Guidelines For Therapeutic Drug Monitoring Research Articles

Therapeutic Drug Monitoring of Oral Anti-Hormonal Drugs in Oncology.

Oral anti-hormonal drugs are essential in the treatment of breast and prostate cancer. It is well known that the interpatient variability in pharmacokinetic exposure is high for these agents and exposure-response relationships exist for many oral anti-hormonal drugs. Yet, they are still administered at fixed doses. This could lead to underdosing and thus suboptimal efficacy in some patients, while other patients could be overdosed resulting in unnecessary side effects. Therapeutic drug monitoring(TDM), individualized dosing based on measured blood concentrations of the drug, could therefore be a valid option to further optimize treatment. In this review, we provide an overview of relevant clinical pharmacokinetic and pharmacodynamic characteristics of oral anti-hormonal drugs in oncology and translate these into practical guidelines for TDM. For some agents, TDM targets are not well established yet and as areference the median pharmacokineticexposure could be targeted (exemestane: minimum plasma concentration(Cmin) 4.1ng/mL and enzalutamide: Cmin 11.4mg/L). However, for most drugs, exposure-efficacy analyses could be translated into specific targets (abiraterone: Cmin 8.4ng/mL, anastrozole: Cmin 34.2ng/mL, and letrozole: Cmin 85.6ng/mL). Moreover, prospective clinical trials have shown TDM to be feasible for tamoxifen, for which the exposure-efficacy threshold of its active metabolite endoxifen is 5.97ng/mL. Based on the available data, we therefore conclude that individualized dosing based on drug concentrations is feasible and promising for oral anti-hormonal drugs and should be developed further and implemented into clinical practice.

F224. UTILITY OF SALIVA FOR MONITORING OF CLOZAPINE LEVELS

BackgroundClozapine has specific indication for use in Treatment Resistant Schizophrenia (TRS) with guidelines for therapeutic drug monitoring. Though a plasma level > 350 ng/ml has been cited as the therapeutic threshold, many other studies have shown poor or inconsistent associations between blood levels of clozapine and side effects. Clozapine is about 95% bound to plasma proteins with a small biologically active fraction. Saliva presents as a promising alternative for therapeutic drug monitoring where clozapine levels would be at equilibrium with free unbound clozapine in the plasma. This provides the added advantage of a potentially stronger relationship with efficacy and adverse effects when compared to plasma levels because of saliva’s closer representation of biologically-active clozapine. Salivary collection is also non-invasive and can be sampled serially for more precise evaluation of intra-individual variations. In the present investigation, we set out to evaluate the agreement and comparative clinical utility between plasma and salivary clozapine levels.Methods53 participants with schizophrenia and on stable doses of clozapine for at least 2 weeks were recruited for the study. Participants had to undergo a clinical interview and the SCID, PANSS, plus side effect scales were administered. Symptomatic remission status was defined using the symptom criteria proposed by Andreasen et al (2005). A fasting sample of venous blood and salivary sample were collected at the same time. Assays for clozapine and norclozapine were performed using high performance liquid chromatography. A total of 106 saliva and plasma samples have been analysed.ResultsOur results showed strong correlations between plasma and salivary levels of clozapine (r=0.61, P<0.05) and norclozapine (r=0.63, P<0.05). Twenty (37.7%) participants achieved symptomatic remission at the time of recruitment. Non-remitters had a significantly higher level of plasma clozapine. Thirty-one (93.9%) participants in the non-remitter group have plasma clozapine levels greater than 350ng/ml.DiscussionOur study shows potential for salivary samples to be an alternate non-invasive source for therapeutic drug monitoring of clozapine. This will be useful in serial monitoring of clozapine levels to evaluate treatment adherence and fluctuating pharmacokinetic profiles. There is a significant proportion of patients who do not achieve symptomatic remission on clozapine, which highlights a pressing need to identify new pharmacological agents or modalities of treatment.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Comparison of Measured Trough Values after Deriving the Initial Dose Setting of Vancomycin with a Conventional Computer Software and a Nomogram Based on the Revised Japanese 2016 Therapeutic Drug Monitoring Guidelines for Antimicrobial Agents

Background: Due to the relatively high renal toxicity of vancomycin injection (VCM), setting an initial dose that achieves a trough that ranges between 10 and 20 μg/mL on day 3 is important to ensure safety and minimize side-effects, especially for patients with low renal function. To address these issues, the revised 2016 Therapeutic Drug Monitoring (TDM) Guidelines for Antimicrobial Agents (GL2016) proposed the use of a renal function-based, estimate glomerular filtration rate (eGFR) nomogram for setting the dose of VCM in Japan. Methods: Our hospital introduced the use of the GL2016 in September 2016 for the patients administered VCM. After setting the initial VCM dose using 1) a conventional VCM analysis software and 2) the GL2016 eGFR nomogram, the measured trough values on day 3 were compared and evaluated in this study. Results: With the VCM analysis software, the mean measured trough value in the a-total group (n = 53) was 12.8 ± 4.7 μg/mL. With the eGFR nomogram, the mean measured trough value in the b-total group (n = 13) was 9.6 ± 4.6 μg/mL. However, when the different severities of renal function were compared, the mean measured trough value was more significantly lower in the b-1 group than in the a-1 group among subjects with G2 and above (eGFR ≥ 60 mL/min/1.73 m2), but it was similar between the a-2 group and the b-2 group among subjects with G3 and below (eGFR 60 mL/min/1.73 m2). The proportion of subjects reaching the various trough ranges shows similar tendency. Conclusions: These data suggested that the measured trough value on day 3 was generally lower when the initial dose was established using the eGFR nomogram based on the GL2016, and this was especially prominent among patients with normal renal function. As for subjects with low renal function, the trough values were relatively high while ensuring safety.

Therapeutic drug monitoring of benznidazole and nifurtimox: a systematic review and quality assessment of published clinical practice guidelines.

The pharmacological management of adults with chronic-phase Chagas disease is challenging despite it being the recent focus of extensive research. One of the challenges in the current clinical practice guidelines (CPGs) landscape is the existence of non-evidence-based recommendations for the use of laboratory tests in treatment monitoring. This study aimed to systematically assess the quality and consistency of recommendations of CPGs on the pharmacological management of adults with chronic-phase Chagas disease. Systematic literature searches were conducted in MEDLINE, EMBASE, SciELO and Google to identify all published CPGs relevant to the pharmacological management of Chagas disease, between January 2010 and March 2016. Three independent reviewers assessed the quality of each CPG using the Appraisal of Guidelines Research and Evaluation (AGREE) II instrument. A total of five CPGs were included and the overall quality of the guidelines for therapeutic drug monitoring of Chagas disease was moderate-to-low. There was considerable variation in the quality of the CPGs across the AGREE II domains. The domains of scope/purpose, stakeholder involvement, and clarity of presentation were rated well, and the domains of applicability and editorial independence received poor ratings. This review showed that the methodological quality of CPGs for Chagas disease was generally inappropriate, and there was no explicit link between the best available evidence and current recommendations.

A Critical Commentary on the 2017 AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology.

In 2004, 2011, and 2017, the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP), a group of German-speaking psychiatric researchers and psychiatrists, published successive versions of therapeutic drug monitoring (TDM) expert group consensus guidelines. The 2017 version has as a major strength its encyclopedic nature, including 1358 references. The guideline has 3 major sections: 1) theoretical aspects of TDM, 2) drug concentration levels in blood to guide neuropsychopharmacotherapy, and 3) practical aspects of TDM in psychiatry and neurology. The writer hopes the time is right for a TDM guideline in psychiatry, which is indicated for: 1) psychiatric researchers ready to value how TDM can contribute to moving psychopharmacology forward, 2) flexible clinicians ready to improve their patient care by personalizing dosing, and 3) today's psychiatry residents prepared as a new generation ready to be trained in TDM and willing to continue incorporating TDM as new psychiatric drugs are marketed.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Variation in Gentamicin Dosing and Monitoring in Pediatric Units across New South Wales.

Introduction:Gentamicin is an aminoglycoside antibiotic with broad-spectrum bactericidal activity and is widely used in pediatric units to treat infection with susceptible organisms. This study aimed to describe the dosage regimen for gentamicin and approach to its therapeutic drug monitoring (TDM) among the pediatric units within the state of New South Wales (NSW).Methods:A questionnaire was sent electronically to representatives of 40 pediatric units in NSW, requesting details of each unit’s gentamicin dosing and TDM policy.Results:A total of 35 units responded to the survey. The majority (63%) of the units used a dose of 7.5 mg/kg of gentamicin in patients with normal renal function. More than half of the units (54%) did not have a local gentamicin dosing protocol and relied on other sources for dosing regimens. Dosing responses varied from a dose of 6 mg/kg once daily for patients more than 10 years of age to 7 mg/kg once daily on day 1, followed by 5 mg/kg once daily for patients over 10 years of age. For TDM of gentamicin, 63% of units indicated use of trough levels and 23% units used the Hartford Nomogram.Conclusions:A significant variation exists in clinical practice among pediatric units in NSW on gentamicin dosing and TDM guidelines. There is an urgent need for collaboration among nursing, medical, and pharmacy experts to achieve consensus to develop and adopt statewide uniform guidelines on gentamicin dosing and TDM.

Therapeutic Drug Monitoring of Carbamazepine

Carbamazepine is one of the classical antiepileptic drugs, chemically related to the Tricyclic Antidepressants. There are different methods to detect Carbamazepine in plasma i.e. Therapeutic Drug monitoring (TDM). Various studies claim the usefulness of TDM of Carbamazepine but clear-cut guidelines for TDM are still lacking. This article is authors’ endeavour to summarize facts in different publications on TDM of Carbamazepine. Electronic databases MEDLINE/PubMed, Google Scholar, IMSEAR (Index Medicus for South-East Asia Region) and Scopemed were extensively searched with Mesh (Medical Subject Headings) terms “Carbamazepine” AND “drug monitoring” from earliest possible date (1966) to December, 2016. Articles in any language especially those published in recent years were given preference. For non-English articles, Google translation was used and only abstracts were included. Review is mostly centred on toxic effects, poorly adjusted therapies and poor seizure control. Individualization of drug dose with the help of plasma level detection is a must in case of Carbamazepine therapy. TDM helps better outcome by minimizing the risk of under or overdosing due to drug/food interaction or genetic polymorphism of enzymes and transporters involved in the metabolism of Carbamazepine.

Adherence to guidelines for therapeutic monitoring of glycopeptide and aminoglycoside antibiotics

Introduction Guidelines for therapeutic drug monitoring (TDM) have been established for glycopeptide and aminoglycoside antibiotics due to their narrow therapeutic windows to ensure therapeutic efficacy and to avoid toxic overdosing with nephro- or ototoxicity. The purpose of this quality control study was to determine the adherence to TDM guidelines for the aminoglycoside gentamicin (G) and the glycopeptides vancomycin (V) and teicoplanin (T) in order to assess the need for improvements. Methods We included all inpatients admitted to the University Hospital Zurich over a 3-year-period from 01/01/2012 to 31/12/2014. All electronic orders of intravenously administered G, V, and T and the corresponding TDM-lab-orders were analyzed retrospectively. Medication orders during intensive care stays were not electronically available and were therefore excluded. Institutional guidelines released 2011 provided recommendations for initial monitoring no later than 72 h for G, 60 h for V and 96 h for T, respectively. Shorter initial TDM intervals have been advised for patients with impaired renal function and for thrice in contrast to once daily dosing of G. Guidelines released 2014 propose shorter intervals for G and T. In this analysis, however, these shortened intervals have not been considered. Drug therapies may be prescribed as single or multiple subsequent orders (e.g. for dose adjustments). Therefore, subsequent prescriptions being separated by ≤ 24h were considered as single continuous therapies. To analyze the adherence to guidelines we measured the time period between the start of drug therapy and the initial TDM. Results Drug therapies administered to 115’509 inpatients were analyzed, including 470 G therapies consisting of 1’045 orders, 2’396 V therapies with 6’168 orders and 807 T therapies with 2’184 orders. Therapies were administered for less than 72 h in 40% (188/470) of G, 41% (985/2’396) of V and 26% (209/807) of T. Therapies lasting ≥ 72 h were monitored according to guidelines for G in 72% (203/282), for V in 67% (939/1411) and for T in 63% (379/598). Therapies of ≥ 96 h, were monitored within 72 h for G in 74% (178/241), for V in 74% (907/1’224), and for T in 50% (275/552). Therapies of ≥ 120 h were not monitored at all for G in 7% (14/208), for V in 7% (68/1046), and for T in 13% (66/512), respectively. Conclusion Physicians’ adherence to TDM guidelines was only 72% or below, with the best compliance for G. Overall TDM adherence offers room for improvement and quality assurance actions have to be considered. Educational programs require a continuous effort. As a complementary measure computerized decision support might be implemented. Automated reminders could be displayed in the medical record whenever TDM is overdue. The same algorithms might also be applied to other therapies that have to be monitored according to guidelines. Studies are needed to evaluate the impact of these concepts on patients’ safety, treatment efficacy and physicians’ over-alerting.

Therapeutic drug monitoring of vancomycin: a guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

Guideline development should be based on the quality of evidence, balance of benefits and harms, economic evaluation and patients' views and preferences. Therefore, these factors were considered in the development of a new guideline for therapeutic drug monitoring (TDM) of vancomycin. To develop an evidence-based guideline for vancomycin TDM and to promote standardized vancomycin TDM in clinical practice in China. We referred to the WHO Handbook for Guideline Development and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and grade the strength of recommendations, according to economic evaluation and patients' views and preferences. We used the GRADE Grid method to formulate the recommendations. The guideline presents recommendations about who should receive vancomycin TDM, how to monitor vancomycin efficacy and renal safety, therapeutic trough concentrations, time to start initial vancomycin TDM, loading dose and how to administer and adjust the vancomycin dose. We developed an evidence-based guideline for vancomycin TDM, which provides recommendations for clinicians and pharmacists to conduct vancomycin TDM in China.

A protocol for developing a clinical practice guideline for therapeutic drug monitoring of vancomycin.

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).

Application of the AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry to patients under therapy with the antipsychotics clozapine, olanzapine, and risperidone in a community hospital in Germany

Application of the AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry to patients under therapy with the antipsychotics clozapine, olanzapine, and risperidone in a community hospital in Germany

Voriconazole dosing and therapeutic drug monitoring in children: experience from a paediatric tertiary care centre.

Therapeutic drug monitoring (TDM) of voriconazole is recommended to achieve trough concentrations of 1-5 mg/L. In children, this is challenging due to age-related variability in voriconazole pharmacokinetics. This study describes our experience with voriconazole, focusing on dosing regimens, dose adjustment and TDM. We reviewed the medical records of immunocompromised children who received voriconazole from July 2009 to January 2015 and had TDM. Demographic, clinical and voriconazole dosing and monitoring data were collected. Fifty-five children received 62 courses of voriconazole and had TDM, with a total of 256 samples taken. Only 71.0% of courses (44/62) had TDM at the correct time, and at least one therapeutic level was achieved in only 52.3% (23/44) of these. Twenty-six courses had at least one sub-therapeutic level and in only 61.5% was the dose adjusted. Patients aged <6, 6-12 and >12 years required median intravenous doses of 8.8, 7.5 and 4.0 mg/kg twice daily, respectively (P < 0.001). With oral administration, patients aged 6-12 and >12 years required median doses of 4.7 and 4.3 mg/kg twice daily, respectively (P = 0.307). Levels within the target range were observed to fall below 1 mg/L in 36.4% of unchanged dosing regimens. Photosensitive skin reactions (20.0%) and hepatotoxicity (12.7%) were the most frequent adverse events and occurred in children with voriconazole levels <5 mg/L. There is significant intra- and inter-individual variability in voriconazole concentrations in children, particularly in children <6 years of age. This warrants repeated TDM throughout treatment. Standardized guidelines for TDM and dose adjustment are required in children.

Consensus guideline for therapeutic drug monitoring in psychiatry (2004): Bibliometric analysis of citations for the period 2004–2011

Objective: To evaluate the awareness of guidelines for the therapeutic monitoring (TDM) of neuropsychiatric drugs by the scientific community, a bibliometric analysis was carried out. Methods: Citations of a guideline for TDM of psychotropic drugs from the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP-TDM) were compared with those of a guideline for TDM of antiepileptic drugs from the International League Against Epilepsy (ILAE-TDM), published in Pharmacopsychiatry in 2004 and in Epilepsia in 2008, respectively. Citations for the period 2004–2011 were obtained from the Web of Science database (31 December 2012). The study included an analysis of the geographical distribution of the first authors and of the cited journals. Citing articles were classified according to five categories and 10 subcategories. Results: The AGNP-TDM and the ILAE-TDM were cited 214 and 67 times, respectively. For the AGNP-TDM, written by 14 authors from German speaking countries, the number of self-citations was 83 (39%). Most citations were found in the following categories: reviews in clinical pharmacology (85 times), clinical pharmacological studies in patients (49). Four out of the 74 different AGNP-TDM citing journals displayed 41% of the citations. The ILAE-TDM was published by five European authors and four authors from the USA. Europe (40) and North America (15) had the highest citation rates. For both guidelines, reviews in clinical pharmacology had the highest percentage of citations, 40% for the AGNP-TDM and 49% for the ILAE-TDM. Conclusion: The observations obtained in this pilot study allowed an analysis of the visibility of two expert guidelines by the scientific community.

Therapeutic Drug Monitoring of Selective Serotonin Reuptake Inhibitors in Elderly Patients.

Elderly patients are at increased risk for elevated serum concentrations from treatment with selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to examine the use of therapeutic drug monitoring (TDM) of SSRIs in elderly compared with younger patients. All serum concentration measurements of SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) performed at our laboratory in 2011 were included. The use of TDM (relative frequency) in older versus younger patients was examined by comparing the use of TDM in patients aged 60 years or older with that in patients younger than 60 years and by evaluating the use of TDM relative to age (age groups in decennials). The number of patients with an SSRI dispensed by prescription in the same region and period (the Norwegian Prescription Database) was used as reference. Additionally, the number of samples above the upper limit of the recommended reference range in patients aged 60 years or older and patients younger than 60 years was evaluated. TDM of an SSRI had been performed in 6333 patients. For all SSRIs, the use of TDM was significantly lower (8.2% versus 10.6% for citalopram, 10.0% versus 13.8% for escitalopram, 8.6% versus 17.0% for fluoxetine, 5.6% versus 10.3% for paroxetine, and 8.1% versus 15.0% for sertraline) in patients aged 60 years or older compared with those younger than 60 years (P < 0.001). There was a gradual decline in the use of TDM with increasing age, with a 3-fold difference between the youngest (10-19) and oldest (90+) patients (P < 0.0001). The percentage of samples above the upper limit of the recommended reference range was 2-fold higher in patients aged 60 years or older (6.7%) compared with patients younger than 60 (3.4%) years (P < 0.0001). Clinical follow-up of patients with TDM of SSRIs is less frequent in older patients compared with younger patients. This is in contrast to the general guidelines for TDM where patients of advanced age are considered of particular importance to monitor closely.

Retrospective evaluation of therapeutic drug monitoring of clozapine and norclozapine in Belgium using a multidrug UHPLC–MS/MS method

ObjectiveClozapine is an atypical antipsychotic with a narrow therapeutic range and serious toxic side effects. According to AGNP–TDM consensus guidelines, therapeutic drug monitoring (TDM) of clozapine and its metabolite norclozapine is strongly recommended. 330 serum samples, sent to the toxicological laboratory of Ziekenhuis Netwerk Antwerpen for monitoring of clozapine, were tested with a new ultra-high performance liquid chromatography–tandem mass spectrometric method (UHPLC–MS/MS). The aim of this research was to evaluate this method for TDM of clozapine and norclozapine, but also to determine other antipsychotics present in these serum samples. Design and methodsSerum samples were taken just prior to the morning dose of the antipsychotic (trough concentration). All samples were, after a simple liquid–liquid extraction with methyl t-butylether, analyzed using a fully validated UHPLC–MS/MS method which is able to quantitate 16 different antipsychotics and 8 of their major metabolites. Serum concentrations were compared with the therapeutic ranges as defined by the AGNP–TDM guidelines. ResultsFor clozapine, only 22.3% of the serum concentrations were within the therapeutic range of 350–600ng/mL, while 67.9% of the concentrations were below 350ng/mL. For norclozapine, 68.2% of the serum samples were within the therapeutic range of 100–600ng/mL. The mean clozapine:norclozapine ratio was 1.7 (SD 0.8). 218 of the 330 serum samples contained other antipsychotics than clozapine. Only 52.5% of these concentrations were within the proposed range. ConclusionThis retrospective study highlights the importance of TDM for clozapine and other APs, since many patients show suboptimal serum concentrations.

Practical Guidelines for Therapeutic Drug Monitoring of Anticancer Tyrosine Kinase Inhibitors: Focus on the Pharmacokinetic Targets

There is accumulating evidence for potential benefits of therapeutic drug monitoring (TDM) in the treatment of cancer with tyrosine kinase inhibitors (TKIs). Relationships between exposure and response (efficacy/toxicity) have been established for several TKIs. For example, the pharmacokinetic targets for efficacy of imatinib, sunitinib and pazopanib have been defined as trough plasma concentrations (Ctrough) of >1,000, >50 and >20,000 ng/mL for selected indications, respectively. Dose adjustment based on pharmacokinetic targets could therefore increase response rates and duration. Furthermore, with appropriate target concentrations defined, excessive side effects in patients using the current fixed dosing strategy may be prevented. This review provides a practical guideline for TDM for the currently approved TKIs at 28 February 2013. The focus of this article is on the elaboration of exposure and response relationships of TKIs with proposed pharmacokinetic targets, mainly Ctrough, and further on the interpretation of the pharmacokinetic targets with recommendations for dose titrations.

Clinical practice guidelines for therapeutic drug monitoring of arbekacin: A consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring

Arbekacin (ABK) was approved and widely used in Japan for treatment of patients infected with MRSA, and TDM was introduced in clinical practice. The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring decided to develop a clinical practice guidelines for TDM of ABK for the following reasons. First, although the daily dose of 150-200mg was approved in Japan, recent PK-PD studies revealed that higher serum concentration is required to achieve better clinical efficacy and several findings concerning the usefulness of higher dosage regimen have obtained recently. Second, although maximal concentrations that obtained immediately after the end of administration (Cmax) was generally adopted, the serum concentration at 1h after initiation of administration [peak serum concentration (Cpeak)] proved to be more suitable as an efficacy indicator of aminoglycosides. Lastly, as ABK is approved only in Japan, no international practice guideline for TDM has not been available in ABK to date. This guideline evaluated the scientific data associated with serum ABK monitoring and provided recommendations based on the available evidence. Potential limitations of this guideline, however, include the findings that few prospective clinical trials of TDM of ABK are available in the treatment of MRSA infections and that most of the published literature describes observational studies.

Comparative Incidence of Nephrotoxicity by Age Group among Adult Patients Receiving Vancomycin.

IntroductionLittle is known regarding age-related risk of nephrotoxicity during vancomycin therapy after the publication of the 2009 vancomycin consensus guidelines for therapeutic drug monitoring. We sought to evaluate incidence and risk factors for acute kidney injury in three age groups.MethodsMatched cohort study of patients receiving vancomycin, grouped by age: young adults (18–64 years), older adults (65–79 years) and very elderly (≥80 years), matched on previously published risk factors for nephrotoxicity. Outcomes included traditional vancomycin nephrotoxicity and Acute Kidney Injury Network-modified definition of nephrotoxicity.ResultsThe incidence of acute kidney injury was 34.1% vs. 34.1% vs. 31.8% in the young, older adults and very elderly groups, respectively (p = 0.97). In the logistic regression model, after adjusting for baseline risk factors, age was not a significant predictor of acute kidney injury. Lower respiratory tract infection (adjusted odds ratio [aOR] 5.18; 95% confidence interval [CI] 2.15–12.41) and duration of treatment (aOR 1.12; 95% CI 1.03–1.22) were found to be independently associated with outcome.ConclusionNo differences in risk of acute kidney injury were identified between young, older, and very elderly adults when adjusting for other risk factors. Further research is required to identify strategies to optimize the safety of vancomycin in the aging population.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-013-0022-6) contains supplementary material, which is available to authorized users.