in the range of 0.1 μM-1 mM, and the recoveries in spiked blood samples were in the range of 70.7 %-104.6 % and 74.8 %-113.9 %, respectively. The precision and accuracy of the E-AB sensor for measuring Ima-Mes concentration in blood was similar to the standard LC-MS method. These results demonstrate that the developed E-AB sensor is an effective tool for rapid monitoring of Ima and Ima-Mes in blood.

An antibiofouling electrochemical sensor consisting of amphiphilic copolymer on CNT-COOH electrodes for point-of-care monitoring of propofol blood concentration in surgical patients

The monitoring of propofol (PPF) blood concentration is vital for the safety of intravenous anesthesia. Electrochemical sensors represent a powerful tool for the detection of PPF. Our previous research has demonstrated that CNT-COOH electrodes exhibit advantages in resisting electrochemical fouling from PPF oxidation products. Nevertheless, biofouling remains a critical challenge hindering the clinical transformation of PPF electrochemical sensors. To address this issue, we employed in-situ electrodeposition to deposit zwitterionic sulfobetaine methacrylate (SBMA) and overoxidation polydopamine (OPDA) onto CNT-COOH screen-printed electrodes (SPEs) and proposed an innovative CNT-COOH/OPDA-SBMA (CNT-COOH/OPS) amphiphilic antifouling biosensor. This amphiphilic electrode, featuring both hydrophilic and hydrophobic properties, demonstrated excellent antifouling performance through electrochemical characterization in ex-vivo blood assays, coupled with commendable sensitivity, stability, and selectivity. CNT-COOH/OPS SPEs were also applied in point-of-care monitoring of the PPF blood concentrations in animals and clinical surgical patients and exhibited good accuracy and linearity (Ipa=0.0084c+0.4458, R2=0.995) with a limit of detection of 2.948 μM. Further, the electrodes demonstrated a high recovery and the blood concentrations determined by electrochemical detection had robust negative correlation with the depth of anesthesia. Therefore, CNT-COOH/OPS SPEs hold promise as a significant tool in point-of-care monitoring of PPF, offering patients safer and more personalized medical care.

Analysis of the Impact of TKI Dose Adjustment Under the Guidance of Blood Concentration Monitoring on the Efficacy, Safety and Quality of Life in Patients with CML

Analysis of the Impact of TKI Dose Adjustment Under the Guidance of Blood Concentration Monitoring on the Efficacy, Safety and Quality of Life in Patients with CML

Establishment and validation of a population pharmacokinetic model for apatinib in patients with tumors

ObjectiveThis study aimed to develop a population pharmacokinetic (PPK) model for oral apatinib in Chinese oncology patients and investigate the factors influencing the pharmacokinetics of apatinib.MethodsWe gathered 199 blood concentration monitoring data points from 91 inpatient oncology participants receiving oral apatinib at the Third Affiliated Hospital of Soochow University. Covariates, such as age, gender, body weight, and indices of liver and renal function, were examined to assess their influence on the pharmacokinetic parameters of apatinib. The PPK model was developed using the nonlinear mixed-effects modeling procedure (NONMEM), and model validation was conducted using the bootstrap method and normalized prediction distribution error (NPDE) method.ResultsThe structural model adopted a one-compartment structure with first-order elimination. Notably, aspartate aminotransferase (AST) and the co-administered drug type emerged as primary covariates affecting apatinib clearance (CL/F). The finalized model was expressed as CL/F (L/h) = 56.7 × (AST/26.6)−0.298 × θ, when apatinib was combined with monoclonal antibodies, θ was 1; when combined with paclitaxel, θ was 0.58; when combined with other drugs (e.g., platinum, capecitabine, or the combination of tegafur, gimeracil, and oteracil potassium), θ was 1.60; When used as monotherapy, θ was 1.38. V/F = 674 L, and the absorption rate constant (Ka) was fixed at 0.08 h−1. Bootstrap results affirmed the model’s reliability and stability, while NPDE outcomes attested to the model’s fit.ConclusionOur study successfully established a PPK model for apatinib in oncology patients, revealing that liver function status and co-administered drug types significantly impacted apatinib CL/F. This finding underscored the potential necessity for dose adjustments to optimize efficacy, particularly in patients undergoing different chemotherapy regimens involving apatinib.

Layered double hydroxide nanozyme (LDHzyme)-assisted high-performance electrochemical analysis of organ transplant therapeutic drug concentration

The variability in mycophenolic acid (MPA) exposure levels among organ transplant patients is substantial and directly influences the drug’s therapeutic efficacy. Therefore, precise monitoring of MPA blood concentrations is imperative to devise personalized diagnostic and treatment plans tailored to individual patient profiles. In this study, we developed a screen-printed carbon electrode (SPCE) incorporating Layered Double Hydroxide-based nanozymes (LDHzymes) and multi-walled carbon nanotubes (MWCNT) to achieve high-sensitivity and stable determination of MPA in blood samples. We synthesized three distinct LDHzymes via a straightforward co-precipitation method, selecting CuMn-LDHzyme for its superior electrochemical properties and laccase activity in the context of MPA detection. The sensor’s performance was enhanced by the amalgamation of CuMn-LDHzyme with MWCNT, leveraging the laccase-like activity of CuMn-LDHzyme and the exceptional conductivity of MWCNT to amplify the oxidation current response to MPA. This integration significantly bolstered the sensor’s detection capabilities. The developed electrochemical sensor exhibited remarkable characteristics, including high selectivity, stability, repeatability, and reproducibility. It demonstrated a notable sensitivity with a detection range of 0.5 µM to 200 µM for MPA, and a detection limit of 0.1 µM, effectively detecting MPA in mouse blood samples. These attributes underscore the sensors as promising tool for clinical drug detection, ensuring fast and precise monitoring of MPA levels in organ transplant patients. This innovative approach holds significant promise for advancing personalized medical care and improving therapeutic outcomes.

Blood concentration monitoring and renal function changes during gentamicin administration for infective endocarditis: a retrospective observational study

BackgroundEstablished guidelines for monitoring gentamicin blood concentration are lacking; therefore, we focused on improving pharmacological interventions and ensuring their safety. We aimed to optimize gentamicin administration for infective endocarditis (IE) treatment.MethodsThe study involved adult patients diagnosed with IE and treated with gentamicin from January 2014 to December 2022. Clinical presentation and drug therapy regimen were comprehensively evaluated. We performed a retrospective chart review of the frequency of gentamicin dose adjustments and changes in renal function while on gentamicin. In addition, we attempted to extract risk factors for renal impairment using univariate analysis.ResultsOn average, a 7.1% decline [changed to − 6.7 ± 20.4 (standard deviation) mL/min/1.73 m2] in the estimated glomerular filtration rate was observed after gentamicin administration, but it was statistically insignificant. Notably, 58% of patients required dosage adjustments, with a subset requiring multiple adjustments. Among the cases in which dosage adjustments were made, 61% were within the first week of treatment. There were no patients with gentamicin levels below the target peak concentration. Furthermore, no independent risk factors were identified in patients requiring dose reduction.ConclusionsDose adjustment was necessary in many cases after treatment initiation. The time to dose adjustment varied widely. These findings highlight the importance of consistent blood concentration monitoring in patients of all demographics, at least weekly, and underscore that routine peak concentration assessments may not be essential when a 3 μg/mL target is maintained. This study provides information on monitoring gentamicin blood level, which can improve IE treatment safety.

Preparation and evaluation of novel oral tacrolimus nanocochleates for organ transplantation to reduce individual differences and improve drug safety

After organ transplantation, patients require treatment with immunosuppressive drugs to prevent immune rejection and transplantation failure. Tacrolimus (FK506) is a widely used immunosuppressant known for its potent immunosuppressive effect and narrow therapeutic range. Monitoring of FK506 blood concentrations is essential to avoid nephrotoxicity. In this study, a novel FK506 nanomedicine (FK506 cochleates) was developed using a microfluidic method to reduce variability among individuals and improve drug safety. The particle size of FK506 cochleates was (183.3 ± 1.4) nm, the zeta potential was −(39.28 ± 2.12) mV, and the encapsulation efficiency was more than 85 %. Particle size of FK506 cochleates could be maintained for up to 12 weeks in freeze-dried powder form. Small-angle X-ray scattering (SAXS) experiment confirmed the formation of cochleates by adding calcium solution. In vitro release studies demonstrated a sustained-release profile of FK506 from the cochleates carrier. Furthermore, the cochleates carrier could protect FK506 from the influence of stomach acid and slowly release the drug in the intestine. After oral administration, FK506 cochleates exhibited sustained-release properties in rats, accumulating in the spleen and lymph nodes − key anatomical sites for FK506’s pharmacological action. Importantly, FK506 cochleates significantly prolonged the survival time in the rabbit heart transplantation model while maintaining good safety profiles. In conclusion, the FK506 cochleates showed promising potential for enhancing drug safety in therapeutic organ transplantation.

Effects of genetic and clinical factors on thiopurine drugs pharmacokinetics in Tunisian patients.

Aim: Thiopurine drugs are used in the treatment of various diseases including inflammatory bowel disease. Thiopurine-S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are the crucial enzymes involved in thiopurines metabolism. The present study aims to investigate in Tunisian patients, the influence of genetic and nongenetic factors on thiopurine drugs pharmacokinetics.Experimental approach: We have included patients having received thiopurine drugs and have undergone 6-thioguanine nucleotides (6-TGN) concentration monitoring. The identification of TPMT and ITPA polymorphisms was performed using the polymerase chain reaction-restriction fragment length polymorphism method. The impact of both genetic and nongenetic factors on the variability of the 6-TGN C/D ratio was analyzed through a stepwise multiple regression model.Key results: One hundred and twenty-three patients were included in the study. For TPMT, the most frequent variant allele was TPMT*3B (3.3%). For ITPA, the predominant polymorphism was the c.IVS2+21A> C (7%). We have demonstrated that only gender, the TPMT*3A and TPMT*3C alleles are significantly involved on the variability of thiopurines pharmacokinetics.Conclusion: Our study is the first to evaluate, in African patients, the impact of both genetic and nongenetic factors on the thiopurine drugs pharmacokinetics. Considering the narrow therapeutic range of these drugs, TPMT genotyping combined with 6-TGN blood concentration monitoring may enhance their efficacy and safety.

Effect of hydroxychloroquine blood concentration on the efficacy and ocular toxicity of systemic lupus erythematosus.

In the absence of evidence-based guidance on the impact of hydroxychloroquine (HCQ) blood concentration on efficacy and ocular toxicity in systemic lupus erythematosus (SLE), the clinical monitoring of HCQ blood concentration is not yet widely performed, which raised concerns about the necessity of conducting HCQ blood concentration monitoring. In this retrospective study, we consecutively enrolled 135 patients with SLE who received HCQ treatment for more than 6months from July 2022 to December 2022. Ocular toxicity was evaluated by collecting relevant retinal parameters using optical coherence tomography angiography (OCTA). Therapeutic efficacy was evaluated using the SLE disease activity index (SLEDAI) and relevant clinical parameters. HCQ blood concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Spearman correlation analysis revealed that the cumulative dose of HCQ was positively correlated with the foveal avascular zone (FAZ) perimeter and FAZ area (r = 0.734, P < 0.001; r = 0.784, P < 0.001). Meanwhile, the treatment duration of HCQ was positively correlated with FAZ perimeter and FAZ area (r = 0.761, P < 0.001; r = 0.882, P < 0.001). The univariate and multivariate logistic regression analyses indicated that HCQ blood concentration was associated with the disease activity of patients with SLE (odds ratio 0.994, 95% CI 0.990-0.999). HCQ blood concentration may be an important factor in assessing the therapeutic effectiveness of SLE patients. The HCQ-related ocular toxicity was a long-term effect related to long term exposure, rather than the blood concentration of HCQ at the time of testing. More importantly, when addressing HCQ-related ocular toxicity, it may be crucial to pay attention to the cumulative dose and treatment duration of HCQ.

Safety assessment of cenobamate: real-world adverse event analysis from the FAERS database.

This study aims to analyze adverse drug events (ADEs) associated with cenobamate from the FAERS database, covering the third quarter of 2020 to the second quarter of 2023. Data related to cenobamate-associated ADEs from the third quarter of 2020 to the second quarter of 2023 were collected. After standardizing the data, various signal quantification techniques, including ROR, MHRA, BCPNN, and MGPS, were employed for analysis. Among 2535 ADE reports where cenobamate was the primary suspected drug, 94 adverse reactions involving 11 different System Organ Class (SOC) categories were identified through the application of four signal quantification techniques. More specifically, neurological disorders and injuries resultant from complications are frequent adverse reactions associated with cenobamate. Our research findings align with established results, affirming the favorable safety profile of cenobamate. Effective prevention of adverse reactions induced by cenobamate can be achieved through the establishment of efficient blood concentration monitoring and dose adjustments.

Construction of a Prediction Model for Voriconazole-Induced Hepatotoxicity Based on Mixed-Effects Random Forest.

Voriconazole is a second-generation triazole antifungal agent with strong antifungal activity against a variety of clinically significant pathogens. Controlling blood concentrations within guideline limits through blood concentration monitoring can reduce the probability of hepatotoxicity in patients with voriconazole. However, statistical analysis based on real-world data found that there were still several patients who had blood concentration monitoring developed voriconazole induced hepatotoxicity. Therefore, it has important clinical significance to predict whether hepatotoxicity will occur in patients who meet the guidelines for voriconazole plasma concentration requirements. In this study, based on real-world data, the mixed-effects random forest was used to analyze the electronic medical record data of patients who met the guidelines for voriconazole blood concentration requirements during hospitalization, and a predictive model was constructed to predict whether patients would develop hepatotoxicity within 30 days after using voriconazole.

Monitoring vancomycin blood concentrations reduces mortality risk in critically ill patients: a retrospective cohort study using the MIMIC-IV database.

The incidence and mortality of severe Gram-positive cocci infections are particularly high in intensive care units (ICUs). Vancomycin remains the treatment of choice for severe infections caused by Gram-positive cocci, particularly methicillin-resistant Staphylococcus aureus (MRSA). Some guidelines recommend therapeutic drug monitoring (TDM) for critically ill patients treated with vancomycin; however, there is currently a lack of evidence to support that TDM improves the mortality rates of these patients. Therefore, we designed this cohort study to compare the impact of monitoring vancomycin blood concentrations on mortality rates in critically ill patients and to provide evidence to support this routine clinical practice. Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database for a retrospective cohort analysis of critically ill patients receiving intravenous vancomycin treatment. The primary outcome was the 28day mortality rate. The propensity score matching (PSM) method was used to match the baseline characteristics between patients in the TDM group and the non-TDM group. The relationship between 28day mortality and vancomycin TDM in the critically ill cohort was evaluated using Cox proportional hazards regression analysis and Kaplan-Meier survival curves. Validation of the primary outcomes was conducted by comparing the PSM model and the Cox proportional hazards regression model. The robustness of the conclusion was subsequently verified by subgroup and sensitivity analyses. Data for 18,056 critically ill patients who met the study criteria were collected from the MIMIC-IV database. Of these, 7,451 patients had at least one record of vancomycin blood concentration monitoring, which we defined as the TDM group. The TDM group exhibited a 28day mortality rate of 25.7% (1,912/7,451) compared to 16.2% in the non-TDM group (1,723/10,605). After PSM, 4,264 patients were included in each of the TDM and non-TDM groups, with a 28day mortality rate of 20.0% (1,022/4,264) in the TDM group and 26.4% (1,126/4,264) in the non-TDM group. Multivariate Cox proportional hazards analysis revealed a significantly lower 28day mortality risk in the TDM group when compared to the non-TDM group (adjusted hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.79, 0.93; p < 0.001). Further PSM analyses (adjusted HR: 0.91; 95% CI: 0.84, 0.99; p = 0.033) confirmed the lower risk of mortality in the TDM group. Kaplan-Meier survival analysis revealed a significantly higher survival rate at 28 days for the TDM group (log-rank test, p < 0.001). Subgroup analysis results indicated that patients with sepsis, septic shock, estimated glomerular filtration rate ≤ 60mL/min/1.73m2, undergoing renal replacement therapy, using vasoactive drugs, on mechanical ventilation, and those with higher severity scores (Acute Physiology Score III ≥40, Oxford Acute Severity of Illness Score ≥30, Simplified Acute Physiology Score II ≥ 30) significantly benefited from monitoring vancomycin blood concentrations. The results remained unchanged excluding patients staying in ICU for less than 48h or those infected with MRSA. This cohort study showed that monitoring vancomycin blood concentrations is associated with a significantly lower 28day mortality rate in critically ill patients, highlighting the importance of routinely performing vancomycin TDM in these patients.

Optimizing the therapeutic window of sirolimus by monitoring blood concentration for the treatment of immune thrombocytopenia

Previous studies have demonstrated that sirolimus (SRL) is an effective agent for the treatment of refractory/relapsed (R/R) ITP. However, the therapeutic window of sirolimus in the treatment of ITP has not been established. As the toxicity of sirolimus increases with higher blood concentrations, it is crucial to determine the optimal therapeutic concentration of SRL for the treatment of ITP. Thus, in this study, we used a retrospective cohort of ITP patients treated with sirolimus to propose the therapeutic dosage window for sirolimus. A total of 275 laboratory results of SRL blood concentration from 63 ITP patients treated with SRL were analyzed retrospectively. The ITP patients were divided into five groups based on their SRL blood concentration: 0−4 ng/ml, 4−8 ng/ml, 8−12 ng/ml, 12−16 ng/ml and ≥16 ng/ml. In addition to the SRL blood concentration, platelet counts and adverse events that occurred during the first 6 weeks of SRL treatment were analyzed. These findings were then used to establish the decision matrix tables and ROC curves, which helped identify the therapeutic window of SRL. Based on the values and trends of true-positive rate (TPR) and false-positive rate (FPR) in the ROC curve, patients who achieved a SRL blood concentration of 4−12 ng/ml displayed a higher response rate compared to those with a SRL concentration of 0−4 ng/ml or ≥16ng/ml. Additionally, the response rate was better for patients with a SRL concentration of 8−12 ng/ml compared to 4−8 ng/ml. Adverse events were related to the concentration of SRL; however, there was no significant difference in the incidence of adverse events between the concentrations of 4–8 ng/ml and 8–12 ng/ml (P > .05). Regression analysis suggested that the concentration of SRL correlated with the patient’s age, PLT count at the start of SRL administration, and the dose of SRL. It is suggested that the optimal blood concentration of SRL monotherapy for managing ITP is 8–12 ng/ml. This range may achieve a favorable balance between clinical efficacy and the severity of adverse events.

High-throughput detection of mycophenolic acid in human plasma based on sensitive and rapid fluorescence nitrogen-doped carbon dots sensing platform

In this experiment, a water-soluble, nitrogen-doped yellow-green fluorescent N-doped carbon dots (N-CDs) were synthesized by one-step hydrothermal method using β-cyclodextrin as carbon source and L-phenylalanine as nitrogen source. The fluorescence quantum yield of the obtained N-CDs was as high as 9.96%, and the N-CDs exhibited photostability at different pH, ionic strength and temperature. The morphology of the N-CDs was approximately spherical with an average particle size of about 9.4 nm. Based on the fluorescence enhancement effect of mycophenolic acid (MPA) on N-CDs, a quantitative detection method of MPA was established. This method had good selectivity and high sensitivity for MPA. The fluorescence sensing system was applied to the detection of MPA in human plasma. The linear range of MPA were 0.06–3 μg·mL−1 and 3–27 μg·mL−1 with a detection limit of 0.016 μg·mL−1, and the recoveries were 97.03∼100.64 % with the RSDs of 0.13∼2.90 %. The interference experiment results showed that the interference of other coexisting substances, including Fe3+, can be ignored in the actual detection. Comparing the results measured by the established method with the EMIT method, it was found that the results obtained by the two methods were similar, and the relative error was within ± 5 %. This study provided a simple, rapid, sensitive, selective and effective method for the quantitative analysis of MPA, and was expected to be applied to clinical MPA blood concentration monitoring.

Rational use of tigecycline and tigecycline blood concentration monitoring in patients with severe infection.

Tigecycline, a tetracycline antibiotic, is widely used against antimicrobial resistance; therefore, medical staff should use tigecycline rationally to improve clinical efficacy and reduce resistance to this drug. The present study aimed to enhance the rate of rational tigecycline usage. The patients were divided into a low-dose (50 mg tigecycline twice daily, every 12 h) and a high-dose group (100 mg twice daily, every 12 h). The blood concentrations of tigecycline were examined and the area under the curve (AUC)0-12 h values of the two groups were calculated. Prescriptions of tigecycline for 40 intensive care unit (ICU) cases were reviewed to evaluate the rationality of tigecycline usage. The peak plasma concentrations (the 7th administration after 1 h) of tigecycline were significantly higher in the high-dose group (2.46±0.43 µg/ml) compared with those in the low-dose group (1.25±0.16 µg/ml). The AUC0-12 h was 16.35±3.09 h µg/ml in the high-dose group and 9.83±1.23 h µg/ml in the low-dose group (P<0.001). There were 29 irrational prescriptions identified, involving: i) Lack of consultation records (n=20); ii) inappropriate usage or dosage (n=17); iii) inappropriate drug selection (n=2); or iv) lack of dynamic laboratory tests to evaluate the efficacy (n=4). The irrational use of tigecycline in ICU patients is common. The rate of rational tigecycline usage can be improved by strengthening the management, training and participation of clinical pharmacists.

A Joint Pharmacokinetic Model for the Simultaneous Description of Plasma and Whole Blood Tacrolimus Concentrations in Kidney and Lung Transplant Recipients.

Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The therapeutic and adverse effects are however expected to be driven by the unbound exposure, which could be better represented by measuring plasma concentrations. We aimed to establish plasma concentration ranges reflecting whole blood concentrations within currently used target ranges. Plasma and whole blood tacrolimus concentrations were determined in samples of transplant recipients included in the TransplantLines Biobank and Cohort Study. Targeted whole blood trough concentrations are 4-6 ng/mL and 7-10 ng/mL for kidney and lung transplant recipients, respectively. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. Simulations were performed to infer plasma concentration ranges corresponding to whole blood target ranges. Plasma (n=1973) and whole blood (n=1961) tacrolimus concentrations were determined in 1060 transplant recipients. A one-compartment model with fixed first-order absorption and estimated first-order elimination characterised observed plasma concentrations. Plasma was linked to whole blood using a saturable binding equation (maximum binding 35.7 ng/mL, 95% confidence interval (CI) 31.0-40.4 ng/mL; dissociation constant 0.24 ng/mL, 95% CI 0.19-0.29 ng/mL). Model simulations indicate that patients within the whole blood target range are expected to have plasma concentrations (95% prediction interval) of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively. Whole blood tacrolimus target ranges, currently used to guide TDM, were translated to plasma concentration ranges of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.

Pharmacokinetic Drug-Drug Interaction With Coadministration of Cannabidiol and Everolimus in a Phase 1 Healthy Volunteer Trial.

When highly purified cannabidiol (CBD; Epidiolex) and the mammalian target of rapamycin inhibitor everolimus are used concomitantly in the treatment of tuberous sclerosis complex, there is evidence of a pharmacokinetic (PK) interaction, leading to increased everolimus systemic exposure. We evaluated the effect of steady-state CBD exposure following multiple clinically relevant CBD doses on everolimus PK in healthy adult participants in a single-center, fixed-sequence, open-label, phase 1 study. All participants received oral everolimus 5mg on day 1, followed by a 7-day washout. On days 9-17, participants received CBD (100mg/mL oral solution) at 12.5mg/kg in the morning and evening. On the morning of day 13, participants also received a single dose of oral everolimus 5mg. Medications were taken 30 or 45minutes (morning or evening dose) after starting a standardized meal. Maximum concentration and area under the concentration-time curve (AUC) from time of dosing to the last measurable concentration and extrapolated to infinity, of everolimus in whole blood were estimated using noncompartmental analysis, with geometric mean ratios and 90% confidence intervals for the ratios of everolimus dosed with CBD to everolimus dosed alone. A single dose of everolimus 5mg was well tolerated when administered with multiple doses of CBD. Log-transformed everolimus maximum concentration, AUC from time of dosing to the last measurable concentration, and AUC extrapolated to infinity values increased by ≈2.5-fold, and everolimus half-life remained largely unchanged in the presence of steady-state CBD relative to everolimus dosed alone. Everolimus blood concentration monitoring should be strongly advised with appropriate dose reduction when coadministered with CBD.

Prediction of metabolic activity of rowing athletes based on serum biochemical analysis

Determination of the metabolic state is an important topic in sports medicine. Biochemical and hematological blood parameters reflect the predominance of anabolic or catabolic processes in metabolism, these parameters depend on intensity and duration of workouts. The aim of the present study was to determine whether metabolic processes are dominant. 21 male rowing athletes (age: 22.55 ± 3.68 years, height: 189.62 ± 6.34 cm, weight: 88.65 ± 8.55 kg) participated in the experiment. Monitoring of blood concentrations in samples collected from participating athletes and measuring workout intensity led to the use of a linear-discriminant function. With this technique, the eight main blood count parameters: creatinine (p &lt; 0.001), uric acid (p &lt; 0.001), urea (p &lt; 0.001), testosterone (p &lt; 0.001), ALP (p &lt; 0.001), albumin (p &lt; 0.05), total calcium (p &lt; 0.05), and total protein (p &lt; 0.05) for the prediction of the metabolic state have been determined. The reliability of test results using a linear-discriminant function for the prediction of the metabolic state in athletes was supported by a strong positive correlation (r = 0.88, p &lt; 0.001) with the results of the neuroendocrine system activity assessments. The accuracy of the metabolic state prediction was 91.8%.