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Objective To explore the pharmacokinetics/pharmacodynamics(PK/PD)parameters and influencing factors in patients with augmented renal clearance(ARC)to provide the basis for the rational use of meropenem.Methods Using the method of retrospective study,the patients with increased renal clearance who used meropenem monitored the concentration from January 2018 to December 2021.The PK/PD parameters of meropenem were analyzed,and multiple linear retrospective analyses discussed the influencing factors of meropenem valley concentration.Results A total of 58 patients were included in the study,and the trough concentration was 1.35[0.23,1.86]μg·mL-1,taking 100%fT>MIC as PK/PD target value,the compliance rate was 20.69%.The compliance rate of daily dose<3 g·d-1 was 8.70%,and≥3 g·d-1 was 31.43%,the difference was statistically significant.With MIC of 0.5,1,2,4,and 8 μg·mL-1,PK/PD compliance rates were 62.07%,48.28%,20.69%,8.62%and 0.Respectively.Multiple linear retrospective analyses showed that dose was an independent factor affecting meropenem valley concentration.Conclusion The PK/PD compliance rate of meropenem in patients with augmented renal clearance is low,even if MIC≤0.5 μg·mL-1,the routine dose is difficult to achieve the ideal PK/PD,so the clinical should recognize ARC and perform TDM as soon as possible,and use TDM to guide the medication regimen of meropenem for ARC patients.
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OBJECTIVE To establish a method for determining the blood concentration of apatinib and apply it clinically. METHODS Ultra-high performance liquid chromatography (UPLC) was used for the determination of blood concentration. The chromatographic column was ACQUITY UPLC BEH C18 with the mobile phase consisted of acetonitrile-0.1% formic acid aqueous solution (gradient elution) at the flow rate of 0.2 mL/min; the column temperature was 40 ℃, and the injection volume was 5 μL. The data of 26 cancer patients taking apatinib were collected, and their blood concentrations were measured. The correlation between patient’s blood concentration and age, dosage, adverse reactions, and combination therapy were analyzed; the levels of serum kidney injury-related factors [cystatin C (CysC), kidney injury molecule 1 (KIM-1), interleukin-18 (IL-18), tumor necrosis factor-α (TNF-α)] were determined before and after treatment. RESULTS The linear range of apatinib was 500-2 000 ng/mL, with a precision RSD of 3.7%, stability RSD of 4.9%, and an average sample recovery rate of 96.0% (RSD was 2.1%). The lowest blood concentration of apatinib was 103 ng/mL and the highest was 1 932 ng/mL among 26 patients. The blood concentration of apatinib in patients showed a fluctuating downward trend with age. At a dosage of 0.125 or 0.25 g, the blood concentration of patients taking apatinib was concentrated within the range of 1 000-2 000 ng/mL. Among 26 cancer patients, 13 experienced adverse reactions, and no adverse reaction was observed in those with blood concentrations ranging from 500 to <1 000 ng/mL. Twenty patients were simultaneously treated with other drugs,resulting in varying blood concentration. After treatment, the levels of serum CysC, KIM-1, IL-18 and TNF- α were significantly higher than before treatment (P<0.05). CONCLUSIONS The established UPLC method can quickly E-mail:duanxc@ahtcm.edu.cn detect the blood concentration of apatinib. When using apatinib in clinical practice, comprehensive consideration should be given to the patient’s age, drug combination, and the attention should be paid to preventing possible acute kidney damage caused by apatinib.
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OBJECTIVE To provide reference for the adjustment of antibiotic treatment regimens, identification of adverse reactions, and individualized pharmaceutical care for melioidosis sepsis (MS). METHODS Clinical pharmacists participated in the intensive and eradicating therapeutic processes for an MS patient by using blood concentration and gene detection. Based on the literature, antibiotic treatment regimens of MS were adjusted by determining the blood concentrations of β-lactam and trimethoprim/ sulfamethoxazole (TMP/SMZ) and calculating PK/PD parameters. The causes of adverse drug reactions were analyzed and addressed by detecting drug-related gene polymorphisms through high-throughput sequencing. RESULTS Clinical pharmacists used blood concentration and genetic testing methods to propose adjustments to imipenem-cilastatin sodium dosage and analyze the causes of various adverse drug reactions. PK/PD targets were calculated by measuring the blood concentrations of β-lactam and TMP/SMZ. Clinical pharmacists explained to clinical doctors the compliance status of patients with melioidosis in sepsis and non- sepsis stages through reviewing guidelines and literature; the results of blood concentration and genetic test were used to analyze the correlation of neurotoxicity of MS patients with B14) IMP cmin, and it was found that nephrotoxicity was not related to the cmax of TMP/SMZ, but to the patient’s water intake. After whole-process antibiotic treatment, the patient’s condition improved and was discharged, and the adverse reactions were effectively treated. CONCLUSIONS Clinical pharmacists use blood concentration and genetic tests to assist clinicians in formulating MS treatment regimens, and provide whole-course pharmaceutical care for a MS patient. This method has improved the safety and effectiveness of clinical drug therapy.
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OBJECTIVE To investigate the monitoring of tacrolimus blood concentration in patients with nephrotic syndrome (NS),and to establish a prediction model for tacrolimus blood concentration. METHODS Data from 509 concentration monitoring sessions of 166 NS patients using tacrolimus were collected from January 1, 2020 to August 31, 2023 in Zhongshan Hospital Affiliated to Xiamen University. The relationship of efficacy and adverse drug reaction(ADR) with blood concentration was analyzed. A multilayer perceptron (MLP) prediction model was established by using the blood concentration monitoring data of 302 times from 109 NS patients with genetic information, and then verified. RESULTS In terms of efficacy, the median blood concentration of tacrolimus in the non-remission group was 2.20 ng/mL, which was significantly lower than that in the partial remission group (4.00 ng/mL, P<0.001) and the complete remission group (3.60 ng/mL, P=0.002). In terms of ADR, the median blood concentration of tacrolimus in the ADR group was 5.01 ng/mL, which was significantly higher than that in the non-ADR group (3.37 ng/mL) (P=0.001). According to the subgroup analysis of the receiver operating characteristic curve, when the blood concentration of tacrolimus was ≥6.65 ng/mL, patients were more likely to develop elevated blood creatinine [area under the curve (AUC) was 0.764, P<0.001); when the blood concentration of tacrolimus was ≥6.55 ng/mL, patients were more likely to develop blood glucose (AUC=0.615, P= 0.005). The established MLP prediction model has a loss function of 0.9, with an average absolute error of 0.279 5 ng/mL between the predicted and measured values. The determination coefficient of the validation scatter plot was 0.984, indicating an excellent predictive performance of the model. CONCLUSION Tacrolimus blood concentration has an impact on both efficacy and ADR in NS patients. The use of the MLP model for predicting blood concentration exhibits high accuracy with minimal error between predicted and measured values. The model can be used as an important tool in clinical individualized medication regimens.
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Objective To evaluate the predictive ability and influencing factors of individualized drug administration adjuvant decision-making system Java PK® for Desktop (JPKD) for tacrolimus blood concentration in kidney transplant recipients. Methods The monitoring data of tacrolimus blood concentration from 149 recipients early after kidney transplantation were collected. The trough blood concentration of tacrolimus was predicted by JPKD. The absolute weighted deviation and relative prediction deviation between the actual and predicted concentration were calculated. The influencing factors of the absolute weighted deviation were analyzed by univariate and multivariate logistic regression analyses, and the predictive values of these influencing factors on the accuracy of software prediction were assessed by delineating the receiver operating characteristic (ROC) curve. Results Two hundred and sixty-six samples of tacrolimus blood concentration data were collected from 149 patients. The measured blood concentration of tacrolimus was (6.5±3.0) ng/mL (1.1-16.6 ng/mL), and the predicted value calculated by JPKD was (5.6±2.5) ng/mL (1.4-14.4 ng/mL). The absolute weighted deviation of the calculated data was 28.38%, and the relative prediction deviation was −13.55%. Univariate analysis showed that gender, albumin, changes in hematocrit, cytochrome P450 (CYP)3A5*3 genotype and C3435T genotype were associated with the inaccurate prediction results. Multivariate logistic regression analysis found that CYP3A5*3 genotype of AA and the changes in hematocrit were the independent risk factors affecting the accuracy of tacrolimus blood concentration predicted by JPKD. ROC curve analysis showed that when the changes in hematocrit exceeded 2.25%, the risk of inaccurate software prediction was increased. Conclusions JPKD possesses certain accuracy in predicting the blood concentration of tacrolimus in kidney transplant recipients, which may improve the qualified rate of tacrolimus blood concentration. Nevertheless, CYP3A5*3 genotype and the changes of hematocrit may affect the accuracy of predictions.
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Objective:To evaluate the therapeutic effect of hemopurification on acute chlorfenapyr poisoning according to the blood concentration of chlorfenapyr and to provide experience for clinical treatment.Methods:Two patients who presented to our Emergency Department following an ingestion of chlorfenapyr and then were treated with hemopurification in 2022 were included. The concentrations of chlorfenapyr and its highly toxic metabolite tralopyril were dynamically monitored, and the clinical data of the patients were collected.Results:Case 1 was given hemoperfusion for the first time 13 hours after ingestion. During l hour hemoperfusion, the tralopyril decreased by 28.82%. The concentration increased and exceeded the pre-perfusion level after 2 hours of hemoperfusion. After three times of hemoperfusion, the concentrations of chlorfenapyr and tralopyril were still higher than those before the first time, reaching 248 ng/mL and 1 307 ng/mL respectively. The concentration of chlorfenapyr showed a downward trend after 130 h, and the tralopyril in blood reached the peak 3 164 ng/mL at 130 h and decreased to 2 707 ng/mL at 178 h. In case 2, the blood chlorfenapyr and tralopyril concentration was 392 ng/mL and 7 598 ng/mL respectively 150 hours after ingestion. The blood chlorfenapyr concentration decreased by 37.75% respectively after first hemoperfusion, and the tralopyril concentration decreased by 38.02% respectively. During 85 hours of continuous veno-venous hemodiafiltration (CVVHDF), the concentration of tralopyril was maintained at 4 234~6 410 ng/mL. Case 1 was followed up to 12 days and lost follow-up. Case 2 died and the survival time was 247 hours.Conclusions:Hemoperfusion can scavenge tralopyril, but CVVHDF has poor scavenging ability for tralopyril. And the apparent volume of distribution (Vd) of chlorfenapyr and tralopyril are large. After ingestion, chlorfenapyr spreads to various tissues quickly, and it is easy to accumulate in the adipose tissue. The chlorfenapyr in the tissue slowly is released back to the blood and stays in the blood for a long time. The peak concentration of chlorfenapyr appeared earlier than that of tralopyril. Clinicians should pay attention to the early removal of toxins from the digestive tract.
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OBJECTIVE To establish a method to detect the blood concentration of ibrutinib and apply it to the clinic. METHODS Using zanubrutinib as internal standard, the concentration of ibrutinib was detected by high performance liquid chromatography (HPLC) after plasma samples were processed by solid-phase extraction. The separation was performed on an Agilent 5 TC-C18(2) column with acetonitrile-0.5% potassium dihydrogen phosphate solution (43∶57, V/V) as the mobile phase at a flow rate of 1 mL/min, a detection wavelength of 260 nm, a column temperature of 40 ℃ , a sample size of 20 μL, and a run time of 25 min. The concentration of ibrutinib was measured in the plasma of 9 patients with non-Hodgkin’s lymphoma 2 h after drug administration on the 30th day by the above method. RESULTS The linear range of the assayed mass concentration of ibrutinib was 10-500 ng/mL (R 2=0.998 9), the lower limit of quantification was 10 ng/mL, and the RSDs of the intra-batch and inter-batch precision tests were not higher than 12.77%. The recoveries of the extraction were 74.80% and 97.70%, with both RSDs<2.90%, and the RSDs of the stability tests were not higher than 7.10%. The peak plasma concentrations of 9 patients were 15.341-279.628 ng/mL. CONCLUSIONS The established HPLC method is simple and rapid, and can be used for the determination of ibrutinib concentration in plasma samples.
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OBJECTIVE To discuss the factors affecting the blood concentration of high-dose methotrexate (HD-MTX) and the occurrence of adverse drug reactions (ADR) when treating lymphoma with HD-MTX. METHODS From July 2020 to November 2021, the information of HD-MTX patients who had been monitored for HD-MTX blood drug concentration in the First Affiliated Hospital of Guangdong Pharmaceutical University was collected by retrospective analysis, such as medical record number, age, sex, height, body mass, chemotherapy plan, dosage; test indexes such as alanine transaminase, aspartate transaminase, total bilirubin, creatinine clearance (CrCl), albumin (ALB) and other indexes were also collected before and after administration. The blood concentrations (c6 h, c24 h, c48 h) of HD-MTX were recorded, drug information of proton pump inhibitors (PPIs) was extracted and used, and ADR occurring within 48 h after administration were all evaluated. Single factor analysis, multiple linear regression and χ2 test were used to analyze the influential factors. RESULTS A total of 133 patients were included in this paper. The results of the single factor analysis of HD-MTX blood drug concentration showed that age, CrCl had an effect on c 6 h (P<0.05); age, CrCl and ALB had an effect on c24 h (P<0.05); age, body mass index (BMI), CrCl, combined use of PPIs and ALB had an effect on c48 h (P<0.05). The results of multiple linear regression analysis showed that age and CrCl had no effect on c 6 h (P>0.05), age was the main influential factor of c 24 h (P<0.05), and CrCl and combined use of PPIs were the main influential factors of c48 h (P<0.05); the coefficient of variance expansion was between 1 and 3.5, indicating that the analysis results were acceptable. The overall incidence of adverse reactions was 51.13%, of which the blood and lymphatic system reactions were the most common. The results of the influential factors of ADR showed that age, BMI, liver function and CrCl had effect on the incidence of ADR (P<0.05). CONCLUSIONS During the process of HD-MTX in the treatment of lymphoma, the patient’s age, CrCl and combined use of PPIs should be considered, and the patient’s blood concentration should be monitored; at the same time, the age of patients, BMI, liver function and CrCl have an impact on the incidence of ADR.
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OBJECTIVE To explore the effects of posaconazole combined with proton pump inhibitors (PPI) on the blood concentration and the risk of invasive fungal disease (IFD) in patients with malignant hematological disorder. METHODS In accordance with the random number table method, 40 patients with malignant hematological disorders who were admitted to the hematology department of our hospital between December 2020 and December 2021 were chosen and divided into control group (20 cases) and observation group (20 cases). The control group received Posaconazole oral suspension alone, while the observation group received Posaconazole oral suspension combined with PPI. The incidence of IFD, attainment rate of blood concentration, the time from the start of prophylaxis to IFD onset, the fatality associated with IFD, treatment of infected patients, and blood concentrations of posaconazole on 7th, 14th, 21st, and 28th day after posaconazole application were compared between 2 groups; the occurrence of adverse events during drug administration in the two groups was recorded. RESULTS The study was stopped because 2 patients in the observation group and 9 patients in the control group received hospital departures after taking posaconazole for fewer than 7 days. The incidence of IFD in the observation group was significantly higher than control group, and the attainment rate of blood concentration in the observation group was significantly lower than control group (P<0.05). There was no significant difference in the time from the start of prophylaxis to IFD onset, the fatality associated with IFD, treatment of infected patients and the incidence of adverse events (P> 0.05). The blood concentration of posaconazole in the observation group was significantly lower than control group on 7th day of medication (P<0.05); there was no significant in blood concentration of posaconazole between 2 groups on the 14th day of medication (P>0.05). CONCLUSIONS Posaconazole combined with PPI can reduce the blood concentration of patients with malignant hematological disorders, increase the risk of IFD. Clinical practice should try to avoid the combination of the two or use them under the guidance of therapeutic drug monitoring.
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Objective:To investigate factors associated with the concentration of hydroxychloroquine (HCQ) and its metabolites in peripheral blood of patients with systemic lupus erythematosus (SLE) who were receiving long-term oral HCQ treatment.Methods:SLE patients who had been taking HCQ for more than 3 months were recruited. Clinical characteristics, laboratory test results and SLE disease activity index (SLEDAI) scores were examined. The concentrations of HCQ and its metabolites from peripheral blood were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Student's-test and Nonpara-metric tests were used to compare quantitative data, Chi-square and Fisher's exact tests were used to analyze qualitative data. Correlation between the test results was assessed by correlation coefficient. Variables with P values less than 0.05 in univariate analysis were entered into a logistic regression model. Results:In total, 191 SLE patients on long-term HCQ treatment were included in the analysis. Medians of HCQ blood concentrations ([HCQ]), desethylhydroxychloroquine (DHCQ) blood concentrations ([DHCQ]), desethylchloroquine (DCQ) blood concentrations ([DCQ]) and bisdesethylchloroquine (BDCQ) blood concentrations ([BDCQ]) were 523.19 (402.63, 677.88) ng/ml, 291.79 (212.30, 432.51) ng/ml, 49.37 (35.00, 73.05) ng/ml, 21.78(14.37, 52.46) ng/ml respectively. On multivariate analysis, weight-adjusted oral HCQ dose [ OR(95% CI)=1.366 (1.053, 1.772) , P=0.019], the course of hydroxychloroquine [ OR (95% CI) =0.991 (0.984, 0.999), P=0.026], estimated glomerular filtration rate [ OR(95% CI)=0.984 (0.971, 0.997), P=0.014] and platelet count [ OR (95% CI)=1.010 (1.005, 1.015), P<0.001] were associated with [HCQ]. [HCQ], [DCQ], [BDCQ], [BDCQ]/[HCQ] were negatively correlated with estimated glomerular filtration rate (eGFR) ( r=-0.20, P=0.006; r=-0.19, P=0.010; r=-0.26, P<0.001; r=-0.15, P=0.044, respectively) after adjusted for age, course of disease, duration of HCQ treatment and weight adjusted HCQ dosage, [DHCQ]/[HCQ] was negatively correlated with the SLEDAI score ( r=-0.16, P=0.027) when the effects of glucocorticoid was controlled, [BDCQ]/[HCQ] among different renal function levels was statistically significant ( H=12.46, P=0.014). Conclusion:The factors associated with HCQ blood concentrations in SLE patients on long-term oral HCQ treatment are weight-adjusted HCQ dosage, duration of hydroxychloroquine intake and renal function. In addition, [BDCQ] is closely correlated with renal function, [DHCQ] is correlated with SLE disease activity.
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Objective:To investigate the safety and efficacy of individualized sunitinib schedule for patients with metastatic renal cell carcinoma (mRCC) according to the monitoring results of plasma drug concentration.Methods:The clinical data of patients with mRCC who received sunitinib treatment in our center from January 2014 to December 2020 were retrospectively analyzed, including 20 patients who underwent monitoring of plasma drug concentration (monitoring group), and 45 patients, matched by propensity score matching, received sunitinib but did not undergo monitoring of plasma drug concentration during the same period (unmonitored group). In the monitoring group, there were 12 males and 8 females. The mean age was 52.9 years, and ECOG score ≤1 in 16 cases (80%). Three patients were in the IMDC favorable-risk group, 15 patients were in the intermediate-risk group, and 2 patients were in the high-risk group. There were 18 cases of clear cell carcinoma and 2 cases of non-clear cell carcinoma, 5 cases of ISUP grade 1-2 and 11 cases of grade 3-4. In the unmonitored group, there were 31 males and 14 females. The mean age was 57.7 years, and 30 patients had ECOG score ≤1, 15 cases ≥2. There were 10 cases in IMDC favorable-risk group, 23 cases in intermediate-risk group, and 12 cases in high-risk group. Thirty-seven cases were clear cell carcinoma and 8 cases were non-clear cell carcinoma, 8 cases were in ISUP grade 1-2 and 28 cases in grade 3-4. There were no statistically significant differences between the two groups in the above parameters ( P>0.05). The monitoring group used the regimen of taking sunitinib for 4 weeks and stopping for 2 weeks (4/2 week) in the first cycle. The blood concentration of sunitinib was monitored before the first cycle and on days 4, 7, 10, 14, 21 and 28, and personalized medication plan was formulated according to the curve of the blood concentration. The 4/2 week scheme was adopted in the undetected monitoring group.The two groups were compared in the incidence of adverse events (AEs), progression-free survival (PFS), overall survival (OS), tumor treatment response and other clinical outcomes. Results:In the monitoring group, 90% (18/20) of patients receiving sunitinib had a steady-state plasma concentration of more than 150ng/ml, of which 10 patients (50%) had a plasma concentration of 150-200 ng/ml and 8 patients (40%) had a plasma concentration of more than 200 ng/ml. Meanwhile, all patients with plasma concentration higher than 150 ng/ml developed severe AEs (grade 3 and above) after treatment. The other two patients' plasma concentration were 100-150 ng/ml, and did not have severe AEs.All patients in the monitoring group received individualized medication schedule adjustment according to the plasma drug concentration and the occurrence point of severe AEs, ensuring that the peak plasma drug concentration was maintained at about 100-150 ng/ml. Among them, 6 patients were changed to take 2 weeks and stop for 1 week (2/1 week schedule), 4 patients were changed to take 10 days and stop for 5 days (10/5 d schedule), 7 patients were changed to take 7 days and stop for 3 days (7/3 d schedule), and 3 patients were changed to take 5 days and stop for 2 days (5/2 d schedule). The incidence of severe AEs significantly decreased from 90% (18/20) to 35% (7/20), and the difference was statistically significant ( P=0.003), while the incidence of grade 3 and higher AEs was 55.6% (25/45) in the standard group, which was statistically significant compared with the incidence of severe AEs before adjustment in the monitoring group ( P=0.006). Further analysis of the efficacy difference between the two groups showed that the overall objective response rate in the monitoring group (40%, 8/20) was higher than that in the standard group (20%, 9/45), although the difference was not statistically significant ( P=0.09). Median PFS and OS were significantly longer in the monitored group than in the standard group (PFS: 23 vs. 10 months, P=0.002; OS: not reached vs.25 months, P=0.005). Conclusions:The bioavailability of sunitinib is high in mRCC patients, which may lead to higher plasma drug concentration, adjustment of medication regimen based on blood concentration monitoring significantly improved patient safety and clinical outcomes. However, further validation by larger-scale, multi-center and prospective studies is needed.
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Objective To investigate the exposure difference of different dosage forms of mycophenolic acid (MPA) between children aged ≤12 and > 12 years old after kidney transplantation. Methods Clinical data of 73 children undergoing kidney transplantation from donation after cardiac death (DCD) were retrospectively analyzed. Postoperative immunosuppressive regimen was MPA+ tacrolimus+glucocorticoid. According to different dosage forms of MPA, all recipients were divided into group A (n=37, mycophenolate mofetil capsules), group B (n=28, enteric-coated mycophenolate sodium) and group C (n=8, mycophenolate mofetil dispersible tablets). All children were divided into ≤12 and > 12 years old groups according to the age of kidney transplantation. The daily dosage of different dosage forms was calculated. The blood concentration (C) of MPA and the area under the curve (AUC) were detected by enzyme-multiplied immunoassay technique. The MPA blood concentration was statistically compared between two age groups at different time points. The recovery of renal function and postoperative complications were assessed. Results No significant differences were observed in the dosage and blood concentration of drug at different time points among groups A, B and C (all P > 0.05). The MPA-C4 h and AUC in the ≤12 years old group were significantly higher than those in the > 12 years old group (both P < 0.05). In group B, the MPA-C4 h of children aged ≤12 years old was significantly higher compared with that in those aged > 12 years old (P=0.016). The MPA-C4 h of children aged ≤12 years old in group B was higher than those in group A and group C, but the differences were not statistically significant (P=0.080). There was no significant difference in the incidence of acute rejection and infection among three groups (both P > 0.05). Conclusions Children of different ages who are given with different dosage forms of MPA after kidney transplantation obtain different exposure rates. The exposure rate of kidney transplant recipients aged ≤12 years old tends to be higher than that of their counterparts aged > 12 years old, mainly seen in the recipients treated with enteric-coated mycophenolate sodium. Therefore, it is necessary to monitor the exposure level of MPA, which provides significant guidance for adjusting the drug dosage of different dosage forms.
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Objective To analyze the drug-drug interaction (DDI) between intravenous voriconazole (VRZ) and intravenous cyclosporine (CsA) in patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and provide an individualized and accurate clinical drug delivery. Methods In a self-contrast study, Allo-HSCT patients from January 2019 to December 2019 were enrolled according to the inclusion and exclusion criteria. These patients were treated with CsA and VRZ successively and the blood concentration of CsA and VRZ before and after 5-7 days of VRZ administration were determined with LC-MS/MS. The correlation between the concentration of VRZ and concentration/dose (C/D) ratio of CsA was analyzed with SPSS20.0. Results A total of 15 patients with ALLo-HSCT were enrolled. Wilcoxon sign rank sum test was used to compare the change of median C/D of CsA before and after VRZ administration, which had shown significant difference (P<0.001). Spearman correlation analysis was conducted on the increase of C/D ratio between VRZ and CsA, which had no significant correlation between them (ρ=−0.273, P=0.32). Conclusions There was obvious drug-drug interaction (DDI) between CsA and VRZ. VRZ increased CsA blood concentration significantly, but there was no significant correlation between VRZ blood concentration and the degree of concentration increase, which might be related to individual difference.
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OBJECTIVE To expl ore the clinical significance of folic acid metabolic gene detection in methotrexate (MTX) treatment of acute myeloid leukemia (AML). METHODS Therapeutic drug monitoring (TDM)pharmacists participated in the treatment process of an AML patient who had neurotoxic side effects such as dizziness ,headache,and vomiting after intrathecal injection of MTX. According to the results of the test of the folic acid metabolic gene MTHFR C677T(rs1801133)(mutant homozygous)and the results of MTX blood concentration monitoring (<0.05 μmol/L),combined with clinical manifestations ,it was recommended to stop MTX ,give intravenous drip of calcium folinate for rescue ,and consider using azacytidine for follow-up treatment. RESULTS The doctor took the advice of TDM pharmacist ,and the above symptoms were significantly relieved after the patient rescued for 2 times and successfully discharged from the hospital. CONCLUSIONS For AML patients who meet the indications and receive intrathecal injection of MTX ,drug metabolism genetics testing and MTX drug concentration monitoring can be performed before medication ,which helps doctors and pharmacists evaluate the feasibility of drug treatment options and reduce medical risks.
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OBJECTIVE To establis h and validate a population pharmacokinetic model of docetaxel in malignant tumor patients. METHODS The clinical data of malignant tumor patients treated with chemotherapy regimen containing docetaxel in our hospital from June 2019 to December 2021 were retrospectively collected . According to the results of blood concentration detection , based on the three -compartment model the nonlinear mixed effect model (NONMEM)was used ;covariates(age,weight,height, body surface area ,Karnofsky performance scale ,total protein ,albumin,total bilirubin ,aspartate aminotransferase ,alanine aminotransferase and serum creatinine )affecting clearance (CL)were screened by “forward inclusion and backward exclusion ”; the population pharmacokinetic model of docetaxel was established . The model was tested for goodness -of-fit diagnosis and internal validation by Bootstrap . RESULTS A total of 264 measured blood concentrations of 132 patients with malignant tumors during chemotherapy were included . The covariates that had significant effect on CL of docetaxel were serum creatinine and total bilirubin (P<0.01). The results of Bootstrap analysis (parameter median values and 95% confidence intervals )were close to predict results of the established model ;the final model estimated that the population typical value of docetaxel CL was 37.82 L/h. CONCLUSIONS The population pharmacokinetic model of docetaxel in malignant tumor patients is established successfully , which can be used for the formulation and optimization of clinical individualized regimen .
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Objective To establish a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneous determination of sodium valproate and vancomycin in human serum. Methods Valproic acid-d6 and kanamycin B were used as the internal standard of sodium valproate and vancomycin, the serum samples were treated by acetonitrile precipitation protein method. The mobile phase was 0.1% formic acid aqueous solution-acetonitrile for gradient elution. The flow rate was 0.5 ml/min, with column temperature at 25 ℃. The sample volume was 4 μl and total analysis time was 12 min. The positive and negative ion mode was monitored by electrospray ion source and the multiple reaction monitoring mode was used for quantitative analysis. The specificity, standard curve, lower limit of quantification, precision, recovery, matrix effect, and stability of the method were examined. Results Sodium valproate and vancomycin had good linear relationships in the range of 1 - 200 μg/ml and 0.5 - 100 μg/ml, respectively. The quantitative lower limits were 1 μg/ml and 0.5 μg/ml, respectively. The extraction recoveries were above 70%. The inter- and intra-batch precision RSD values were less than 10%. The stability was good and there was no obvious matrix effect. Conclusion This method is simple, quick, sensitive, specific and accurate, which could be used to simultaneously determine the concentration of sodium valproate and vancomycin in human serum.
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AIM: To investigate the effects of age, gender, duration of medication and combined medication on the steady-state blood concentration of tacrolimus in patients with autoimmune diseases, and to establish the reference range of steady-state blood concentration of tacrolimus in combination with liver and kidney function, so as to provide theoretical basis for clinical individual medication. METHODS: A total of 107 patients with autoimmune diseases treated with tacrolimus in the department of rheumatology and immunology of our hospital from August 2017 to June 2021 were included. Their gender, age, dose, drug combination, blood concentration, and liver and kidney function were statistically analyzed by SPSS 22.0 statistical software. RESULTS: In the treatment of autoimmune diseases with tacrolimus, there was statistical significance in the blood concentration of different genders (P0.05) and a statistically significant difference in the dosage of tacrolimus (P<0.05), the duration of medication did not affect the effective dose, target blood concentration, liver and kidney functions. There was a weak correlation between tacrolimus dose and blood concentration (r=0.115, P=0.047). When the blood concentration of tacrolimus ranged from 4.20 to 9.48 ng/mL, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and urea increased significantly. When tacrolimus blood concentration ranged from 0.08 to 4.20 ng/mL, there was no significant difference in serum creatinine, AST, ALT, albumin, total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL). CONCLUSION: Tacrolimus is used for the treatment of autoimmune diseases, and the blood concentration varies greatly among individuals. To avoid the risk of potential damage to liver and kidney function. It is recommended that clinicians control the blood concentration at 0.08-4.20 ng/mL, and adjust the dose and optimize the dose according to the patient's gender, age, and clinical efficacy.
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Objective To establish a detection system of ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for everolimus concentration in whole blood of liver transplant recipients. Methods The proteins of samples were precipitated with methanol and zinc sulfate, and everolimus-D4 was used as the internal standard. Phenomenex Kinetex PFP column was used. The mobile phase A was water (containing 2 mmol/Lammonium formate and 0.1% formic acid), and the mobile phase B was methanol (containing 2 mmol/L ammonium formate and 0.1% formic acid). The gradient elution was performed with the flow rate of 1 mL/min, the column temperature of 50 ℃ and the injection volume of 1 μL. The multi-reaction monitoring mode was used to quantitatively analyze with electrospray positive ionization. The UPLC-MS/MS detection system required only 100 μL of whole blood, and could achieve a sufficient lower limit of quantification without complicated sample preparation. The total running time was within 4.5 min. Linear regression (1/x2) analysis was performed using peak area of everolimus / peak area of everolimus-D4 (y) and concentration of everolimus/concentration of everolimus-D4 (x) to calculate the calibration function and analyze its accuracy and linear relationship. UPLC-MS/MS was used to detect the trough blood concentration of everolimus in blood samples of 5 recipients after liver transplantation. Results The accuracy of quality control was within 15%, and the linear relationship of everolimus was good in the blood concentration range of 1-100 ng /mL(R2 > 0.990). Trough blood concentration of everolimus measured in blood samples of 5 liver transplant recipients ranged from 3.77 to 9.27 ng/mL. Conclusions The detection system of UPLC-MS/MS in this study is suitable for monitoring the concentration of everolimus in whole blood of liver transplant recipients because of its high accuracy, simple sample processing method and short detection time.
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Methadone is a difficult medicine to assess the efficacy at an initial stage because the blood concentration of it varies greatly among individuals and it takes days to reach a steady state and cannot be increased for 7 days. Nevertheless, there are few reports of blood concentration together with effects after administration of methadone about Japanese cancer patients. In this study, we investigated changes in blood concentration and pain score (NRS), and factors that affect blood concentration. Dose per body weight was only correlated with blood concentration of methadone. In the effective cases, NRS decreased chronologically until the 7th day after treatment initiation, and significantly decreased from the 1st day compared to before treatment initiation, but in the ineffective cases, it tended to decrease until the 3rd day, but there was no change thereafter. The blood concentration increased to 110 ng/ml on the 7th day in the effective cases, and in the ineffective cases, it reached the concentration on the 3rd day. Thus there was no correlation between the blood concentration and the drug efficacy. The individual blood concentrations tended to increase slightly or decrease after the 3rd day, but in only one case, it continued to increase. From the above-mentioned, it was shown that the effect could be judged at an early stage, however, since there was a case in which the blood concentration continued to rise until the 7th day, it was considered that the early dose increase within 7 days after initiation should be performed carefully.
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OBJECTIVE:To investigate the consistency and difference of f luorescence immunochromatographic and liquid chromatography-tandem mass spectrometry (LC-MS/MS)and enzyme multiplied immunoassay technique (EMIT)in the blood concentration monitoring of mycophenolic acid. METHODS :Fluorescence immunochromatography ,LC-MS/MS and EMIT were used to detect the blood concentration of mycophenolic acid in 61 blood samples of children treated with mycophenolate mofetil ester orally at different time points. Kolmogorov-Smirnov method ,Wilcoxon pairing test ,Passing-Bablok regression ,Cusum method,Spearman correlation analysis ,Bland-Altman scatter diagram were adopted for statistical analysis. RESULTS :Blood concentrations of mycophenolic acid ,which were determined by fluorescence immunochromatography ,LC-MS/MS and EMIT , showed non-normal distribution. Passing-Bablok regression analysis showed that regression equation of fluorescence immunochromatography and LC-MS/MS ,fluorescence immunochromatographic method and EMIT were CFI=0.928 3CLC-MS/MS+0.961 7 and CFI=0.880 7CEMIT-0.488 2(FI means fluorescence immunochromatographic ). Spearman correlation analysis showed that the correlation coefficients between fluorescence immunochromatography and LC-MS/MS ,fluorescence immunochromatography and EMIT were 0.968 and 0.929, respectively (P<0.000 1). Bland Altman scatter plot analysis showed that 3.28% of the 358341451@qq.com difference between fluorescence immunochromatography and LC-MS/MS was outside the consistency limit (±1.96SD), and 1.64% of the difference between fluorescence immuno- chromatography and EMIT was outside the consistency limit (± 1.96SD). Wilcoxon pairing test showed that the results of fluorescence immunochromatography were higher than those of LC-MS/MS (Z=3.76,P=0.000 2)and lower than those of EMIT (Z=-5.96,P<0.000 1). CONCLUSIONS :Fluorescence immunochromatography shows good consistency and correlation with LC-MS/MS and EMIT ;the blood concentrations of mycophenolic acid detected by fluorescence immunochromatography were higher than those by LC-MS/MS and lower than those by EMIT . It can be used for bedside rapid detection. When using the test results of different methods for clinical medication ,the differences of test methods need to be considered.