The spread of tuberculosis(TB),especially multidrug-resistant TB and extensively drug-resistant TB,has strongly motivated the research and development of new anti-TB drugs.New strategies to facilitate drug combination...The spread of tuberculosis(TB),especially multidrug-resistant TB and extensively drug-resistant TB,has strongly motivated the research and development of new anti-TB drugs.New strategies to facilitate drug combinations,including pharmacokinetics-guided dose optimization and toxicology studies of first-and second-line anti-TB drugs have also been introduced and recommended.Liquid chromatography-mass spectrometry(LC-MS)has arguably become the gold standard in the analysis of both endo-and exo-genous compounds.This technique has been applied successfully not only for therapeutic drug monitoring(TDM)but also for pharmacometabolomics analysis.TDM improves the effectiveness of treatment,reduces adverse drug reactions,and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target window.Based on TDM,the dose would be optimized individually to achieve favorable outcomes.Pharmacometabolomics is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs,aiding in the discovery of potential biomarkers for TB diagnostics,treatment monitoring,and outcome evaluation.This article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two decades.Besides,we discussed the advantages and disadvantages of this technique in practical use.The pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was highlighted.Lastly,we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies(pharmacometrics,drug and vaccine developments,machine learning/artificial intelligence,among others)to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients.展开更多
Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine...Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways.However,there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites,which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments,alongside other potential side effects or adverse reactions.Therefore,an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods,clinical pharmacokinetics,and therapeutic drug monitoring of different TKIs.This paper provides a comprehensive overview of the advancements in pretreatment methods,such as protein precipitation(PPT),liquid-liquid extraction(LLE),solid-phase extraction(SPE),micro-SPE(μ-SPE),magnetic SPE(MSPE),and vortex-assisted dispersive SPE(VA-DSPE)achieved since 2017.It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)methods,capillary electrophoresis(CE),gas chromatography(GC),supercritical fluid chromatography(SFC)procedures,surface plasmon resonance(SPR)assays as well as novel nanoprobes-based biosensing techniques.In addition,a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.展开更多
BACKGROUND The efficacy and safety of anti-tumor necrosis factor-α(TNF-α)monoclonal antibody therapy[adalimumab(ADA)and infliximab(IFX)]with therapeutic drug monitoring(TDM),which has been proposed for inflammatory ...BACKGROUND The efficacy and safety of anti-tumor necrosis factor-α(TNF-α)monoclonal antibody therapy[adalimumab(ADA)and infliximab(IFX)]with therapeutic drug monitoring(TDM),which has been proposed for inflammatory bowel disease(IBD)patients,are still controversial.AIM To determine the efficacy and safety of anti-TNF-αmonoclonal antibody therapy with proactive TDM in patients with IBD and to determine which subtype of IBD patients is most suitable for proactive TDM interventions.METHODS As of July 2023,we searched for randomized controlled trials(RCTs)and observa-tional studies in PubMed,Embase,and the Cochrane Library to compare anti-TNF-αmonoclonal antibody therapy with proactive TDM with therapy with reactive TDM or empiric therapy.Pairwise and network meta-analyses were used to determine the IBD patient subtype that achieved clinical remission and to determine the need for surgery.RESULTS This systematic review and meta-analysis yielded 13 studies after exclusion,and the baseline indicators were balanced.We found a significant increase in the number of patients who achieved clinical remission in the ADA[odds ratio(OR)=1.416,95%confidence interval(CI):1.196-1.676]and RCT(OR=1.393,95%CI:1.182-1.641)subgroups and a significant decrease in the number of patients who needed surgery in the proactive vs reactive(OR=0.237,95%CI:0.101-0.558)and IFX+ADA(OR=0.137,95%CI:0.032-0.588)subgroups,and the overall risk of adverse events was reduced(OR=0.579,95%CI:0.391-0.858)according to the pairwise meta-analysis.Moreover,the network meta-analysis results suggested that patients with IBD treated with ADA(OR=1.39,95%CI:1.19-1.63)were more likely to undergo TDM,especially in comparison with patients with reactive TDM(OR=1.38,95%CI:1.07-1.77).CONCLUSION Proactive TDM is more suitable for IBD patients treated with ADA and has obvious advantages over reactive TDM.We recommend proactive TDM in IBD patients who are treated with ADA.展开更多
A sensitive, accurate and robust Liquid Chromatography Tandem Mass Spectrometry method has been developed and validated to measure voriconazole trough levels in human plasma. The plasma samples were mixed with flucona...A sensitive, accurate and robust Liquid Chromatography Tandem Mass Spectrometry method has been developed and validated to measure voriconazole trough levels in human plasma. The plasma samples were mixed with fluconazole as an Internal Standard and directed to protein precipitation and drug extraction. An aliquot of 1 μl was injected into the chromatographic system and separated by the Acquity BEH C18 column at a flow rate of 0.30 ml/min in a gradient mobile phase consisting of acetonitrile, Ultrapure water (UPW), methanol and formic acid. Voriconazole was detected by a Triple Quadrupole Detector (TQD) operating on Multiple Reaction Monitoring (MRM) and a positive ion mode Electrospray ionization (ESI) Q1 mass: 350.1 m/z, Q3 mass: 281.1 m/z. Method linearity of the calibration curve (0.10 - 8.00 μg/ml) indicated a correlation coefficient r ≥ 0.99. The intra and inter-assay accuracy was within 85% - 115% and the intra and inter-assay precision was ≤5.76%. Voriconazole recovery percentage was between 97.69 - 119.62%. The method was successively applied in routine voriconazole TDM.展开更多
Objective:Voriconazole(VCZ)is a triazole antifungal agent widely used in immunocompromised patients with suspected or proven invasive fungal infections.The achievement of therapeutic range(1-5 mg/L)is essential to max...Objective:Voriconazole(VCZ)is a triazole antifungal agent widely used in immunocompromised patients with suspected or proven invasive fungal infections.The achievement of therapeutic range(1-5 mg/L)is essential to maximize VCZ efficacy,as its pharmacokinetics is characterized by a wide inter-and intra-individual variability.This study aims to quantify the variability of VCZ trough concentrations in children and adolescents with haematological diseases and optimize therapeutic drug monitoring in clinical practice.Methods:We analysed the monitoring concentrations of all children(<18 years old)treated with VCZ in the Haematology Department of Robert DebréHospital between January 2014 and December 2016.Demographic,clinical data,and VCZ dosing and monitoring concentrations measured by high-performance liquid chromatography with ultraviolet detection(HPLC-UV)were analysed.Non-parametric tests were performed using SPSS IBM 24.0.Results:380 trough VCZ concentrations at steady-state(Ctrough,ss)were available in 79 children:45.6%had first Ctrough,ss in the therapeutic range at first monitoring,46.8%had Ctrough,ss below 1 mg/L and 7.6%had Ctrough,ss over 5 mg/L.Forty-one patients were treated with recommended doses but only 53%of them reached the therapeutic range.There was no impact of age,sex,biological parameters,or indication of VCZ on Ctrough,ss values.The number of Ctrough,ss in the therapeutic range increases with the number of monitoring per patient following dosage adaptations.Conclusion:The wide inter-and intra-individual variability of VCZ trough concentrations at recommended doses confirm the need to standardize VCZ monitoring and identify factors to be considered to prospectively adapt treatment for each patient.展开更多
Aim To develop a method to estimate population pharmacokinetic parameters with the limited sampling time points provided clinically during therapeutic drug monitoring. Methods Various simulations were attempted using ...Aim To develop a method to estimate population pharmacokinetic parameters with the limited sampling time points provided clinically during therapeutic drug monitoring. Methods Various simulations were attempted using a one-compartment open model with the first order absorption to determine PK parameter estimates with different sampling strategies as a validation of the method. The estimated parameters were further verified by comparing to the observed values. Results The samples collected at the single time point close to the non-informative sampling time point designed by this method led to bias and inaccurate parameter estimations. Furthermore, the relationship between the estimated non-informative sampling time points and the values of the parameter was examined. The non-informative sampling time points have been developed under some typical occasions and the results were plotted to show the tendency. As a result, one non-informative time point was demonstrated to be appropriate for clearance and two for both volume of distribution and constant of absorption in the present study. It was found that the estimates of the non-informative sampling time points developed in the method increase with increases of volume of distribution and the decrease of clearance and constant of absorption. Conclusion A rational sampling strategy during therapeutic drug monitoring can be established using the method present in the study.展开更多
Inflammatory bowel disease(IBD)is a chronic condition that significantly affects the quality of life of its patients.Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their ...Inflammatory bowel disease(IBD)is a chronic condition that significantly affects the quality of life of its patients.Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution,there remains a proportion of patients that do not respond or lose response to treatment.Therapeutic drug monitoring(TDM)involves measuring levels of serum drug concentrations and anti-drug antibodies.TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases.This was then introduced in IBD to rationalize primary non-response or secondary loss of response,given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure.The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure.This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations,in everyday practice.A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management,through an electronic search using PubMed and ScienceDirect.TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment.Despite a trend towards an association between clinical outcomes and drug concentrations,proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes.In the clinical setting,TDM has proven to be useful in managing IBD patients,and its use in the reactive setting,as an additional tool to help manage patients with treatment failure,is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.展开更多
In recent years,scientific researchers have increasingly become interested in noninvasive sampling methods for therapeutic drug monitoring and disease diagnosis.As a result,dried saliva spot(DSS),which is a sampling t...In recent years,scientific researchers have increasingly become interested in noninvasive sampling methods for therapeutic drug monitoring and disease diagnosis.As a result,dried saliva spot(DSS),which is a sampling technique for collecting dried saliva samples,has been widely used as an alternative matrix to serum for the detection of target molecules.Coupling the DSS method with a highly sensitive detection instrument improves the efficiency of the preparation and analysis of biological samples.Furthermore,dried blood spots,dried plasma spots,and dried matrix spots,which are similar to those of the DSS method,are discussed.Compared with alternative biological fluids used in dried spot methods,including serum,tears,urine,and plasma,saliva has the advantage of convenience in terms of sample collection from children or persons with disabilities.This review aims to provide integral strategies and guidelines for dried spot methods to analyze biological samples by illustrating several dried spot methods.Herein,we summarize recent advancements in DSS methods from June 2014 to March 2021 and discuss the advantages and disadvantages of the key aspects of this method,including sample preparation and method validation.Finally,we outline the challenges and prospects of such methods in practical applications.展开更多
Therapeutic drug monitoring(TDM)was one of most sought-after objective tools to determine therapeutic efficiency of different biologics and its role in the management of patients with inflammatory bowel disease(IBD)wa...Therapeutic drug monitoring(TDM)was one of most sought-after objective tools to determine therapeutic efficiency of different biologics and its role in the management of patients with inflammatory bowel disease(IBD)was regarded with great anticipation.But implementation of the TDM in clinical practice was challenged by several factors including uncertainty of the optimal cut-off values,assay variable sensitivity in detecting drug levels and antibodies and,most importantly,individual pharmacokinetics.While reactive TDM was embraced in clinical practice as a useful tool in assessing lack of response to therapy,the utility of proactive TDM in managing IBD therapy is still challenged by the lack of consistency between evidence.Described here,there are four groups of IBD patients for whom proactive TDM has the potential to greatly impact their therapeutic outcomes:Patients with perianal Crohn’s disease,patients with severe ulcerative colitis,pregnant women with IBD and children.As the future of IBD management moves towards personalizing treatment,TDM will be an important decision node in a machine learning based algorithm predicting the best strategy to maximize treatment results while minimizing the loss of response to therapy.展开更多
This study aimed to develop a guideline for therapeutic drug monitoring（TDM） of vancomycin. We adopted the new guideline definition from the Institute of Medicine（IOM）, adhered closely to the six domains of the Ap...This study aimed to develop a guideline for therapeutic drug monitoring（TDM） of vancomycin. We adopted the new guideline definition from the Institute of Medicine（IOM）, adhered closely to the six domains of the Appraisal of Guidelines for Research ＆ Evaluation Ⅱ（AGREE Ⅱ）, and made recommendations based on systematic reviews. We established a Guideline Steering Group and a Guideline Development Group, formulated 12 questions in the form of Population, Intervention, Comparison, Outcome（PICO） and completed a literature search. As far as we know, we will develop the first evidenced-based guideline for vancomycin TDM under the framework of the Grade of Recommendations Assessment, Development and Evaluation（GRADE）.展开更多
Recently,biological drugs have played a leading role in the treatment of inflammatory bowel disease,and therapeutic drug monitoring(TDM)may be useful in maximizing their effectiveness.TDM involves the measurement of s...Recently,biological drugs have played a leading role in the treatment of inflammatory bowel disease,and therapeutic drug monitoring(TDM)may be useful in maximizing their effectiveness.TDM involves the measurement of serum drug and anti-drug antibodies concentrations as the basis for dosage adjustments or drug conversions to achieve a higher response rate.We believe that concentration thresholds should be individualized based on patients’disease severity,extent and phenotype,and therapeutic purposes should also be considered,with higher cut-offs mainly needed for endoscopic and fistula healing than for symptomatic remission.Proactive and reactive TDM can help optimize treatment,especially in patients receiving anti-tumour necrosis factor,and guide dose adjustment or drug conversion with lower cost.TDM is a promising approach to achieve precision medicine and targeted medicine in the future.展开更多
Biologics and immunomodulators(IMM)are generally considered the most effective therapies for the treatment of ulcerative colitis and Crohn’s disease.However,despite the efficacy of these therapies,many patients eithe...Biologics and immunomodulators(IMM)are generally considered the most effective therapies for the treatment of ulcerative colitis and Crohn’s disease.However,despite the efficacy of these therapies,many patients either have a primary lack of response or a secondary loss of response to these medications.Therapeutic drug monitoring(TDM)is a systematic approach to managing such patients.In this review,we summarize the latest data on TDM,including reactive and proactive TDM,in patients with inflammatory bowel disease on biologics and/or IMM.展开更多
Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk t...Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk toxicity,treatment failure,and emergence of resistance,there is an urgent clinical need to perform therapeutic drug monitoring(TDM)to optimize the use of polymyxin B.It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use.We report a consensus on TDM guidelines for polymyxin B,as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society.The consensus panel was composed of clinicians,pharmacists,and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations,sample collection,reporting,and explanation of TDM results.The guidelines provide the first-ever consensus on conducting TDM of polymyxin B,and are intended to guide optimal clinical use.展开更多
In vivo lung perfusion(IVLP)is a novel isolated lung technique developed to enable the local,in situ administration of high-dose chemotherapy to treat metastatic lung cancer.Combination therapy using folinic acid(FOL)...In vivo lung perfusion(IVLP)is a novel isolated lung technique developed to enable the local,in situ administration of high-dose chemotherapy to treat metastatic lung cancer.Combination therapy using folinic acid(FOL),5-fluorouracil(F),and oxaliplatin(OX)(FOLFOX)is routinely employed to treat several types of solid tumours in various tissues.However,F is characterized by large interpatient variability with respect to plasma concentration,which necessitates close monitoring during treatments using of this compound.Since plasma drug concentrations often do not reflect tissue drug concentrations,it is essential to utilize sample-preparation methods specifically suited to monitoring drug levels in target organs.In this work,in vivo solid-phase microextraction(in vivo SPME)is proposed as an effective tool for quantitative therapeutic drug monitoring of FOLFOX in porcine lungs during pre-clinical IVLP and intravenous(IV)trials.The concomitant extraction of other endogenous and exogenous small molecules from the lung and their detection via liquid chromatography coupled to high resolution mass spectrometry(LC-HRMS)enabled an assessment of FOLFOX's impact on the metabolomic profile of the lung and revealed the metabolic pathways associated with the route of administration(IVLP vs.IV)and the therapy itself.This study also shows that the immediate instrumental analysis of metabolomic samples is ideal,as long-term storage at80℃ results in changes in the metabolite content in the sample extracts.展开更多
Lamotrigine (LTG) is a widely used antiepileptic drug (AED) for the treatment of new-onset, as well as refractory epilepsy. Due to the narrow treatment window and large individual variability in the pharmacokinetics a...Lamotrigine (LTG) is a widely used antiepileptic drug (AED) for the treatment of new-onset, as well as refractory epilepsy. Due to the narrow treatment window and large individual variability in the pharmacokinetics and pharmacodynamics of LTG, therapeutic drug monitoring (TDM) is necessary in clinical practice to guide dose adjustments. Individual differences and drug combinations can also affect protein binding rate, which further affects the unbound concentration of LTG. The unbound fraction is more closely related to adverse reactions and therapeutic efficacy than total concentration. Therefore, it may be more meaningful to determine the unbound LTG concentration in plasma than the total concentration.Unbound LTG in plasma was extracted by ultrafiltration. High-performance liquid chromatography (HPLC) was used to measure unbound LTG concentration. This method was validated by studies of its selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, recovery, and stability.The method was validated over a linear range of 0.2 to 10.0 μg·mL–1, and its LLOQ was 0.2 μg·mL–1. The method’s relative standard deviations (RSDs) for intra-day and inter-day precision were less than 15%, and its accuracy (RE) was ±4.69%. The recoveries of unbound LTG at three different concentrations satisfied the requirements for the analysis of biological samples, and no significant degradation of LTG was observed under different storage conditions.A simple HPLC method showed good performance when used to measure unbound LTG concentration. This method might be used to study the relationship between unboundLTG concentrations and its effectiveness according to TDM.展开更多
A reliable liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and va- lidated for the simultaneous determination of vancomycin and voriconazole in human plasma. The analytes and internal ...A reliable liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and va- lidated for the simultaneous determination of vancomycin and voriconazole in human plasma. The analytes and internal standard 10-hydroxycarbazepine were separated at a flow rate of 0.9 mL/min using a Zorbax SB-C18 column （50 min×4.6 mm, 2.7 μm）. Positive ion electrospray ionization was used to detect vancomycin, voriconazole and intrenal standard（IS） 10-hydroxycarbazepine followed by multiple reaction monitoring（MRM） of the transition at m/z 725.5→144.2, 350.3→281.0 and 253.1→208.0, respectively. The total run time for both vancomycin and voriconazole samples was 5 min; 0.30μg/mL was the lower limit of quantification. The precision of intraday and interday was no more than 12.4%. The method was successfully and resoundingly applied in therapeutic drug monitoring of 156 patients treated with vancomycin and voriconazole.展开更多
BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there ar...BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.展开更多
Background: Use of inappropriate amikacin dose is one of the most important factors in inducing toxicity, prolonged hospitalization as well as in increasing patient’s mortality. Objective: The aims of this study are ...Background: Use of inappropriate amikacin dose is one of the most important factors in inducing toxicity, prolonged hospitalization as well as in increasing patient’s mortality. Objective: The aims of this study are the analysis of amikacin dose, serum level and the examination of the effectiveness of the clinical pharmacologist (CP) therapeutic drug monitoring (TDM) intervention to guarantee the safety of amikacin use. Methods: This is a one-year retrospective observational chart review study, which evaluates amikacin dose, serum drug level, development of adverse effects in patients on amikacin with or without CP TDM consultation. Results: Amikacin was prescribed for 393 complex patients, with median age 83. Amikacin group (AG) included 140 (32%) courses with CP consultation (AG1) and 292 (68%) courses without CP consultation (AG2). The distribution of most study characteristics in both groups was similar including amikacin dose (9-10 mg/kg/day), renal failure (14%) and mortality (12%). Acceptance for CP consultation was in 46% of amikacin courses and dose changes were done in 63% after CP intervention. Prolonged antibiotic course (4.6 ± 1.5 vs 3.8 ± 1.6 days, p < 0.0001) and the patient’s hemodynamic instability (15% vs 7%, p = 0.01) were more frequent in the AG1 compared to the AG2. There was a strong association between CP consultation and prolonged hospitalization (p = 0.005), while no association between it and amikacin adverse effects, renal failure or mortality. Conclusions: There was no trend to reducing amikacin toxicity, days of hospitaliza tion or mortality in patients with CP consultation. CP TDM intervention was more in the management of complicated clinical situations. However, it is necessary to optimize it.展开更多
Invasive pulmonary aspergillosis(IPA)is a lethal infectious disease with high mortality in patients with liver failure.Early recognition of the risk factors prompting earlier diagnosis and treatment may improve the ou...Invasive pulmonary aspergillosis(IPA)is a lethal infectious disease with high mortality in patients with liver failure.Early recognition of the risk factors prompting earlier diagnosis and treatment may improve the outcomes.Voriconazole is recommended as the first-line drug for IPA,but hepatotoxicity limits its use in the context of liver diseases.We report a case of a 63-year-old female who was admitted to the Third Affiliated Hospital of Hebei Medical University due to IPA after glucocorticoid therapy for liver failure.The polymorphism of cytochrome P450(CYP)isoenzymes showed CYP2C19∗1/∗2 genotype associated with intermediate metabolism of voriconazole.However,the patient developed side effects such as skin rash,vomiting,hyperbilirubinemia,and alteration of consciousness,even if she received half of the recommended dosage for voriconazole.Therapeutic drug monitoring(TDM)was applied to guide the dosage adjustment of voriconazole in this patient,and consequently,the patient presented a favorable outcome.In conclusion,genotyping screening plus TDM dependent individualized treatment of voriconazole may improve the survival of liver failure patient with IPA.展开更多
Objective: To examine therapeutic drug monitoring in managing hyperbilirubinemia caused by capecitabine in patients with gastric adenocarcinoma with extensive liver metastases. Results: The initial liver function test...Objective: To examine therapeutic drug monitoring in managing hyperbilirubinemia caused by capecitabine in patients with gastric adenocarcinoma with extensive liver metastases. Results: The initial liver function tests showed an elevation of transaminases (aspartate amino transferase 615 UI/l, alanine aminotransferase 385.9 UI/l), hyperbilirubinemia (total bilirubin at 246.1 μmol/l), and alkaline phosphatase at 694.6 UI/l. We initiated capecitabine based combination chemotherapy, and the clinical pharmacist conducted a full-course medication monitoring of the patient’s treatment including design of individualized dosing regimens and monitoring of bilirubin, infection, cancer pain, parenteral nutrition support and adverse events. After 21 days of supervision by clinical pharmacist and clinicians, the patient’s bilirubin and transaminase decreased progressively, with aspartate aminotransferase, total bilirubin and alkaline phosphatase falling back to 57 UI/l, 69.8 μmol/l, 307.2 UI/l, respectively. The patient’s condition improved significantly at the time of discharge, with the jaundice subsided, and the bloating relieved. Conclusion: Due to adverse reactions, capecitabine requires medication monitoring during use. The relationship between effectiveness and adverse effects is controversial. Adverse reactions should not be the sole criterion for the use of drugs. Clinical pharmacists can improve the safety and effectiveness of patients’ medications and promote rational drug use by monitoring patients, which may be useful to help the doctors identify the high-risk patients for taking efficient treatment strategy decisions.展开更多
基金sponsored by the National Research Foundation of Korea(NRF)Grant funded by the Korean government(MSIT)(Grant No.:2018R1A5A2021242).
文摘The spread of tuberculosis(TB),especially multidrug-resistant TB and extensively drug-resistant TB,has strongly motivated the research and development of new anti-TB drugs.New strategies to facilitate drug combinations,including pharmacokinetics-guided dose optimization and toxicology studies of first-and second-line anti-TB drugs have also been introduced and recommended.Liquid chromatography-mass spectrometry(LC-MS)has arguably become the gold standard in the analysis of both endo-and exo-genous compounds.This technique has been applied successfully not only for therapeutic drug monitoring(TDM)but also for pharmacometabolomics analysis.TDM improves the effectiveness of treatment,reduces adverse drug reactions,and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target window.Based on TDM,the dose would be optimized individually to achieve favorable outcomes.Pharmacometabolomics is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs,aiding in the discovery of potential biomarkers for TB diagnostics,treatment monitoring,and outcome evaluation.This article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two decades.Besides,we discussed the advantages and disadvantages of this technique in practical use.The pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was highlighted.Lastly,we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies(pharmacometrics,drug and vaccine developments,machine learning/artificial intelligence,among others)to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients.
基金supported by the Natural Science Foundation of Liaoning Province,China(Grant No.:2023-MS-172).
文摘Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways.However,there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites,which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments,alongside other potential side effects or adverse reactions.Therefore,an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods,clinical pharmacokinetics,and therapeutic drug monitoring of different TKIs.This paper provides a comprehensive overview of the advancements in pretreatment methods,such as protein precipitation(PPT),liquid-liquid extraction(LLE),solid-phase extraction(SPE),micro-SPE(μ-SPE),magnetic SPE(MSPE),and vortex-assisted dispersive SPE(VA-DSPE)achieved since 2017.It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)methods,capillary electrophoresis(CE),gas chromatography(GC),supercritical fluid chromatography(SFC)procedures,surface plasmon resonance(SPR)assays as well as novel nanoprobes-based biosensing techniques.In addition,a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.
基金Supported by National College Students Innovation and Entrepreneurship Training Program of Shenyang Pharmaceutical University,No.202210163003.
文摘BACKGROUND The efficacy and safety of anti-tumor necrosis factor-α(TNF-α)monoclonal antibody therapy[adalimumab(ADA)and infliximab(IFX)]with therapeutic drug monitoring(TDM),which has been proposed for inflammatory bowel disease(IBD)patients,are still controversial.AIM To determine the efficacy and safety of anti-TNF-αmonoclonal antibody therapy with proactive TDM in patients with IBD and to determine which subtype of IBD patients is most suitable for proactive TDM interventions.METHODS As of July 2023,we searched for randomized controlled trials(RCTs)and observa-tional studies in PubMed,Embase,and the Cochrane Library to compare anti-TNF-αmonoclonal antibody therapy with proactive TDM with therapy with reactive TDM or empiric therapy.Pairwise and network meta-analyses were used to determine the IBD patient subtype that achieved clinical remission and to determine the need for surgery.RESULTS This systematic review and meta-analysis yielded 13 studies after exclusion,and the baseline indicators were balanced.We found a significant increase in the number of patients who achieved clinical remission in the ADA[odds ratio(OR)=1.416,95%confidence interval(CI):1.196-1.676]and RCT(OR=1.393,95%CI:1.182-1.641)subgroups and a significant decrease in the number of patients who needed surgery in the proactive vs reactive(OR=0.237,95%CI:0.101-0.558)and IFX+ADA(OR=0.137,95%CI:0.032-0.588)subgroups,and the overall risk of adverse events was reduced(OR=0.579,95%CI:0.391-0.858)according to the pairwise meta-analysis.Moreover,the network meta-analysis results suggested that patients with IBD treated with ADA(OR=1.39,95%CI:1.19-1.63)were more likely to undergo TDM,especially in comparison with patients with reactive TDM(OR=1.38,95%CI:1.07-1.77).CONCLUSION Proactive TDM is more suitable for IBD patients treated with ADA and has obvious advantages over reactive TDM.We recommend proactive TDM in IBD patients who are treated with ADA.
文摘A sensitive, accurate and robust Liquid Chromatography Tandem Mass Spectrometry method has been developed and validated to measure voriconazole trough levels in human plasma. The plasma samples were mixed with fluconazole as an Internal Standard and directed to protein precipitation and drug extraction. An aliquot of 1 μl was injected into the chromatographic system and separated by the Acquity BEH C18 column at a flow rate of 0.30 ml/min in a gradient mobile phase consisting of acetonitrile, Ultrapure water (UPW), methanol and formic acid. Voriconazole was detected by a Triple Quadrupole Detector (TQD) operating on Multiple Reaction Monitoring (MRM) and a positive ion mode Electrospray ionization (ESI) Q1 mass: 350.1 m/z, Q3 mass: 281.1 m/z. Method linearity of the calibration curve (0.10 - 8.00 μg/ml) indicated a correlation coefficient r ≥ 0.99. The intra and inter-assay accuracy was within 85% - 115% and the intra and inter-assay precision was ≤5.76%. Voriconazole recovery percentage was between 97.69 - 119.62%. The method was successively applied in routine voriconazole TDM.
文摘Objective:Voriconazole(VCZ)is a triazole antifungal agent widely used in immunocompromised patients with suspected or proven invasive fungal infections.The achievement of therapeutic range(1-5 mg/L)is essential to maximize VCZ efficacy,as its pharmacokinetics is characterized by a wide inter-and intra-individual variability.This study aims to quantify the variability of VCZ trough concentrations in children and adolescents with haematological diseases and optimize therapeutic drug monitoring in clinical practice.Methods:We analysed the monitoring concentrations of all children(<18 years old)treated with VCZ in the Haematology Department of Robert DebréHospital between January 2014 and December 2016.Demographic,clinical data,and VCZ dosing and monitoring concentrations measured by high-performance liquid chromatography with ultraviolet detection(HPLC-UV)were analysed.Non-parametric tests were performed using SPSS IBM 24.0.Results:380 trough VCZ concentrations at steady-state(Ctrough,ss)were available in 79 children:45.6%had first Ctrough,ss in the therapeutic range at first monitoring,46.8%had Ctrough,ss below 1 mg/L and 7.6%had Ctrough,ss over 5 mg/L.Forty-one patients were treated with recommended doses but only 53%of them reached the therapeutic range.There was no impact of age,sex,biological parameters,or indication of VCZ on Ctrough,ss values.The number of Ctrough,ss in the therapeutic range increases with the number of monitoring per patient following dosage adaptations.Conclusion:The wide inter-and intra-individual variability of VCZ trough concentrations at recommended doses confirm the need to standardize VCZ monitoring and identify factors to be considered to prospectively adapt treatment for each patient.
基金National Natural Science Foundation of China(Grant No. 30472165) the 985 Projects of the State KeyLaboratory of Natural and Biomimetic Drugs (Grant No.268705077280).
文摘Aim To develop a method to estimate population pharmacokinetic parameters with the limited sampling time points provided clinically during therapeutic drug monitoring. Methods Various simulations were attempted using a one-compartment open model with the first order absorption to determine PK parameter estimates with different sampling strategies as a validation of the method. The estimated parameters were further verified by comparing to the observed values. Results The samples collected at the single time point close to the non-informative sampling time point designed by this method led to bias and inaccurate parameter estimations. Furthermore, the relationship between the estimated non-informative sampling time points and the values of the parameter was examined. The non-informative sampling time points have been developed under some typical occasions and the results were plotted to show the tendency. As a result, one non-informative time point was demonstrated to be appropriate for clearance and two for both volume of distribution and constant of absorption in the present study. It was found that the estimates of the non-informative sampling time points developed in the method increase with increases of volume of distribution and the decrease of clearance and constant of absorption. Conclusion A rational sampling strategy during therapeutic drug monitoring can be established using the method present in the study.
文摘Inflammatory bowel disease(IBD)is a chronic condition that significantly affects the quality of life of its patients.Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution,there remains a proportion of patients that do not respond or lose response to treatment.Therapeutic drug monitoring(TDM)involves measuring levels of serum drug concentrations and anti-drug antibodies.TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases.This was then introduced in IBD to rationalize primary non-response or secondary loss of response,given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure.The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure.This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations,in everyday practice.A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management,through an electronic search using PubMed and ScienceDirect.TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment.Despite a trend towards an association between clinical outcomes and drug concentrations,proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes.In the clinical setting,TDM has proven to be useful in managing IBD patients,and its use in the reactive setting,as an additional tool to help manage patients with treatment failure,is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82173782 and 32160234)the Science and Technology Development Project,Education Department of Jilin Province of China(Grant No.:JJKH20191151KJ).
文摘In recent years,scientific researchers have increasingly become interested in noninvasive sampling methods for therapeutic drug monitoring and disease diagnosis.As a result,dried saliva spot(DSS),which is a sampling technique for collecting dried saliva samples,has been widely used as an alternative matrix to serum for the detection of target molecules.Coupling the DSS method with a highly sensitive detection instrument improves the efficiency of the preparation and analysis of biological samples.Furthermore,dried blood spots,dried plasma spots,and dried matrix spots,which are similar to those of the DSS method,are discussed.Compared with alternative biological fluids used in dried spot methods,including serum,tears,urine,and plasma,saliva has the advantage of convenience in terms of sample collection from children or persons with disabilities.This review aims to provide integral strategies and guidelines for dried spot methods to analyze biological samples by illustrating several dried spot methods.Herein,we summarize recent advancements in DSS methods from June 2014 to March 2021 and discuss the advantages and disadvantages of the key aspects of this method,including sample preparation and method validation.Finally,we outline the challenges and prospects of such methods in practical applications.
文摘Therapeutic drug monitoring(TDM)was one of most sought-after objective tools to determine therapeutic efficiency of different biologics and its role in the management of patients with inflammatory bowel disease(IBD)was regarded with great anticipation.But implementation of the TDM in clinical practice was challenged by several factors including uncertainty of the optimal cut-off values,assay variable sensitivity in detecting drug levels and antibodies and,most importantly,individual pharmacokinetics.While reactive TDM was embraced in clinical practice as a useful tool in assessing lack of response to therapy,the utility of proactive TDM in managing IBD therapy is still challenged by the lack of consistency between evidence.Described here,there are four groups of IBD patients for whom proactive TDM has the potential to greatly impact their therapeutic outcomes:Patients with perianal Crohn’s disease,patients with severe ulcerative colitis,pregnant women with IBD and children.As the future of IBD management moves towards personalizing treatment,TDM will be an important decision node in a machine learning based algorithm predicting the best strategy to maximize treatment results while minimizing the loss of response to therapy.
文摘This study aimed to develop a guideline for therapeutic drug monitoring（TDM） of vancomycin. We adopted the new guideline definition from the Institute of Medicine（IOM）, adhered closely to the six domains of the Appraisal of Guidelines for Research ＆ Evaluation Ⅱ（AGREE Ⅱ）, and made recommendations based on systematic reviews. We established a Guideline Steering Group and a Guideline Development Group, formulated 12 questions in the form of Population, Intervention, Comparison, Outcome（PICO） and completed a literature search. As far as we know, we will develop the first evidenced-based guideline for vancomycin TDM under the framework of the Grade of Recommendations Assessment, Development and Evaluation（GRADE）.
文摘Recently,biological drugs have played a leading role in the treatment of inflammatory bowel disease,and therapeutic drug monitoring(TDM)may be useful in maximizing their effectiveness.TDM involves the measurement of serum drug and anti-drug antibodies concentrations as the basis for dosage adjustments or drug conversions to achieve a higher response rate.We believe that concentration thresholds should be individualized based on patients’disease severity,extent and phenotype,and therapeutic purposes should also be considered,with higher cut-offs mainly needed for endoscopic and fistula healing than for symptomatic remission.Proactive and reactive TDM can help optimize treatment,especially in patients receiving anti-tumour necrosis factor,and guide dose adjustment or drug conversion with lower cost.TDM is a promising approach to achieve precision medicine and targeted medicine in the future.
文摘Biologics and immunomodulators(IMM)are generally considered the most effective therapies for the treatment of ulcerative colitis and Crohn’s disease.However,despite the efficacy of these therapies,many patients either have a primary lack of response or a secondary loss of response to these medications.Therapeutic drug monitoring(TDM)is a systematic approach to managing such patients.In this review,we summarize the latest data on TDM,including reactive and proactive TDM,in patients with inflammatory bowel disease on biologics and/or IMM.
基金the Shanghai Leading Talents Award,Shanghai Municipal Health Commission(No.LJ2016-01)the Clinical Research Plan of Shanghai Hospital Development Center(No.SHDC2022CRW004)。
文摘Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk toxicity,treatment failure,and emergence of resistance,there is an urgent clinical need to perform therapeutic drug monitoring(TDM)to optimize the use of polymyxin B.It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use.We report a consensus on TDM guidelines for polymyxin B,as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society.The consensus panel was composed of clinicians,pharmacists,and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations,sample collection,reporting,and explanation of TDM results.The guidelines provide the first-ever consensus on conducting TDM of polymyxin B,and are intended to guide optimal clinical use.
基金Institutes of Health Research(CIHR)-Natural Sciences and Engineering Research Council(NSERC)of the Canada Collaborative Health Research Projects program for their financial support(Grant No.:355935)the Natural Sciences and Engineering Research Council of Canada Industrial Research Chair(IRC)program。
文摘In vivo lung perfusion(IVLP)is a novel isolated lung technique developed to enable the local,in situ administration of high-dose chemotherapy to treat metastatic lung cancer.Combination therapy using folinic acid(FOL),5-fluorouracil(F),and oxaliplatin(OX)(FOLFOX)is routinely employed to treat several types of solid tumours in various tissues.However,F is characterized by large interpatient variability with respect to plasma concentration,which necessitates close monitoring during treatments using of this compound.Since plasma drug concentrations often do not reflect tissue drug concentrations,it is essential to utilize sample-preparation methods specifically suited to monitoring drug levels in target organs.In this work,in vivo solid-phase microextraction(in vivo SPME)is proposed as an effective tool for quantitative therapeutic drug monitoring of FOLFOX in porcine lungs during pre-clinical IVLP and intravenous(IV)trials.The concomitant extraction of other endogenous and exogenous small molecules from the lung and their detection via liquid chromatography coupled to high resolution mass spectrometry(LC-HRMS)enabled an assessment of FOLFOX's impact on the metabolomic profile of the lung and revealed the metabolic pathways associated with the route of administration(IVLP vs.IV)and the therapy itself.This study also shows that the immediate instrumental analysis of metabolomic samples is ideal,as long-term storage at80℃ results in changes in the metabolite content in the sample extracts.
基金Liaoning Province Natural Science Foundation of China(Grant No.2013021079)
文摘Lamotrigine (LTG) is a widely used antiepileptic drug (AED) for the treatment of new-onset, as well as refractory epilepsy. Due to the narrow treatment window and large individual variability in the pharmacokinetics and pharmacodynamics of LTG, therapeutic drug monitoring (TDM) is necessary in clinical practice to guide dose adjustments. Individual differences and drug combinations can also affect protein binding rate, which further affects the unbound concentration of LTG. The unbound fraction is more closely related to adverse reactions and therapeutic efficacy than total concentration. Therefore, it may be more meaningful to determine the unbound LTG concentration in plasma than the total concentration.Unbound LTG in plasma was extracted by ultrafiltration. High-performance liquid chromatography (HPLC) was used to measure unbound LTG concentration. This method was validated by studies of its selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, recovery, and stability.The method was validated over a linear range of 0.2 to 10.0 μg·mL–1, and its LLOQ was 0.2 μg·mL–1. The method’s relative standard deviations (RSDs) for intra-day and inter-day precision were less than 15%, and its accuracy (RE) was ±4.69%. The recoveries of unbound LTG at three different concentrations satisfied the requirements for the analysis of biological samples, and no significant degradation of LTG was observed under different storage conditions.A simple HPLC method showed good performance when used to measure unbound LTG concentration. This method might be used to study the relationship between unboundLTG concentrations and its effectiveness according to TDM.
基金Supported by the National Natural Science Foundation of China（Nos.81603182, 81430087, 81673396）.
文摘A reliable liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and va- lidated for the simultaneous determination of vancomycin and voriconazole in human plasma. The analytes and internal standard 10-hydroxycarbazepine were separated at a flow rate of 0.9 mL/min using a Zorbax SB-C18 column （50 min×4.6 mm, 2.7 μm）. Positive ion electrospray ionization was used to detect vancomycin, voriconazole and intrenal standard（IS） 10-hydroxycarbazepine followed by multiple reaction monitoring（MRM） of the transition at m/z 725.5→144.2, 350.3→281.0 and 253.1→208.0, respectively. The total run time for both vancomycin and voriconazole samples was 5 min; 0.30μg/mL was the lower limit of quantification. The precision of intraday and interday was no more than 12.4%. The method was successfully and resoundingly applied in therapeutic drug monitoring of 156 patients treated with vancomycin and voriconazole.
基金Supported by the National Natural Science Foundation of China,No.82020108031,No.81973398,and No.82104290Guangdong Provincial Key Laboratory of Construction Foundation,No.2020B1212060034Guangdong Basic and Applied Basic Research Foundation,No.2022A1515012549 and No.2023A1515012667.
文摘BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.
文摘Background: Use of inappropriate amikacin dose is one of the most important factors in inducing toxicity, prolonged hospitalization as well as in increasing patient’s mortality. Objective: The aims of this study are the analysis of amikacin dose, serum level and the examination of the effectiveness of the clinical pharmacologist (CP) therapeutic drug monitoring (TDM) intervention to guarantee the safety of amikacin use. Methods: This is a one-year retrospective observational chart review study, which evaluates amikacin dose, serum drug level, development of adverse effects in patients on amikacin with or without CP TDM consultation. Results: Amikacin was prescribed for 393 complex patients, with median age 83. Amikacin group (AG) included 140 (32%) courses with CP consultation (AG1) and 292 (68%) courses without CP consultation (AG2). The distribution of most study characteristics in both groups was similar including amikacin dose (9-10 mg/kg/day), renal failure (14%) and mortality (12%). Acceptance for CP consultation was in 46% of amikacin courses and dose changes were done in 63% after CP intervention. Prolonged antibiotic course (4.6 ± 1.5 vs 3.8 ± 1.6 days, p < 0.0001) and the patient’s hemodynamic instability (15% vs 7%, p = 0.01) were more frequent in the AG1 compared to the AG2. There was a strong association between CP consultation and prolonged hospitalization (p = 0.005), while no association between it and amikacin adverse effects, renal failure or mortality. Conclusions: There was no trend to reducing amikacin toxicity, days of hospitaliza tion or mortality in patients with CP consultation. CP TDM intervention was more in the management of complicated clinical situations. However, it is necessary to optimize it.
基金This work was supported by the National Natural Science Foundation of China(No.81900536).
文摘Invasive pulmonary aspergillosis(IPA)is a lethal infectious disease with high mortality in patients with liver failure.Early recognition of the risk factors prompting earlier diagnosis and treatment may improve the outcomes.Voriconazole is recommended as the first-line drug for IPA,but hepatotoxicity limits its use in the context of liver diseases.We report a case of a 63-year-old female who was admitted to the Third Affiliated Hospital of Hebei Medical University due to IPA after glucocorticoid therapy for liver failure.The polymorphism of cytochrome P450(CYP)isoenzymes showed CYP2C19∗1/∗2 genotype associated with intermediate metabolism of voriconazole.However,the patient developed side effects such as skin rash,vomiting,hyperbilirubinemia,and alteration of consciousness,even if she received half of the recommended dosage for voriconazole.Therapeutic drug monitoring(TDM)was applied to guide the dosage adjustment of voriconazole in this patient,and consequently,the patient presented a favorable outcome.In conclusion,genotyping screening plus TDM dependent individualized treatment of voriconazole may improve the survival of liver failure patient with IPA.
文摘Objective: To examine therapeutic drug monitoring in managing hyperbilirubinemia caused by capecitabine in patients with gastric adenocarcinoma with extensive liver metastases. Results: The initial liver function tests showed an elevation of transaminases (aspartate amino transferase 615 UI/l, alanine aminotransferase 385.9 UI/l), hyperbilirubinemia (total bilirubin at 246.1 μmol/l), and alkaline phosphatase at 694.6 UI/l. We initiated capecitabine based combination chemotherapy, and the clinical pharmacist conducted a full-course medication monitoring of the patient’s treatment including design of individualized dosing regimens and monitoring of bilirubin, infection, cancer pain, parenteral nutrition support and adverse events. After 21 days of supervision by clinical pharmacist and clinicians, the patient’s bilirubin and transaminase decreased progressively, with aspartate aminotransferase, total bilirubin and alkaline phosphatase falling back to 57 UI/l, 69.8 μmol/l, 307.2 UI/l, respectively. The patient’s condition improved significantly at the time of discharge, with the jaundice subsided, and the bloating relieved. Conclusion: Due to adverse reactions, capecitabine requires medication monitoring during use. The relationship between effectiveness and adverse effects is controversial. Adverse reactions should not be the sole criterion for the use of drugs. Clinical pharmacists can improve the safety and effectiveness of patients’ medications and promote rational drug use by monitoring patients, which may be useful to help the doctors identify the high-risk patients for taking efficient treatment strategy decisions.
