Evidence For Therapeutic Drug Monitoring Research Articles

Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

Validation of an LC-MS/MS assay for rapid and simultaneous quantification of 21 kinase inhibitors in human plasma and serum for therapeutic drug monitoring

Kinase inhibitors have revolutionized cancer treatment in the past 25 years and currently form the cornerstone of many treatments. Due to the increasing evidence for therapeutic drug monitoring (TDM) of kinase inhibitors, the need is growing for new assays to rapidly evaluate kinase inhibitor plasma concentrations. In this study, we developed an LC-MS/MS assay for the rapid and simultaneous quantification of 21 kinase inhibitors. First, a literature search was conducted to ensure that the linear ranges of the analytes were in line with the reported therapeutic windows and/or TDM reference values. Subsequently, the assay was validated according to FDA and EMA guidelines for linearity, selectivity, carry-over, accuracy, precision, dilution integrity, matrix effect, recovery, and stability. The assay was fast, with a short run-time of 2 min per sample. Sample pre-treatment consisted of protein precipitation with methanol enriched with stable isotope-labeled internal standards (SIL-IS), and the mixture was vortexed and centrifuged before sample injection. Separation was achieved using a C18 column (3 μm,50 × 2.1 mm) with a gradient of two mobile phases (ammonium formate buffer pH 3.5 and acetonitrile). Analyte detection was conducted in positive ionization mode using selected reaction monitoring. The assay was accurate and precise in plasma as well as in serum. Extraction recovery ranged between 95.0% and 106.0%, and the matrix effect was 95.7%-105.2%. The stability of the analytes varied at room temperature and in refrigerated conditions. However, all drugs were found to be stable for 7 days in the autosampler. The clinical applicability of the analytical method (486 analyzed samples between 1 July 2022–1 July 2023) as well as external quality control testing results were evaluated. Taken together, the results demonstrate that the analytical method was validated and applicable for routine analyses in clinical practice.

Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology.

Although kinase inhibitors (KI) frequently portray large interpatient variability, a 'one size fits all' regimen is still often used. In the meantime, relationships between exposure-response and exposure-toxicity have been established for several KIs, so this regimen could lead to unnecessary toxicity and suboptimal efficacy. Dose adjustments based on measured systemic pharmacokinetic levels-i.e., therapeutic drug monitoring (TDM)-could therefore improve treatment efficacy and reduce the incidence of toxicities. Therefore, theaim of this comprehensive review is to give an overview of the available evidence for TDM for the 77 FDA/EMA kinase inhibitors currently approved (as of July 1st, 2023) used in hematology and oncology. We elaborate on exposure-response and exposure-toxicity relationships for these kinase inhibitors and provide practical recommendations for TDM and discuss corresponding pharmacokinetic targets when possible.

Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis.

Therapeutic drug monitoring (TDM) is a useful strategy in ulcerative colitis (UC). Nearly a quarter of UC patients will experience acute severe UC (ASUC) in their lifetime, including 30% who will fail first-line corticosteroid therapy. Steroid-refractory ASUC patients require salvage therapy with infliximab, cyclosporine, or colectomy. Fewer data are available for the use of TDM of infliximab in ASUC. The pharmacokinetics of ASUC make TDM in this population more complex. High inflammatory burden is associated with increased infliximab clearance, which is associated with lower infliximab drug concentrations. Observational data support the association between increased serum infliximab concentrations, lower clearance, and favorable clinical and endoscopic outcomes, as well as decreased rates of colectomy. Data regarding the benefit of accelerated or intensified dosing strategies of infliximab-as well as target drug concentration thresholds-in ASUC patients remain more equivocal, though limited by their observational nature. Studies are underway to further evaluate optimal dosing and TDM targets in this population. This review examines the evidence for TDM in patients with ASUC, with a focus on infliximab.

Clozapine therapeutic drug monitoring – experience from a large London NHS trust

Abstract Introduction Clozapine is a high-risk drug that is used widely in Secondary and Tertiary Centres.1 Therapeutic Drug Monitoring (TDM) advice and recommendation is readily available from distinguished authors.2,3 The rate of clozapine TDM, appropriate sample collection for TDM, appropriate actions following a clozapine level varies between services and prescribers within our organisation. Aim To establish how many current West London NHS Trust (WLT) patients had a clozapine TDM, how many plasma samples collected for TDM were done appropriately, the proportion of patients with an appropriately collected plasma sample result within the largely accepted therapeutic range, and whether there was documentation that the plasma level was reviewed and if any prescription changes were made. Methods Approval to undertake the service evaluation was given by the Trust clinical governance and audit committee as ethical review as not required. No patient identifiable details were shared or collected. All patients who had been registered on the Trusts clozapine patient monitoring service for over 8 weeks were enrolled. Anonymised patient demographic data was collected including concomitant medication. Plasma levels were sought for every patient enrolled. The appropriateness of the samples taken were scrutinised. The plasma level result was collected. Electronic patient notes were also scrutinised to assess actions following the plasma level result. Data were collected in a binary yes/no format and results calculated as a percentage. Data was stored and collected in accordance to Trust General Data Protection Regulation (GDPR). Results In total 316 patients were included. 97% of these patients had evidence of TDM levels done during the time of the audit. 88% of these patients’ samples were done correctly. Only 45% of patients had levels within the widely acceptable therapeutic range. Of those patients whose levels fell outside the therapeutic range less than half (42%) had documentation that the level was reviewed. Discussion/Conclusion It is widely accepted that clozapine TDM when done accurately can be a vital source of information to inform prescribers on the appropriate dose, concordance and toxicity of clozapine therapy. Our Trust showed evidence of routine clozapine TDM. There was some variation in the appropriate sample collection but what was most alarming is the lack of documentation that action was taken when the TDM level was outside the general acceptable range. Standardising the actions following clozapine TDM needs to be a priority for the Trust if clozapine TDM is to continue to be carried out in almost 100% of the patient population.

Barriers and facilitators for therapeutic drug monitoring of beta-lactams and ciprofloxacin in the ICU: a nationwide cross-sectional study

BackgroundRecent studies demonstrated that failure of achieving pharmacodynamic targets of commonly used antibiotics is common in critically ill patients. Therapeutic drug monitoring (TDM) can contribute to optimize the exposure of beta-lactams and ciprofloxacin. While evidence for TDM of these antibiotics is growing, translation into clinical implementation remains limited. Therefore, perceived barriers and facilitators are important for implementing TDM in this population. The primary aim of this study was to identify healthcare professionals’ barriers and facilitators for the implementation of TDM of beta-lactams and ciprofloxacin in Dutch intensive care units (ICU).MethodsWe conducted a nationwide cross-sectional online survey among healthcare professionals (HCPs) involved in antibiotic treatment of ICU patients. An adapted version of the Measurement Instrument for Determinants of Innovations was sent out. Items were considered barriers when ≥ 20% of participants responded with a negative answer. If ≥ 80% of the participants responded with a positive answer, the item was considered a facilitator.ResultsSixty-four HCPs completed the survey, of which 14 were from academic hospitals, 25 from general hospitals, and 25 from teaching hospitals. Most participants were hospital pharmacists (59%) or medical specialists (23%). Eleven barriers and four facilitators for implementation of TDM of beta-lactams were identified; 17 barriers for TDM of ciprofloxacin and no facilitators. The most important barriers were a lack of conclusive evidence, organizational support, and low availability of assays. Additional barriers were a lack of consensus on which specific patients to apply TDM and which pharmacodynamic targets to use. Identified facilitators for beta-lactam TDM implementation are low complexity and high task perception, combined with the perception that TDM is important to prevent side effects and to adequately treat infections. Twenty-eight percent of participants reported that flucloxacillin could be analyzed in their hospital. Assay availability of other beta-lactams and ciprofloxacin was lower (3–17%).ConclusionSeveral barriers were identified that could obstruct the implementation of TDM of beta-lactams and ciprofloxacin in the ICU. In particular, education, clear guidelines, and organizational support should be considered when creating tailored implementation strategies. Finally, evidence of beneficial clinical outcomes on TDM of beta-lactams and ciprofloxacin can enhance further implementation.

Therapeutic Drug Monitoring of Antibiotics in Critically Ill Patients: Current Practice and Future Perspectives With a Focus on Clinical Outcome.

Early initiation of antibiotics is essential for ameliorating infections in critically ill patients. The correct dosage of antibiotics is imperative to ensure their adequate exposure. Critically ill patients have altered pharmacokinetic parameters and are often infected by less susceptible microorganisms. Differences in drug disposition are not considered with standard doses of antibiotics. This can lead to suboptimal antibiotic exposure in critically ill patients. To overcome this problem of suboptimal dosing, therapeutic drug monitoring (TDM) is a strategy commonly used to support individualized dosing of antibiotics. It is routinely used for vancomycin and aminoglycosides in clinical practice. In recent years, it has become apparent that TDM may also be used in other antibiotics. This review summarizes the evidence for TDM of antibiotics in critically ill patients, focuses on clinical outcomes, and summarizes possibilities for optimized TDM in the future. After reviewing the literature, we can conclude that general TDM implementation is advised for glycopeptides and aminoglycosides, as evidence of the relationship between TDM and clinical outcome is present. For antibiotics, such as beta-lactams, fluoroquinolones, and linezolid, it seems rational to perform TDM in specific patient cases. TDM involving other antibiotics is supported by individual cases, specifically to decrease toxicity. When focusing on future possibilities to improve TDM of antibiotics in critically ill patients, implementation of model-informed precision dosing should be investigated because it can potentially streamline the TDM process. The logistics of TDM, such as turnaround time and available equipment, are challenging but may be overcome by rapid bioanalytical techniques or real-time monitoring of drug concentrations through biosensors in the future. Education, clinical information on targets, and clinical outcome studies are other important factors that facilitate TDM implementation.

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.

Therapeutic Drug Monitoring of Long-Acting Injectable Antipsychotic Drugs.

The use of therapeutic drug monitoring (TDM) to guide treatment with long-acting injectable (LAI) antipsychotics, which are increasingly prescribed, remains a matter of debate. The aim of this review was to provide a practical framework for the integration of TDM when switching from an oral formulation to the LAI counterpart, and in maintenance treatment. The authors critically reviewed 3 types of data: (1) positron emission tomography data evaluating dopamine (D2/D3) receptor occupancy related to antipsychotic concentrations in serum or plasma; D2/D3 receptors are embraced as target sites in the brain for antipsychotic efficacy and tolerability, (2) pharmacokinetic studies evaluating the switch from oral to LAI antipsychotics, and (3) pharmacokinetic data for LAI formulations. Based on these data, indications for TDM and therapeutic reference ranges were considered for LAI antipsychotics. Antipsychotic concentrations in blood exhibited interindividual variability not only under oral but also under LAI formulations because these concentrations are affected by demographic characteristics such as age and sex, genetic peculiarities, and clinical variables, including comedications and comorbidities. Reported data combined with positron emission tomography evidence indicated a trend toward lower concentrations under LAI administration than under oral medications. However, the available evidence is insufficient to recommend LAI-specific therapeutic reference ranges. Although TDM evidence for newer LAI formulations is limited, this review suggests the use of TDM when switching an antipsychotic from oral to its LAI formulation. The application of TDM practice is more accurate for dose selection than the use of dose equivalents as it accounts more precisely for individual characteristics.

Saliva for Precision Dosing of Antifungal Drugs: Saliva Population PK Model for Voriconazole Based on a Systematic Review.

Precision dosing for many antifungal drugs is now recommended. Saliva sampling is considered as a non-invasive alternative to plasma sampling for therapeutic drug monitoring (TDM). However, there are currently no clinically validated saliva models available. The aim of this study is firstly, to conduct a systematic review to evaluate the evidence supporting saliva-based TDM for azoles, echinocandins, amphotericin B, and flucytosine. The second aim is to develop a saliva population pharmacokinetic (PK) model for eligible drugs, based on the evidence. Databases were searched up to July 2019 on PubMed® and Embase®, and 14 studies were included in the systematic review for fluconazole, voriconazole, itraconazole, and ketoconazole. No studies were identified for isavuconazole, posaconazole, flucytosine, amphotericin B, caspofungin, micafungin, or anidulafungin. Fluconazole and voriconazole demonstrated a good saliva penetration with an average S/P ratio of 1.21 (± 0.31) for fluconazole and 0.56 (± 0.18) for voriconazole, both with strong correlation (r = 0.89–0.98). Based on the evidence for TDM and available data, population PK analysis was performed on voriconazole using Nonlinear Mixed Effects Modeling (NONMEM 7.4). 137 voriconazole plasma and saliva concentrations from 11 patients (10 adults, 1 child) were obtained from the authors of the included study. Voriconazole pharmacokinetics was best described by one-compartment PK model with first-order absorption, parameterized by clearance of 4.56 L/h (36.9% CV), volume of distribution of 60.7 L, absorption rate constant of 0.858 (fixed), and bioavailability of 0.849. Kinetics of the voriconazole distribution from plasma to saliva was identical to the plasma kinetics, but the extent of distribution was lower, modeled by a scale factor of 0.5 (4% CV). A proportional error model best accounted for the residual variability. The visual and simulation-based model diagnostics confirmed a good predictive performance of the saliva model. The developed saliva model provides a promising framework to facilitate saliva-based precision dosing of voriconazole.

Is There a Role for the Therapeutic Drug Monitoring of Colistin? An Overview.

Colistin is used as a last-line antibiotic for the treatment of Gram-negative multiresistant bacteria. Due to its high nephrotoxicity, Therapeutic Drug Monitoring (TDM) is recommended for dose adjustment. We aimed to evaluate the available evidence of TDM in patients given colistin to treat Gram-negative infections. In this paper, we offer an overview, using an electronic search of the literature (published up to June 2019, without language restrictions) that compares the clinical outcomes and measurements of colistin TDM. Ultimately, the Therapeutic Drug Monitoring (TDM) of colistin in Plasma could prevent nephrotoxicity risk.

Real-World Use of Azathioprine Metabolites Changes Clinical Management of Inflammatory Bowel Disease

BackgroundThiopurines such as 6-mercaptopurine and azathioprine have complex metabolism, resulting in significant inter-individual differences in clinical efficacy and risk of drug toxicity, making conventional weight-based dosing inaccurate and potentially unsafe. Therapeutic drug monitoring (TDM) of thiopurine metabolites improves clinical outcomes through dose optimization and toxicity monitoring. Despite evidence for TDM, use is limited, due in part to test availability and awareness. The objectives of this study were twofold: (1) to investigate how thiopurine TDM impacts clinical management of IBD patients and (2) to evaluate proportion of patients outside therapeutic 6TGN levels or exhibiting signs of toxicityMethodsPatients who received thiopurine TDM as part of routine care underwent chart review of demographics, disease activity, medication dosing, metabolite levels, and adverse events. Changes in clinical management following TDM were measured. Additionally, we conducted a retrospective review of clinical decision making blinded and unblinded to TDM result.ResultsA total of 92 IBD patients were included. Levels of 6TGN were therapeutic in 29% of patients. 6TGN levels correlated weakly with weight-based dosing (r2 = 0.057, P = 0.02). Adverse reactions were observed in 6.5%. TDM informed clinical management in 64%. Significantly more changes to clinical management occurred in those with active disease than in remission (73% versus 48%; P = 0.02) and in those on mono- versus combination therapy (48% versus 27.5%; P = 0.03).ConclusionsTDM informs clinical decision making in over two-thirds of patients. The demonstrated poor efficacy of weight-based dosing and impact of TDM on clinical management contributes to the evidence supporting the need for greater availability and uptake of thiopurine TDM.

Author response: Clinical utility of therapeutic drug monitoring of antiepileptic drugs.

I appreciated Dr. Sethi's commentary on our recently published article as he raises a number of interesting points.1 Certainly, intraindividual variability is another complicating aspect of therapeutic drug monitoring (TDM) in epilepsy care and, while outside the scope of our review, should be taken into account by all clinicians who choose to incorporate serum antiepileptic drug levels into their clinical decision-making. For my personal practice, I tend to agree that the clinical utility of serum antiepileptic drug levels is limited and that dosing adjustments are best made based on clinical response (seizure control and reported adverse effects). Although our systematic review did identify some studies showing evidence for TDM, the higher quality studies did not show convincing evidence supporting a clinical benefit. In general, we clinicians now have a wealth of diagnostic options available to us, and it is easy to forget that the patient's reported symptoms and clinical examination are almost always the most important outcome measures.

Interest of therapeutic drug monitoring of aminoglycosides administered by a monodose regimen

BackgroundAlthough the once-daily regimen of aminoglycosides (AG) is considered as predominantly used by many centers, the level of evidence of Therapeutic Drug Monitoring (TDM) of AG in cases of once-daily has not been clearly defined. The objective of this study is to evaluate the impact of TDM in achievement or maintaining target serum concentrations in patients receiving once-daily administration of AG. MethodsWe performed a retrospective analysis of data from patients having received a once daily amikacin or gentamicin and underwent routine TDM. A longitudinal follow up was performed. Data were analyzed according to the adhesion or not to recommendations. A logistic regression was performed in order to evaluate the effect of covariates (age, gender, weight, creatinine clearance [CLcr], TDM-based dose adjustment, weighted dose of AG) on the achievement of non-toxic Cmin. ResultsA total 437 blood samples issued from 324 patients were analyzed. The cut-off value of Clcr associated with a risk of toxic Cmin was≤41.66mL/min (OR: 11.29; 95%CI: 7.21–17.61; P<0.0001). Eighty-eight patients (27.1%) have at least two sampling points. The univariate analysis showed that the age, weight, CLcr and TDM-based dose adjustment were found to be significant factors in the achievement of non-toxic Cmin. In multivariate analysis, only TDM-based dose adjustment remains a significant factor in the achievement of non-toxic Cmin (OR: 6.66; 95%CI: 2.26–19.63; P=0.0006). ConclusionOur study demonstrates the usefulness of TDM-based dosing adjustment of AG antibiotics in achieving nontoxic trough concentrations, particularly in critically ill patients, as they are prone to a renal impairment.

Wide variation in the use and understanding of therapeutic drug monitoring for anti-TNF agents in inflammatory bowel disease: an inexact science?

ABSTRACTBackground: We aimed to understand the way in which therapeutic drug monitoring (TDM) is used, understood and interpreted for anti-TNF agents in IBD.Research design and methods: We designed an 18-question survey that included 5 TDM-based clinical scenarios, for which the ‘most appropriate’ responses were based on the BRIDGe groups ‘Anti-TNF Optimizer’. This resource combines TDM evidence with expert consensus.Results: We received 110 complete responses: 50 (45%) consultants, 30 (27%) trainees, 25 (23%) IBD nurse specialists and 5 (5%) gastroenterology pharmacists. Over half (61, 55%) only carry out TDM in non-response. The remainder use TDM routinely, including during stable maintenance therapy for patients in remission. Lower therapeutic thresholds used were variable. Most (82, 75%) were unsure whether their laboratory uses a drug-tolerant or drug-sensitive antidrug antibody assay and few (15, 14%) understand the difference. Consultants, high-frequency users (> 3requests/month) and clinicians with larger anti-TNF cohorts (> 100) were significantly more likely to select the ‘most appropriate’ answer to at least 1 of the 5 TDM-based clinical scenarios.Conclusions: There exists marked heterogeneity in the practical use, understanding and interpretation of biologic TDM. Biologic decision-making, informed by TDM, should involve consultation with experienced clinicians who are frequent TDM users, ideally, as part of a multidisciplinary, biologics-focused IBD meeting.Abbreviations: TDM: therapeutic drug monitoring; CNS: clinical nurse specialist; ELISA: enzyme-linked immunosorbent assay; RIA: radioimmunoassays; HMSA: homogenous mobility shift assays; BSG: British Society of Gastroenterology.

The Evolving Evidence for Therapeutic Drug Monitoring of Monoclonal Antibodies in Inflammatory Bowel Disease.

Biological medications are effective in inflammatory bowel disease (IBD) but adverse events, cost, and loss of response make their use challenging. Therapeutic drug monitoring (TDM) allows clinicians to more safely, effectively, and efficiently use medications. The purpose of this article is to review and summarize the most recent literature pertaining to TDM in IBD. Measurement of biological drug trough levels predicts ongoing patient response and can be used to titrate the medication to be more effective and efficient. Antibodies against the medications predict loss of response and adverse events. Using both parameters can predict response to subsequent biologicals. Newer biologicals show similar characteristics to those more commonly used. Management protocols using drug and antibody levels optimize medication use and may be cost-effective. Recent evidence suggests benefit to TDM of biologicals in IBD.

Evidence for Therapeutic Drug Monitoring of Targeted Anticancer Therapies

Therapeutic drug monitoring (TDM) provides valuable guidance for dose adjustment of antibiotics, immunosuppressives, antiepileptics, and other drugs, but its use for traditional anticancer therapies has been limited. Perhaps the most important obstacle is the impractical requirement of multiple blood samples to adequately define systemic exposure of drugs that have a short elimination half-life and are given by intermittent intravenous injections. However, the newer targeted anticancer therapies have different pharmacokinetic (PK) and dosing characteristics compared with traditional cytotoxic drugs, making it possible to estimate the steady-state drug exposure with a single trough-level measurement. Recent evidence indicates that certain PK parameters, including trough levels, are correlated with clinical outcomes for many of these agents, including imatinib, sunitinib, rituximab, and cetuximab. Although the current evidence is insufficient to mandate TDM in routine practice, a concerted investigation should be encouraged to determine whether the steady-state trough measurements of targeted agents will have a practical place in the clinical care of patients with cancer.

Level of evidence for therapeutic drug monitoring for etoposide after oral administration

Oral etoposide displays high intervariability and intravariability. Convincing relationships were observed between hematological toxicities and exposure of which total etoposide area under the curve seems the more relevant in routine practice. Linear pharmacokinetics, limited sampling strategies and reduction in variability during concentration-controlled studies argue in favor of therapeutic drug monitoring. However, such reduction in variability should be confirmed after oral administration. For these reasons, such practice can be considered as 'potentially useful'. Further studies using Bayesian approach are nevertheless needed to definitely state regarding the level of evidence therapeutic drug monitoring of oral etoposide.

Niveau de preuve pour le suivi thérapeutique pharmacologique de la vancomycine

Level of Evidence for Therapeutic Drug Monitoring of Vancomycin. Vancomycin is an antibiotic for exclusive hospital use administrated in intravenous infusion to treat systemic infections. It is mainly eliminated by kidneys and potentially nephrotoxic. Data available show that Therapeutic Drug Monitoring (TDM) of vancomycin is highly recommended. It aims to ensure efficacy and avoid resistance by maintaining trough plasma concentrations above the MIC. Secondary, vancomycine TDM may be indicated to prevent nephrotoxicity in high risk patients. TDM is often underwent at steady state (48 to 72 h after the treatment initiation) unless in case of renal impairment (24 h). While compared with intermittent administration, continuous infusion did not result in prognosis improvement; however it resulted in lower pharmacokinetic variability and better cost-efficiency. Targeted trough concentrations for intermittent infusion are between 15 and 20 mg/L (up to 25-30 mg/L for GISA). In case of continuous infusion, targets are higher (25 to 40 mg/L).

Niveau de preuve du suivi thérapeutique pharmacologique des aminosides

Aminoglycosides are major antibiotics indicated for the treatment of infection with gram-negative bacilli. They are characterized by high clinical effectiveness but their main drawback is the occurrence of toxicity in a significant number of patients. Pharmacokinetic parameters of aminoglycosides exhibit wide inter-individual variability and the relationships between concentration and effect have been clearly demonstrated. Consistent studies have demonstrated that therapeutic drug monitoring (TDM) of aminoglycosides administered in multiple daily doses was cost-effective in maximising antibiotic efficacy and/or reducing incidence of toxicity. Therefore TDM of aminoglycosides should be considered "essential". Level of evidence for TDM of aminoglycosides administered once daily is not so clearly demonstrated however it should be highly recommended.