Guidelines For Therapeutic Drug Monitoring Research Articles

Emerging therapeutic drug monitoring of anti-infective agents in Australian hospitals: Availability, performance and barriers to implementation.

The purpose of the study was to assess the status of emerging therapeutic drug monitoring (TDM) of anti-infective agents in Australian hospitals. A nationwide cross-sectional survey of all Australian hospitals operating in the public and private health sector was conducted between August and September 2019. The survey consisted of questions regarding institutional TDM practice for anti-infective agents and clinical vignettes specific to β-lactam antibiotics. Responses were received from 82 unique institutions, representing all Australian states and territories. All 29 (100%) of principal referral (major) hospitals in Australia participated. Five surveys were partially complete. Only 25% (20/80) of hospitals had TDM testing available on-site for any of the eight emerging TDM candidates considered: β-lactam antibiotics, anti-tuberculous agents, flucytosine, fluoroquinolones, ganciclovir, human immunodeficiency virus (HIV) drugs, linezolid and teicoplanin. A considerable time lag was noted between TDM sampling and reporting of results. With respect to β-lactam antibiotic TDM, variable indications, pharmacodynamic targets and sampling times were identified. The three greatest barriers to local TDM performance were found to be (1) lack of timely assays/results, (2) lack of institutional-wide expertise and/or training and (3) lack of guidelines to inform ordering of TDM and interpretation of results. The majority of respondents favoured establishing national TDM guidelines and increasing access to dose prediction software, at rates of 89% and 96%, respectively. Translating emerging TDM evidence into daily clinical practice is slow. Concerted efforts are required to address the barriers identified and facilitate the implementation of standardised practice.

The impact of an electronic hospital system on therapeutic drug monitoring.

Australian hospitals have undergone a transformation with both a review and expansion of traditional roles of healthcare professionals and the implementation of an ieMR. The implementation of an ieMR brings large scale organizational change within the health system especially for staff with direct patient contact. This is changing the future of healthcare and the roles of healthcare professionals. There is minimal research on the impact of these electronic systems on the people and processes required to realise the improvements in patient care such as therapeutic drug monitoring (TDM) and the role of the pharmacist within the TDM process. The literature has discussed the use of computerised programs to assist with the interpretation of results and calculating of doses but the impact of an ieMR on the TDM process has not been discussed. This study undertook a retrospective analysis at an Australian tertiary hospital to investigate the impact of a digital hospital system on TDM within the facility. A 2-year retrospective audit was conducted on TDM at an Australian Tertiary Hospital. The periods were 2016 (a paper-based hospital) and 2018 (ieMR). Patients were identified using the pathology database. Patients were excluded if under the age of 18, in an outpatient setting or the emergency department. Progress notes, medication charts, ieMR and other relevant pathology were reviewed. They were assessed for appropriateness of the timing of collection, compliance to recommended TDM guidelines, and pharmacist documentation. A total of 2926 observations were included in the analysis. There was as similar percentage of appropriately collected samples between the paper-based system (2016) and the digital hospital system (2018) with 59% and 58% respectively. Results of logistic regression analysis models show the effect of year was not significant with regards to TDM for either a sample being appropriate or the dose adjustment being appropriate. Samples for TDM were more likely to be appropriate if the pharmacist had documented advice but less likely with regards to appropriate dose adjustment. This study considered the effect of introducing a hospital wide digital system on TDM processes. Overall, the results indicate no difference between the paper-based system and ieMR for appropriate samples and doses adjustments. To our knowledge, this is the first study of this kind looking at the impact of a digital hospital system on TDM. The introduction of a digital hospital system does not appear to have made improvement on the effective use of TDM. Inappropriate sampling as seen in this study can lead to ineffective clinical management of patients, inefficient use of time, and waste of financial resources. Further work is required to incorporate specific guidance and recommendations within the digital system to optimize TDM.

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs-Influence of Smoking Behavior and Inflammation on Pharmacokinetics.

Both inflammation and smoking can influence a drug’s pharmacokinetic properties, i.e., its liberation, absorption, distribution, metabolism, and elimination. Depending on, e.g., pharmacogenetics, these changes may alter treatment response or cause serious adverse drug reactions and are thus of clinical relevance. Antipsychotic drugs, used in the treatment of psychosis and schizophrenia, should be closely monitored due to multiple factors (e.g., the narrow therapeutic window of certain psychotropic drugs, the chronicity of most mental illnesses, and the common occurrence of polypharmacotherapy in psychiatry). Therapeutic drug monitoring (TDM) aids with drug titration by enabling the quantification of patients’ drug levels. Recommendations on the use of TDM during treatment with psychotropic drugs are presented in the Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology; however, data on antipsychotic drug levels during inflammation or after changes in smoking behavior—both clinically relevant in psychiatry—that can aid clinical decision making are sparse. The following narrative review provides an overview of relevant literature regarding TDM in psychiatry, particularly in the context of second- and third-generation antipsychotic drugs, inflammation, and smoking behavior. It aims to spread awareness regarding TDM (most pronouncedly of clozapine and olanzapine) as a tool to optimize drug safety and provide patient-tailored treatment.

Quality Improvement Methodology Optimizes Infliximab Levels in Pediatric Patients with Inflammatory Bowel Disease.

We participated in Intermediate Improvement Science Series, a course at Cincinnati Children's Hospital Medical Center designed to catalyze change using quality improvement methodology. We implemented interventions through plan-do-study-act cycles. Our outcome measure was balanced by 2 process measures to determine what actions impacted improvement. These measures included the percentage of infusion plans revised in response to a drug level <5 μg/mL and the proportion of plans for which a follow-up drug level was ordered. We increased the percentage of infusion plans revised before the next infusion from 63% to 87% and the percentage of plans that had an appropriate drug level recheck from 61% to 83% from July 2017 to January 2018. We increased the percentage of patients with an infliximab level >5 μg/mL, and results checked in the last 12 months, from 73% to 80%. Quality improvement methodology was effective in improving provider adherence to infliximab therapeutic drug monitoring guidelines. Improvement in adherence to guidelines directly improved the percentage of patients achieving target infliximab levels at any time during infliximab therapy.

Vancomycin dosing and therapeutic drug monitoring practices: guidelines versus real-life.

Background Correct dosing and therapeutic drug monitoring (TDM) practices are essential when aiming for optimal vancomycin treatment. Objective To assess target attainment after initial dosing and dose adjustments, and to determine compliance to dosing and TDM guidelines. Setting Tertiary care university hospital in Belgium. Method A chart review was performed in 150 patients, ranging from preterm infants to adults, treated intravenously with vancomycin. Patient characteristics, dosing and TDM data were compared to evidence-based hospital guidelines. Main outcome measures Target attainment of vancomycin after initial dosing and dose adjustments. Results Subtherapeutic concentrations were measured in 68% of adults, in 76% of children and in 52% of neonates after treatment initiation. Multiple dose adaptations (median 2, Q1 1-Q3 2) were required for target attainment, whilst more than 20% of children and neonates never reached targeted concentrations. Regarding compliance to the hospital guideline, some points of improvement were identified: omitted dose adjustment in adults with decreased renal function (53%), delayed sampling (16% in adults, 31% in children) and redundant sampling (34% of all samples in adults, 12% in children, 13% in neonates). Conclusion Target attainment for vancomycin with current dosing regimens and TDM is poor in all age groups. Besides, human factors should not be ignored when aiming for optimal treatment. This study reflects an ongoing challenge in clinical practice and highlights the need for optimization of vancomycin dosing strategies and improvement of awareness of all health care professionals involved.

Assessment of the Implementation of AUC Dosing and Monitoring Practices With Vancomycin at Hospitals Across the United States

Introduction: The latest vancomycin therapeutic drug monitoring guidelines for serious MRSA infections have made a pivotal change in dosing, switching from targeting trough levels to AUC dosing. Because of these new recommendations, antimicrobial stewardship programs across the country are tasked with implementing AUC based dosing. Objectives: To assess plans for institutional adoption of vancomycin AUC dosing programs and perceptions of currently used programs in hospitals across the US. Methods: An electronic survey was distributed to members of the American College of Clinical Pharmacy IDprn Listserv and American Society of Health-System Pharmacists between May and June 2020 to assess current institutional vancomycin dosing. Institutional program use and multiple software user parameters were analyzed using descriptive statistics. Results: Two hundred two pharmacists responded to the survey with the majority practicing in institutions with 251-500 beds. Most respondents have yet to implement AUC dosing (142/202, 70.3%) with many of them planning to do so in the next year (81/142, 57.0%). Of those that already implemented AUC dosing programs, purchased Bayesian software (23/60, 38.3%) and homemade software (21/60, 35.0%) were the 2 methods most frequently utilized. Purchased Bayesian software users were more likely to recommend their software to other institutions and ranked user friendliness higher compared to non-purchased software. Conclusion: Most respondents have not made the switch to vancomycin AUC dosing, but there is a growing interest with many institutions looking to adopt a program within the next year.

基于集成化多柱二维液相色谱系统分析血清中的氨磺必利

快速准确的治疗药物监测对于临床上确保患者用药有效性及安全性至关重要,同时也能够确定患者用药依从性,制定个性化给药方案。该文以两支疏水性略有差异的反相分离柱Supersil ODS2和SinoChrom ODS-BP,及强阳离子交换捕集柱Supersil SCX构建了基于集成化的多柱二维液相色谱系统。通过二维色谱接口,以pH 3.0的磷酸缓冲液调整第一维分离后的洗脱液组成,降低有机相含量并维持pH,改善了中心切割模式下样品转移和捕集的效率。利用该多柱二维液相色谱系统发展了血清中氨磺必利的二维液相色谱检测方法,血清样品经过高氯酸和甲醇混合液沉淀蛋白质并离心后直接300 μL大体积进样,以乙腈/磷酸缓冲液(25 mmol/L, pH 3.0)(20/80, v/v)作为第一维分离流动相,磷酸缓冲液(25 mmol/L, pH 3.0)作为捕集过程的稀释流动相,乙腈/磷酸缓冲液(25 mmol/L, pH 7.0)(25/75, v/v)作为第二维分离流动相,12 min内即可完成分析。方法在10~200 ng/mL的范围内线性相关性良好(r=0.9998)。样品在50 ng/mL和100 ng/mL两个加标浓度下的回收率稳定,在73.7%~76.8%之间。方法的检出限为7.28 ng/mL,定量限为24.27 ng/mL,能够满足《神经精神药理学治疗药物检测共识指南》中推荐的药物监控范围要求。由于该系统日常使用及维护成本较低,且能够实现自动化分析,故该方法适合在临床上用于治疗药物监测研究。

A guide to therapeutic drug monitoring of β-lactam antibiotics.

Therapeutic drug monitoring (TDM) opens the door to personalized medicine, yet it is infrequently applied to β-lactam antibiotics, one of the most commonly prescribed drug classes in the hospital setting. As we continue to understand more about β-lactam pharmacodynamics (PD) and wide inter- and intra-patient variability in pharmacokinetics (PK), the utility of TDM has become increasingly apparent. For β-lactams, the time that free concentrations remain above the minimum inhibitory concentration (MIC) as a function of the dosing interval (%fT>MIC) has been shown to best predict antibacterial effect. Many studies have shown that β-lactam %fT>MIC exposures are often suboptimal across a wide variety of disease states and clinical settings. A limitation to implementing this practice is the general lack of understanding on how to best operationalize this intervention and interpret the results. The instrumentation and expertise needed to quantify β-lactams for TDM is rarely available locally, but certain laboratories advertise these services and perform them regularly. Familiarity with the modalities and nuances of antimicrobial susceptibility testing is crucial to establishing β-lactam concentration targets that meet the relevant exposure thresholds. Evaluation of these concentrations is best accomplished using population PK software and Bayesian modeling, for which a multitude of programs are available. While TDM of β-lactams has shown an ability to increase the rate of target attainment, there is currently limited evidence to suggest that it leads to improved clinical outcomes. Although consensus guidelines for β-lactam TDM do not exist in the United States, guidance would help to promote this important practice and better standardize the approach across institutions. Herein, we discuss the basis for β-lactam TDM, review supporting evidence, and provide guidance for implementation in specific patient populations.

Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin: 2020 Update by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

Clinical practice guidelines or recommendations often require timely and regular updating as new evidence emerges, because this can alter the risk-benefit trade-off. The scientific process of developing and updating guidelines accompanied by adequate implementation can improve outcomes. To promote better management of patients receiving vancomycin therapy, we updated the guideline for the therapeutic drug monitoring (TDM) of vancomycin published in 2015. Our updated recommendations complied with standards for developing trustworthy guidelines, including timeliness and rigor of the updating process, as well as the use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We also followed the methodology handbook published by the National Institute for Health and Clinical Excellence and the Spanish National Health System. We partially updated the 2015 guideline. Apart from adults, the updated guideline also focuses on pediatric patients and neonates requiring intravenous vancomycin therapy. The guideline recommendations involve a broadened range of patients requiring TDM, modified index of TDM (both 24-hour area under the curve and trough concentration), addition regarding the necessity and timing of repeated TDM, and initial dose for specific subpopulations. Overall, 1 recommendation was deleted and 3 recommendations were modified. Eleven new recommendations were added, and no recommendation was made for 2 clinical questions. We updated an evidence-based guideline regarding the TDM of vancomycin using a rigorous and multidisciplinary approach. The updated guideline provides more comprehensive recommendations to inform rational and optimized vancomycin use and is thus of greater applicability.

A survey of therapeutic drug monitoring in a teaching hospital.

ObjectivesTherapeutic drug monitoring (TDM) is one of the tools that aim to improve and ensure the best therapeutic effects while avoiding drug toxicity. This study aimed to identify the clinical utilization and application of TDM at a major teaching hospital in Jeddah.MethodsA cross sectional survey of the clinical utilization and application of TDM at King Abdulaziz University Teaching Hospital across nurses in medical, surgical, pediatric, and intensive care units. The sample size (n = 130) represented 30% of the nursing population. The collection of questionnaires started on the 31st of January 2019 and was completed by the 10th of March 2019.ResultsThe indication to use TDM was well-known to respondents. However, only 64% of respondents reported collection and measuring of the correct drug levels at a precise sampling time with no specific protocols being followed for each drug. Moreover, only 53% reported that the drug levels were being re-measured and adequately monitored for the right indication and proper sampling time. Regarding the presence of clinical pharmacists, 70% of the respondents indicated that no clinical pharmacist worked in their department.ConclusionResults demonstrate that appropriate sampling time was not used for the majority of monitored drugs. In the absence of a TDM request form, this finding probably indicates the lack of national or local TDM guidelines. In conclusion, TDM services, which include standardized forms, references, and an active clinical pharmacist will likely improve the application of TDM.

Development of Sensitive and High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Method for Quantification of Haloperidol in Human Plasma with Phospholipid Removal Pretreatment.

Haloperidol, butyrophenone derivative, is a typical antipsychotic drug used in the treatment of schizophrenia, manic phase of bipolar disorder, and acute psychomotor agitations. According to the recent guidelines for therapeutic drug monitoring, it is strongly recommended to measure plasma level during the therapy with haloperidol. The objective of this study was to develop and validate a simple liquid chromatography-tandem mass spectrometry-based method to quantitate haloperidol in human plasma. After one-step extraction procedure using OSTROTM plate, gradient elution on Acquity UPLC BEH C18 (50 ×2.1mm, 1.7μm) column over 3.2 min was performed. The detection was conducted on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode in positive ionization mode with transitions at m/z 376.29 → 165.14 and m/z 380.28 → 169.17 for haloperidol and haloperidol-d4 (used as an internal standard), respectively. The method was fully validated to cover wide concentration range of 0.05-80 ng/mL in human plasma and meets the criteria for the selectivity, linearity and lower limit of detection, precision and accuracy, matrix effect, extraction recovery, carryover, dilution integrity and stability. The extraction recovery was nearly 100%, and no significant matrix effects were observed. Therefore, the method is applicable to routine therapeutic drug monitoring in patients' plasma.

Appropriate therapeutic drug monitoring of antibiotics contributed to lower nephrotoxicity .

The main objective of this study was to evaluate therapeutic drug monitoring (TDM) services for antibiotics and investigate the association between non-adherence to TDM guidelines and development of nephrotoxicity. This retrospective study was conducted using electronic health records of hospitalized patients who received antibiotics for which TDM was requested over a 1-year period. Adherence to TDM guidelines was measured by reviewing appropriate indications, sampling times, result reporting, and clinical pharmacist interventions. A total of 1,179 patients (65% males), for whom TDM was requested during 2017 were included. Upon an assessment of the appropriateness of sampling times, we found that ~15% of samples were drawn at the wrong time, and in over 46% of the cases, TDM service was inconsistent with guidelines. Further, although physicians accepted the majority of pharmacists' interventions related to the TDM service, the pharmacist did not provide any recommendation in more than one-third of the cases. Nephrotoxicity was the most common adverse reaction and was observed in 19.5% of the patients. Furthermore, we found a significant correlation between nephrotoxicity and non-adherence to TDM guidelines (OR = 1.47; p = 0.014). Our study shows that adherence to the guidelines and implementation of an appropriate and effective TDM service for antibiotics increases the number of patients with adequate plasma levels, optimizes clinical outcomes, and minimizes toxicities. Moreover, there was a strong association between non-adherence to the TDM guidelines and development of nephrotoxicity. The findings suggest that adherence to TDM guidelines not only improves clinical practice but also contributes to the reduction of the cost associated with the development of nephrotoxicity.

Vancomycin therapeutic drug monitoring in paediatrics.

Vancomycin guidelines for therapeutic drug monitoring (TDM) aim to maximise efficacy while minimising toxicity and resistance. Vancomycin is effective against Staphylococcus aureus when it achieves area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) > 400. Studies in children have shown that target trough concentrations poorly correlate to AUC/MIC > 400; however, they are used in practice for clinical convenience. This review in paediatric inpatients aims to audit performance against TDM guidelines and consider what changes are needed to optimise vancomycin monitoring. Vancomycin prescriptions in patients younger than 18 years old were collected over a 15-month period. Primary outcome measures were vancomycin initial dose (mg/kg/day) and the timing and result of first trough concentration (mg/L). Secondary outcome measures were the numbers achieving recommended targets and whether appropriate dose adjustments were made in response to TDM. A total of 133 courses reached the time when TDM should occur. Average patient age was 6.5 years, and the average initial dose was 52.55 mg/kg/day (range 19.05-86.54 mg/kg). Only 25% of courses (n = 34) had a trough concentration measured at the recommended time. The mean trough concentration was 11.6 mg/L (range < 2.0-39.7). Of 40 patients with a low trough concentration, 50% continued without dose adjustment. As shown in the literature, there is a poor correlation between the vancomycin dose given and the trough concentration achieved. Given that recommendations for trough concentration monitoring are designed to simplify the process yet are poorly adhered to, a strategic plan to address these issues is needed.

Quality of therapeutic drug monitoring guidelines is suboptimal: an evaluation using the Appraisal of Guidelines for Research and Evaluation II instrument

ObjectivesAlthough therapeutic drug monitoring (TDM) guidelines are available, systematic evaluations of their methodological quality are scarce. This study aimed to assess the quality of current TDM guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Study Design and SettingWe performed a systematic search to identify the relevant TDM guidelines in PubMed, EMBASE, CNKI, Wan Fang Database, CBM, VIP, four main guideline databases (NICE, NGC, GIN, and WHO guideline databases), and official websites of the governments and societies associated with TDM from the inception date to May 2018. Four independent appraisers rated the quality of each TDM guideline using the AGREE II instrument, and the mean score of each AGREE II item was calculated. The overall agreement among the appraisers was evaluated using the intraclass correlation coefficient (ICC). ResultsTwenty-eight TDM guidelines satisfied the eligibility criteria from among 12,235 references. The overall agreement among the appraisers was substantial (0.700–0.880). The mean scores for the six AGREE II domains were scope and purpose, 67.7% (95% CI, 64.0–71.4%); stakeholder involvement, 39.8% (95% CI, 33.3–46.3%); rigor of development, 36.0% (95% CI, 28.1–43.9%); clarity and presentation, 61.6% (95% CI, 55.7–67.4%); applicability, 30.6% (95% CI, 26.4–34.8%); and editorial independence, 49.2% (95% CI, 40.0–58.6%). The reviewers recommended only four guidelines, and most of the TDM guidelines were rated as “recommended with modifications.” ConclusionOverall, the quality of TDM guidelines is suboptimal according to the evaluation using the AGREE II instrument. The domains of applicability, rigor of development, stakeholder involvement, and editorial independence of the guidelines need to be reported. In addition, guideline developers closely adhering to the AGREE II instrument and the Grading of Recommendations Assessment Development and Evaluation system are required to draft high-quality and reliable TDM guidelines.

Variations in Insurance Policies Regarding Adherence to the AGA Guideline for Therapeutic Drug Monitoring in IBD.

The American Gastroenterological Association (AGA) published guidelines on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) in August 2017 recommending use of reactive TDM to guide treatment changes in patients with active IBD who are being treated with anti-tumor necrosis factor (anti-TNF) agents or thiopurines. We sought to determine if changes in national clinical practice guidelines result in changes in health care insurance policies within 6 months of publication. Using the National Association of Insurance Commissioners Market Share Reports of the top 125 insurance companies by market share in 2016, we reviewed the largest 50 companies for their publicly available online policies regarding TDM of anti-TNF and thiopurine in IBD. For those with available policies, we looked for whether proactive and/or reactive TDM was covered. Policies were also looked for genetic or enzymatic activity of thiopurine methyltransferase (TPMT) testing before use of thiopurine. All these policies were reviewed within the week of publication of the AGA guideline. They were reviewed again 1, 3, and 6 months later for evaluation of any policy changes after the published AGA guidelines. Fifty of the largest insurance company policies were included. With regards to TDM policy for anti-TNF, we did not find a difference between baseline and 6 months values (P=0.38). With regards to TDM policy for thiopurine, we did not find a difference between baseline and 6 months values (P=1.00). About half of the companies did not have a policy regarding TPMT testing for thiopurine use. Of those with available policies for TPMT testing, there was no difference between baseline and 6 months values (P=0.13). Even after publication of national guidelines, a large number of the largest health insurance companies do not have a policy regarding reactive TDM for anti-TNF and/or thiopurines. Majority of those with a policy, fail to meet the current standards set forth by the practice guidelines. A significant gap remains between the insurance policies and AGA guidelines. Further studies are needed to determine how to effectuate change to improve insurance company adherence to clinical practice guidelines.

A review of a recently published guidelines' "strong recommendation" for therapeutic drug monitoring of olanzapine, haloperidol, perphenazine, and fluphenazine.

IntroductionIn addition to clozapine, there is a growing body of evidence that supports therapeutic drug monitoring (TDM) for additional antipsychotics commonly used in the United States.MethodsThe Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) published TDM guidelines for several psychiatric medications. Sources were identified that the authors used to establish therapeutic reference ranges for haloperidol, fluphenazine, perphenazine, and olanzapine—4 antipsychotics commonly used in the United States with a “strong recommendation” for TDM. The sources were then reviewed for content and appropriateness for utilization in establishing the reference ranges.ResultsOlanzapine had 15 citations, haloperidol had 9, perphenazine had 4, and fluphenazine had 2. The studies' methods were reviewed along with the proposed therapeutic reference ranges.DiscussionSeveral limitations of the guidelines were identified. Reference ranges were suggested based on studies of patients with various diagnoses; some patients had an acute exacerbation, and others were in a maintenance phase. An additional publication was identified that reviewed similar (and additional) TDM studies; those conclusions were in slight contrast with those of the AGNP guidelines. In the future, guidance should be given to those looking to conduct TDM studies to standardize methods and make meta-analysis of this data more feasible.

Concentration-Effect Relationships of Psychoactive Drugs and the Problem to Calculate Therapeutic Reference Ranges.

Despite the obvious potential of Therapeutic Drug Monitoring (TDM) as a tool to optimize psychopharmacotherapy, especially treatment with mood-stabilizing, antidepressant and antipsychotic drugs, acceptance of TDM as a routine tool is still limited. A serious scientific argument against the regular use of TDM is the lack of evidence for a concentration-dependent clinical effect. The aim of this review was to highlight methodological problems leading to poor or even negative concentration-effect relationships and to show how therapeutically effective concentrations of psychoactive drugs can be determined using routine TDM databases. Reports on concentration-effect relationships of psychoactive drugs were analyzed with regard to applied methods. From routine TDM databases of patients who had been treated with antidepressant or antipsychotic drugs and whose improvement was measured by the clinical global impressions scale, mean and median drug concentrations were calculated and compared with reference ranges recommended by TDM guidelines. Few fixed-dose studies with adequate design and data analysis demonstrated a correlation between drug concentration and clinical effect for psychoactive drugs. Most studies, however, mostly retrospective analyses of TDM databases, failed to find significant concentration-effect relationships because of flexible dosing. They were not suitable for the determination of therapeutically effective drug concentrations. Using TDM databases of antidepressant and antipsychotic drug concentrations in blood of patients who were categorized as responders by the clinical global impressions score, the interquartile ranges of drug concentrations (25th-75th percent range) can be shown to be very close to the therapeutic reference ranges recommended in guidelines for TDM in psychiatry. This review provides a discussion on why simple correlation analyses of psychoactive drug concentrations in blood and clinical effects are obsolete for flexible-dose studies or TDM databases. TDM databases, however, can and should be used to calculate drug concentrations in blood of patients who had responded to the drugs. Interquartile ranges can be regarded and used as preliminary therapeutic reference ranges.

Itraconazole Dosing and Drug Monitoring at a Tertiary Children's Hospital.

Itraconazole is a broad-spectrum antifungal agent used for prophylaxis and treatment of fungal infections in immunocompromised children. Achieving the recommended target serum itraconazole trough concentration of ≥0.5 mg/L is challenging in children because of variation in itraconazole pharmacokinetics with age. We studied itraconazole use and treatment outcomes in a tertiary children's hospital. We did a 10-year retrospective review of medical records of children at the Royal Children's Hospital Melbourne who received oral itraconazole and had therapeutic drug monitoring (TDM). Overall, 81 children received 92 courses of oral itraconazole and had TDM. Of 222 TDM samples, 183 (82.4%) were taken at the appropriate time (trough level at steady state). Patients ≤12 and >12 years of age required median doses of 6.2 and 3.9 mg/kg/d, respectively, to attain target trough levels (P < 0.001). Of children ≤12 years of age, 71.4% required doses above the recommended dose of 5 mg/kg/d to achieve therapeutic levels, compared with 17.4% of those >12 years of age. At least 1 subtherapeutic trough concentration was reported in 63 (76.8%) courses; in only 18 (28.6%) of these was the dose adjusted. Gastrointestinal symptoms [14/92 (15.2%) courses] and hepatotoxicity [6/92 (6.5%)] were the most frequent adverse events. Neither was associated with elevated trough levels. The poor attainment of target levels with current recommended dosing in children <12 years of age suggests that higher empiric doses are needed in this age group. The poor compliance with TDM guidelines highlights the need for better education about appropriate timing of sampling and dose adjustment.

Validation of a Nomogram for Achieving Target Trough Concentration of Vancomycin: Accuracy in Patients With Augmented Renal Function.

Adjustment of initial vancomycin (VCM) dosage has been recommended on the basis of the renal function nomogram in therapeutic drug monitoring guidelines in Japan. However, this nomogram has not been clinically validated, and few studies have focused on its usefulness in patients with risk of augmented renal function. Therefore, this study aimed to evaluate the validity of the VCM nomogram and the association between patient conditions related to augmented renal function and its accuracy. In this retrospective study, we screened data of 398 patients who received VCM and had estimated glomerular filtration rates ≥30 mL·min·1.73 m. Patients who met nomogram dosing criteria were categorized into a nomogram group, and the associations of age, renal function, and individual conditions such as febrile neutropenia, solid tumor, blood cancer, and brain injury with subtherapeutic concentrations (<10.0 mcg/mL) of VCM were evaluated. In total, 177 patients were categorized into the nomogram group, and 83 (47%), 81 (46%), and 13 patients (7%) had VCM trough concentrations of 10-20, <10, and >20 mcg/mL, respectively. Age <50 years was only significantly associated with subtherapeutic trough concentrations. Specific conditions of patients such as febrile neutropenia, solid tumor, and blood cancer were associated with elevated VCM clearance; however, there was no decline in trough VCM concentrations regardless of the presence of the specific conditions. The Japanese VCM dosing nomogram was effective in minimizing the number of instances of supratherapeutic VCM serum concentrations; however, it lacked accuracy in achieving target trough concentrations. The accuracy of the nomogram could be enhanced by categorizing patients according to age. Nevertheless, this study provides novel evidence of the usefulness of this nomogram in avoiding subtherapeutic concentrations of VCM in patients with risk factors for augmented renal clearance.

Therapeutic Drug Monitoring of Voriconazole in Children from a Tertiary Care Center in China.

Voriconazole is a broad-spectrum triazole antifungal and the first-line treatment for invasive aspergillosis (IA). The aim of this research was to study the dose adjustments of voriconazole as well as the affecting factors influencing voriconazole trough concentrations in Asian children to optimize its daily administration. Clinical data were analyzed of inpatients 2 to 14 years old who were subjected to voriconazole trough concentration monitoring from 1 June 2015 to 1 December 2017. A total of 138 voriconazole trough concentrations from 42 pediatric patients were included. Voriconazole trough concentrations at steady state ranged from 0.02 to 9.35 mg/liter, with high inter- and intraindividual variability. Only 50.0% of children achieved the target range (1.0 to 5.5 mg/liter) at initial dosing, while 35.7% of children were subtherapeutic, and 14.3% of children were supratherapeutic at initial dosing. There was no correlation between initial trough concentrations and initial dosing. A total of 28.6% of children (12/42) received an adjusted dose according to trough concentrations. Children <6, 6 to 12, and >12 years old required a median oral maintenance dose to achieve the target range of 11.1, 7.2, and 5.3 mg/kg twice daily, respectively (P = 0.043). The average doses required to achieved the target range were 7.7 mg/kg and 5.6 mg/kg, respectively, and were lower than the recommended dosage (P = 0.033 and 0.003, respectively). Affecting factors such as administration routes and coadministration with proton pump inhibitors (PPIs) explained 55.3% of the variability in voriconazole exposure. Therapeutic drug monitoring (TDM) of voriconazole could help to individualize antifungal therapy for children and provide guidelines for TDM and dosing optimization in Asian children.