Effect Of Therapeutic Drug Monitoring Research Articles

Effect of Drug Monitoring on Adherence and Blood Pressure: A Multicenter Randomized Clinical Trial.

Drug concentration in blood or urine is an acknowledged method to detect non-adherence. Observational studies suggest that informing patients about low or absent serum drug levels improves blood pressure (BP). We performed a multicenter randomized clinical trial to test the hypothesis that therapeutic drug monitoring (TDM) could improve drug adherence and BP in patients with uncontrolled hypertension and reduced adherence to antihypertensive drugs. Patients were ≥18 years on stable treatment with at least two antihypertensive agents. We planned to randomize 80 non-adherent patients with a systolic daytime ambulatory BP (ABPM) ≥135 mmHg to TDM-intervention or not. The control group and the study-personnel who measured BP remained uninformed about serum drug measurements throughout. All patients and physicians were blinded for BPs. Lifestyle advice and detailed information on disease process and importance of BP treatment were given to both groups. From 2017 to 2022, we randomized 46 diagnosed non-adherent from a total of 606 patients with uncontrolled hypertension. The TDM-group had a 6.7 (±14.5) mmHg reduction from 147.9 (±10.3) to 141.1 (±14.1) mmHg, and the control group experienced a 7.3 (±13.2) mmHg reduction from 147.1 (±9.2) to 139.1 (±17.4) mmHg, p=0.9 between groups. Adherence improved in both groups, 73% in the TDM group and 59% in the control group became adherent at three months, p=0.51. In our prospective multicenter clinical trial of uncontrolled and non-adherent hypertensive patients, we found no additional effect of therapeutic drug monitoring (TDM) on blood pressure and drug adherence compared with standard care.

Therapeutic Drug Monitoring to Optimize Risperidone Treatment in Children with Autism Spectrum Disorder.

Risperidone is an atypical antipsychotic drug used to treat irritability and aggression in children and adolescents with autism spectrum disorder. In an earlier study, the sum trough concentration of risperidone and its metabolite (9-hydroxyrisperidone) was positively correlated with weight gain and effectiveness. The aim of this study was to determine the therapeutic window for risperidone sum trough concentrations that balances weight gain with treatment effectiveness in this population. In addition, the effect of therapeutic drug monitoring (TDM) on treatment optimization was simulated. In a retrospective cohort (n = 24 children), the target window for risperidone leading to the least increase in body mass index z-scores while retaining effectiveness as measured by the irritability subscale of the Aberrant Behavior Checklist was determined using receiver operating curve analysis. This target range was used to simulate the effect of TDM using a population PK model implemented in the software platform InsightRX. Dosing advice was based on plasma trough concentrations and the dose administered at 12 weeks to simulate whether more children would be on target at 24 weeks after the start of treatment. A risperidone sum trough target range of 3.5-7.0 mcg/L would minimize increase in body mass index z-score and optimize effectiveness. Dosing advice using TDM and a population PK model would lead to a larger proportion of children achieving the target concentration range (62.5% versus 16.7%). TDM may be a useful tool for optimizing risperidone treatment in children and adolescents with autism spectrum disorder.

Stability of 10 Beta-Lactam Antibiotics in Human Plasma at Different Storage Conditions.

Recently, several studies have assessed the effects of therapeutic drug monitoring of frequently prescribed beta-lactam antibiotics, for which they were quantified in human plasma samples. Beta-lactams are considered unstable, leading to extra challenges in quantification. Therefore, to ensure sample stability and minimize sample degradation before analysis, stability studies are crucial. This study investigated the stability of 10 frequently used beta-lactam antibiotics in human plasma at relevant storage conditions for clinical use. Amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, imipenem, meropenem, and piperacillin were analyzed using ultraperformance convergence chromatography tandem mass spectrometry and liquid chromatography tandem mass spectrometry. Their short-term and long-term stabilities were investigated by measuring quality control samples at low and high concentrations against freshly prepared calibration standards. Measured concentrations at each time point were compared with the concentrations at T = 0. Antibiotics were considered stable if recovery results were between 85% and 115%. Short-term stability results indicated ceftriaxone, cefuroxime, and meropenem to be stable up to 24 hours at room temperature. All evaluated antibiotics, except imipenem, were stable on ice in a cool box for 24 hours. Amoxicillin, benzylpenicillin, and piperacillin were stable for 24 hours at 4-6°C. Cefotaxime, ceftazidime, cefuroxime, and meropenem were stable at 4-6°C up to 72 hours. Ceftriaxone and flucloxacillin were stable for 1 week at 4-6°C. Long-term stability results showed that all antibiotics were stable up to 1 year at -80°C, except imipenem and piperacillin, which were stable for 6 months at -80°C. Plasma samples for amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, flucloxacillin, and piperacillin may be stored for a maximum of 24 hours in a cool box. Refrigeration is suitable for plasma samples of amoxicillin, benzylpenicillin, meropenem, and piperacillin for up to 24 hours and cefotaxime, ceftriaxone, ceftazidime and cefuroxime for 72 hours. Plasma samples for imipenem should be frozen directly at -80°C. For long-term storage, plasma samples can be stored at -80°C for a maximum of 6 months for imipenem and piperacillin and 12 months for all other evaluated antibiotics.

Therapeutic drug monitoring in cystic fibrosis and associations with pulmonary exacerbations and lung function

BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy have resulted in longer life expectancies, yet pulmonary exacerbations remain a leading cause of morbidity. Intravenous antibiotics is the mainstay treatment, however achieving adequate concentrations remains challenging. The effect of therapeutic drug monitoring (TDM) of beta-lactams on exacerbations and lung function has not been studied. MethodsPatient demographics, antibiotic regimens, forced expiratory volume 1 s (FEV1), and exacerbation history was obtained from 32 patients with cystic fibrosis admitted for exacerbations. All patients were colonized with Pseudomonas aeruginosa, received CFTR therapy for at least one year, and had 3-month interval follow ups. Plasma concentrations, FEV1, and exacerbation history was obtained before and after therapeutic drug monitoring. This included peak and trough plasma concentrations of piperacillin-tazobactam and cefepime using liquid chromatography with mass spectrometry. T-test and Mann-Whitney U test were used to compare medians/means of FEV1 and pulmonary exacerbations pre and post-TDM as well as free trough-to-minimum inhibitory concentration ratio (fCmin/MIC) ≥1 and ≥ 4. ResultsTDM was associated with decreased exacerbations/year from 1.91 to 1.31 (p = 0.04) and among the cohort with >/ = 2 exacerbations per year, there was a longer exacerbation free interval after TDM (196.2 vs 103.7 days, p = 0.02). The decline in FEV1% predicted after therapeutic drug monitoring to the first exacerbation was −4.9 compared to −9.7 prior (p = 0.03). ConclusionsTDM for cystic fibrosis pulmonary exacerbations results in decreased pulmonary exacerbations, longer intervals to pulmonary exacerbation, and lower decline in FEV1% predicted.

The effect of therapeutic drug monitoring of risperidone and aripiprazole on weight gain in children and adolescents: the SPACe 2: STAR (trial) protocol of an international multicentre randomised controlled trial

BackgroundAntipsychotic drugs are an important part of the treatment of irritability and aggression in children with an autism spectrum disorder (ASD). However, significant weight gain and metabolic disturbances are clinically relevant side effects of antipsychotic use in children. In the SPACe study, we showed positive correlations between both risperidone and aripiprazole plasma trough concentrations and weight gain over a 6-month period. The trial SPACe 2: STAR is designed as a follow-up study, in which we aim to research whether therapeutic drug monitoring in clinical practice can prevent severe weight gain, while retaining clinical effectiveness.MethodsSPACe 2: STAR is an international, multicentre, randomised controlled trial (RCT). One hundred forty children aged 6 to 18 who are about to start risperidone or aripiprazole treatment for ASD related behavioural problems will be randomised into one of two groups: a therapeutic drug monitoring (TDM) group, and a care as usual (CAU) group. Participants will be assessed at baseline and 4, 10, 24, and 52 weeks follow-up. In the TDM group, physicians will receive dosing advice based on plasma levels of risperidone and aripiprazole and its metabolites at 4 and 10 weeks. Plasma levels will be measured in dried blood spots (DBS). The primary outcome will be BMI z-score at 24 weeks after start of antipsychotic treatment. Among the secondary outcomes are effectiveness, metabolic laboratory measurements, levels of prolactin, leptin and ghrelin, extrapyramidal side effects, and quality of life.DiscussionThis will be the first RCT evaluating the effect of TDM of antipsychotic drugs in children and adolescents. Thus, findings from SPACe 2: STAR will be of great value in optimising treatment in this vulnerable population.Trial registrationClinicalTrials.gov Identifier: NCT05146245. EudraCT number: 2020–005450-18. Sponsor protocol name: SPACe2STAR. Registered 8 June 2021. Protocol Version 6, Protocol date: 18 august 2022.

A Systematic Review of the Effect of Therapeutic Drug Monitoring on Patient Health Outcomes during Treatment with Carbapenems.

Adjusting dosing regimens based on measurements of carbapenem levels may improve carbapenem exposure in patients. This systematic review aims to describe the effect carbapenem therapeutic drug monitoring (TDM) has on health outcomes, including the emergence of antimicrobial resistance (AMR). Four databases were searched for studies that reported health outcomes following adjustment to dosing regimens, according to measurements of carbapenem concentration. Bias in the studies was assessed with risk of bias analysis tools. Study characteristics and outcomes were tabulated and a narrative synthesis was performed. In total, 2 randomised controlled trials (RCTs), 17 non-randomised studies, and 19 clinical case studies were included. Significant variation in TDM practice was seen; consequently, a meta-analysis was unsuitable. Few studies assessed impacts on AMR. No significant improvement on health outcomes and no detrimental effects of carbapenem TDM were observed. Five cohort studies showed significant associations between achieving target concentrations and clinical success, including suppression of resistance. Studies in this review showed no obvious improvement in clinical outcomes when TDM is implemented. Optimisation and standardisation of carbapenem TDM practice are needed to improve intervention success and enable study synthesis. Further suitably powered studies of standardised TDM are required to assess the impact of TMD on clinical outcomes and AMR.

Korean clinical practice guidelines on biologics and small molecules for moderate-to-severe ulcerative colitis.

Ulcerative colitis (UC), a relapsing-remitting chronic inflammatory bowel disease (IBD), has a variable natural course but potentially severe disease course. Since the development of anti-tumor necrosis factor (TNF) agents has changed the natural disease course of moderate-to-severe UC, therapeutic options for patients who failed conventional treatments are expanding rapidly. IBD clinical trials have demonstrated the potential efficacy and safety of novel biologics such as anti-integrin α4β7 and anti-interleukin-12/23 monoclonal antibodies and small molecules such as a Janus kinase inhibitor. Anti-TNF biosimilars also have been approved and are widely used in IBD patients. Wise drug choices should be made considering evidence-based efficacy and safety. However, the best position of these drugs remains several questions, with limited data from direct comparative trials. In addition, there are still concerns to be elucidated on the effect of therapeutic drug monitoring and combination therapy with immunomodulators. The appropriate treatment regimens in acute severe UC and the risk of perioperative use of biologics are unclear. As novel biologics and small molecules have been approved in Korea, we present the Korean guidelines for medical management of adult outpatients with moderate-to-severe UC and adult hospitalized patients with acute severe UC, focusing on biologics and small molecules.

A systematic review of the effect of therapeutic drug monitoring on patient health outcomes during treatment with penicillins.

BackgroundDosing regimens guided by therapeutic drug monitoring (TDM) may be able to improve penicillin exposure in patients, which could result in improved patient health outcomes.ObjectivesThis systematic review aims to describe the impact penicillin TDM has on health outcomes, including antimicrobial resistance (AMR).MethodsStudies measuring penicillins in patient samples that adjusted regimens according to the result, and reported health outcomes were selected. Study bias was assessed according to study type. Included study characteristics were tabulated and described by narrative synthesis.ResultsThree randomized controlled trials (RCTs), 16 cohort studies, and 9 case studies were included. No RCTs showed statistically significant improvements in health outcomes. Five cohort studies showed improvement in at least one health outcome associated with target attainment. However, there was a high risk of bias in all studies for health outcomes. One study assessed the impact of penicillin TDM on AMR and found that improved target attainment was associated with suppression of resistance. No studies found a detrimental effect of penicillin TDM.ConclusionsThere is little evidence to suggest that TDM improves health outcomes, however neither health outcomes nor impact on AMR were adequately addressed. Variations in TDM implementation meant that a meta-analysis was not suitable. Penicillin TDM needs standardization, however there is currently no clear evidence of optimal conditions. Suitably powered studies are required to resolve the ambiguity surrounding the impact of TDM on clinical outcomes, including AMR. Further, standardized protocols and concentration targets need to be identified for TDM to be implemented successfully.

Therapeutic drug monitoring of vancomycin in neurosurgery patients, from trough concentration to area under the curve: a retrospective single center cohort study in a tertiary hospital.

ObjectiveTo evaluate the effect of therapeutic drug monitoring (TDM) of vancomycin in neurosurgery patients.MethodsIn this retrospective, single-center cohort study, data were collected from patients administered vancomycin after neurosurgery during 2020. Intervention by a pharmacist using an area under the curve (AUC)-based strategy for TDM of vancomycin was started on 1 July 2020. The trough concentration was monitored previously. Data regarding basic demographics, vancomycin application, and TDM were collected and analyzed.ResultsNinety and 155 samples were included in the non-intervention and intervention groups, respectively. No difference in baseline characteristics was detected. After intervention, the attainment rate of vancomycin TDM was significantly increased from 36.7% to 52.3%. The intervention resulted in an increased daily vancomycin dose (28.9 vs. 26.7 mg/kg/day), a more reasonable sample extraction time (sixth vs. ninth dose), reductions in dose adjustments (37.4% vs. 54.4%) and preventative applications (66.7% vs. 52.3%), and no difference in kidney function impact. The intervention group had a shorter hospital stay.ConclusionsIntervention by a clinical pharmacist using an AUC-based strategy for vancomycin TDM can provide benefits other than pharmacokinetic attainment in neurosurgery patients. Further prospective multi-center studies are needed to establish standardized intervention measures and evaluation indicators.

O04 A systematic review of the effect of therapeutic drug monitoring on patient health outcomes during treatment with penicillins

BackgroundDosing regimens guided by therapeutic drug monitoring (TDM) may be able to improve penicillin exposure in patients. Improved penicillin exposure could result in improved patient health outcomes. This systematic review aims to describe the impact TDM in penicillin treatment has on health outcomes, including the emergence of antimicrobial resistance (AMR).MethodsA search of four databases was conducted and supplemented with a hand search of the literature. Studies that measured concentrations of penicillins in patients, adjusted dosing regimens according to the result and reported health outcomes were selected. The risk of bias was assessed according to study type: randomized controlled trials (RCTs) were assessed with the revised Cochrane risk-of-bias tool for randomized trials (RoB2) assessment tool, the risk of bias in non-randomized studies (ROBINS-1) assessment tool was used to assess observational studies, and the Office of Health Assessment and Translation (OHAT) tool was used to assess case studies. The study characteristics were tabulated and described using a narrative synthesis.ResultsThree RCTs, 16 observational cohort studies and 9 case studies were included. None of the studies showed statistically significant improvements in health outcomes, when comparing groups receiving TDM and standard care. Five observational studies showed improvement in at least one health outcome statistically significantly associated with target attainment: mortality,1–5 bacterial persistence,1,4,5 ICU length of stay,4 treatment efficacy,1,4,6 and suppression of AMR.4 However there was a high risk of bias in all of these studies for health outcomes. Most had pharmacological primary outcomes and were underpowered to detect health outcomes. All three RCTs and four (25%) observational studies found that the use of penicillin TDM was associated with improved pharmacological target attainment. Only one study was found that assessed the impact of β-lactams TDM on AMR and found that target attainment of 100% ƒT>4×MIC was significantly associated with suppression of resistance. No studies found a detrimental effect of penicillin TDM on health outcomes. A meta-analysis was not performed due to the heterogeneity of the included studies.ConclusionsThere is little evidence to suggest that TDM improves health outcomes, however neither health outcomes nor reductions in emergence of AMR were adequately addressed by currently published studies. The evaluation of health outcomes was not the primary aim of the majority of the included studies, consequently those that did include these outcomes were underpowered to detect a difference. Observational studies often did not take into account co-interventions, or confounding factors, resulting in a high risk of bias. Large variations in how TDM of penicillins was implemented and the different populations used meant that a quantitative synthesis of results was not suitable. Recommendations to standardize penicillin TDM are a challenge currently, as there is no clear evidence of optimal conditions. Suitably powered studies designed to assess clinical outcomes are required to resolve the ambiguity surrounding the impacts of TDM on clinical outcomes, and to address the gap of the impacts on AMR. Further, appropriate standardized protocols and concentration targets for penicillin TDM in humans need to be identified for it to be implemented successfully.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases

Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. ClinicalTrials.gov Identifier: NCT03074656.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases

Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). The primary end point was clinical remission at week 30. Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. ClinicalTrials.gov Identifier: NCT03074656.

Carbapenem Therapeutic Drug Monitoring in Critically Ill Adult Patients and Clinical Outcomes: A Systematic Review with Meta-Analysis.

Drug monitoring is one strategy of antibiotic stewardship to face antimicrobial resistance. This strategy could have a determinant role in critically ill patients treated with carbapenems to overcome pharmacokinetic variability, reduce the risk of subtherapeutic dosage or toxicity, and reduce the risks inherent to treatment. However, the effectiveness of therapeutic drug monitoring (TDM) is unknown. This paper aims to identify TDM effectiveness in critically ill patients treated with carbapenems. English and ClinicalTrials.gov databases were searched to identify relevant studies evaluating carbapenem TDM. Randomized controlled trials (RCTs) and comparative cohort studies were selected for inclusion if they compared carbapenem TDM to standard care in adult critically ill or sepsis/septic shock patients. The primary outcome was mortality. Secondary outcomes included morbidity, clinical cure, microbiological eradication, antimicrobial resistance, drug-related side effects, and achievement of target plasma concentrations. Overall, performing carbapenem TDM was not associated with a decrease in mortality. However, it could be evidence for a relationship with clinical cure as well as target attainment. Some studies found favorable outcomes related to clinical and microbiological responses, such as lower procalcitonin levels at the end of the monitored therapy compared to standard care. For the primary and secondary outcomes analyzed, strong evidence was not identified, which could be due to the size, risk of bias, and design of selected studies.

Therapeutic Drug Monitoring of Olanzapine and Cytochrome P450 Genotyping in Nonsmoking Subjects.

The relationship between a daily dose of olanzapine, its serum concentration, and the genotype of young nonsmoking men treated for schizophrenia or schizophreniform disorder was investigated in day-to-day clinical practice. Pharmacogenetics was also examined for the selected patients. A total of 49 participants were recruited as in-patients at the Mental Health Research Center (Moscow, Russia). Inclusion criteria were patients who had been diagnosed with schizophrenia or schizoaffective disorder (following DSM-IV guidelines) and were being treated with OLZ. A prospective, observational, open-study design was implemented. In line with the literature, patients were only included if they attained steady-state OLZ concentrations lasting for at least 8 days. A liquid chromatographic-tandem mass spectrometric method was developed for analyzing OLZ in human serum. The single cytochrome P450 polymorphisms were genotyped using an amplifier real-time polymerase chain reaction system following standard protocols. Evidence indicating that CYP2D6 polymorphism has a significant (P = 0.046) effect on the pharmacokinetics of olanzapine was obtained, confirming the beneficial effects of therapeutic drug monitoring (TDM) for olanzapine. TDM should therefore be used as a standard care during olanzapine therapy. TDM is also useful in assessing adherence and may have a role in limiting olanzapine dosage geared at minimizing the risk of long-term toxicity.

The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial

BackgroundCritically ill patients undergo extensive physiological alterations that will have impact on antibiotic pharmacokinetics. Up to 60% of intensive care unit (ICU) patients meet the pharmacodynamic targets of beta-lactam antibiotics, with only 30% in fluoroquinolones. Not reaching these targets might increase the chance of therapeutic failure, resulting in increased mortality and morbidity, and antibiotic resistance. The DOLPHIN trial was designed to demonstrate the added value of therapeutic drug monitoring (TDM) of beta-lactam and fluoroquinolones in critically ill patients in the ICU.MethodsA multi-centre, randomised controlled trial (RCT) was designed to assess the efficacy and cost-effectiveness of model-based TDM of beta-lactam and fluoroquinolones. Four hundred fifty patients will be included within 24 months after start of inclusion. Eligible patients will be randomly allocated to either study group: the intervention group (active TDM) or the control group (non-TDM). In the intervention group dose adjustment of the study antibiotics (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, amoxicillin, amoxicillin with clavulanic acid, flucloxacillin, piperacillin with tazobactam, meropenem, and ciprofloxacin) on day 1, 3, and 5 is performed based upon TDM with a Bayesian model. The primary outcome will be ICU length of stay. Other outcomes amongst all survival, disease severity, safety, quality of life after ICU discharge, and cost effectiveness will be included.DiscussionNo trial has investigated the effect of early TDM of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients. The findings from the DOLPHIN trial will possibly lead to new insights in clinical management of critically ill patients receiving antibiotics. In short, to TDM or not to TDM?Trial registrationEudraCT number: 2017–004677-14. Sponsor protocol name: DOLPHIN. Registered 6 March 2018 . Protocol Version 6, Protocol date: 27 November 2019.

Cost effectiveness of therapeutic drug monitoring for imatinib administration in chronic myeloid leukemia.

BackgroundImatinib mesylate (IM) is a first-line treatment option for patients with chronic myeloid leukemia (CML). Patients who fail or are intolerant to IM therapy are treated with more expensive second and third-generation tyrosine kinase inhibitors. Patients show wide variation in trough concentrations in response to standard dosing. Thus, many patients receive subtherapeutic or supratherapeutic doses. Therapeutic drug monitoring (TDM) may improve dose management that, in turn, may reduce costs and improve outcomes. However, TDM also adds to the cost of patient care. The objective of this study was to determine the cost-effectiveness of TDM for generic IM therapy.MethodsWe developed a microsimulation model for the trough plasma concentration of IM which is related to a cytogenetic or molecular response. We compared two cohorts: one with TDM and one without TDM (NTDM). The lifetime incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life years (QALYs) as the effectiveness measure. One-way and probabilistic sensitivity analyses were performed.ResultsThe lifetime cost and QALY of treatment with TDM were $2,137K [95% Ci: 2,079K; 2,174K] and 12.37 [95% CI: 12.07; 12.55], respectively. The cost and QALY of NTDM were $2,132K [95% CI: 2,091K; 2,197K] and 12.23 [95% CI: 11.96; 12.50], respectively. The incremental cost and QALY for TDM relative to NTDM was $4,417 [95% CI: -52,582; 32,097]) and 0.15 [95% CI: -0.13; 0.28]. The ICER for TDM relative to NTDM was $30,450/QALY. Probabilistic sensitivity analysis showed that TDM was cost-effective relative to NTDM in 90% of the tested scenarios at a willingness-to-pay threshold of $100,000/QALY.ConclusionsAlthough the impact of TDM is modest, the cost-effectiveness over a lifetime horizon (societal perspective, ($30,450/QALY) falls within the acceptable range (< $100k/QALY).

Single Arm, Single Centre Prospective Study to Assess the Effect of Therapeutic Drug Monitoring (TDM) Based Dosage Adjustment of Posaconazole on the Incidence of Invasive Fungal Infections (IFIs) in AML Patients on Induction Chemotherapy on Posaconazole Prophylaxis

Background: Invasive fungal infections (IFIs) continue to remain a significant cause of morbidity and mortality in AML patients affecting the final outcomes and increasing health care costs. Posaconazole is commonly used as prophylaxis against IFIs due to its broad spectrum of action. The incidence of breakthrough IFIs is particularly high in our setting - one of the several reasons being suboptimal drug levels as we use posaconazole suspension whose absorption is influenced by multiple factors. A breakthrough IFI rate of 51% was seen in a previous study from our centre by Sengar et.al (ASH 2016) and it was seen that sub-optimal drug levels (&lt; 700ng/ml) were associated with a higher rate of breakthrough IFI. This group can benefit from TDM but there are not many studies to guide TDM-based dosing of posaconazole. TDM is expensive and time consuming and the final impact on clinical outcomes has been difficult to estimate. To determine the impact of TDM-based dosing of posaconazole on breakthrough IFI rate, we have undertaken this prospective study. Methods: This prospective, single-arm interventional study included patients 16 years or older undergoing induction chemotherapy for de novo AML with no evidence of IFI at baseline (normal CT chest and normal serum galactomannan ) who have consented for participation (assent and guardian consent were used for those who were &lt; 18 years). Concomitant drugs during induction were recorded everyday. 3 dosing schedules for posaconazole were used based on the drug level : Level 1 - 200mg TDS which was the starting dose in all patients, Level 2 - 200mg QID and Level 3 - 400mg TDS which was the maximum dose. Posaconazole was given with a high fat meal or an aerated drink to improve its absorption. The cut off for day 2 drug level (i.e after atleast 3-4 doses ) was 350ng/ml and the cut-off level at subsequent time points was 700 ng/ml. At any time point, if the patient's drug level was below this cut off, the dose was escalated and a repeat level was sent 5 complete days after the changed dose to allow for re-establishment of the pharmacokinetic equilibrium. A day 2 level was sent for all the patients and the timing of subsequent levels was based on dose escalation. Patients who were continued on the same dose due to adequate drug levels were sampled once in 7 days. QTc interval and liver function tests were monitored for posaconazole toxicity. Posaconazole was continued till the absolute neutrophil count recovered to more than 500 cells/ µl or till the patient was started on an alternative anti-fungal for a proven , possible or probable IFI or empirically at the clinician's discretion for reasons like persistent fever, cough, breathlessness, diarrhoea or vomiting. Relevant imaging and microbiological tests were performed as needed for investigating a suspected IFI. To analyze the primary endpoint chi-square test was used to compare the breakthrough IFI rate with that in a historical cohort from our own centre in which TDM based dosing was not used. Results: A total of 278 samples were collected for drug levels in these 90 patients with a mean of 3.08 (range 1 to 6 samples) per patient . 2 patients were proven to have mixed phenotypic acute leukemia after enrollment and hence were excluded from the analysis. 46 out of 88 patients i.e 52.3% were changed to alternative antifungals. Out of these 46, 13 patients (i.e 28.3%) had proven, probable or possible IFI as per the Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) . The change to alternative antifungals in the remaining 33 out of 46 patients (i.e 71.7%) was empirical due to persistent fever spikes, vomiting or diarrhoea. Thus overall 13 out of 88 patients i.e 14.8% had developed a breakthrough IFI. A similar historical cohort from our own institute, without the TDM based dosing of posaconazole, had a breakthrough IFI rate of 52%. The difference between the breakthrough IFI rate of these 2 cohorts was 37.2% which was statistically significant (p &lt; 0.0001, 95% CI 27.9% to 52.4%). 1 patient had developed grade 3 transaminitis and 1 patient had grade 3 rise in total bilirubin while on posaconazole. Conclusion: TDM-based dose escalation of prophylactic posaconazole in AML patients during induction leads to a significant reduction in the breakthrough IFI rates. Disclosures No relevant conflicts of interest to declare.

1067O - The influence of TDM on achieving busulfan target exposure and related determinants, in both children and adults who underwent an allogeneic hematopoietic cell transplantation

BackgroundBusulfan is widely used as conditioning in allogeneic haematopoietic cell transplantation (allo-HCT) and has a narrow therapeutic range (80-100mg*hr/L). Primary objective was to examine the effect of therapeutic drug monitoring (TDM) on attaining busulfan target exposure in children and adults undergoing allo-HCT. Secondarily, we studied potential predictors for within-person variability in busulfan clearance. MethodsAll children and adults who underwent allo-HCT with intravenous busulfan were prospectively included (July 2011 – July 2016, UMC Utrecht, NL). Busulfan was administered once daily on four consecutive days and drug levels were measured on days 1 and 4. Cumulative exposure (cAUC) and clearance were estimated using a population model. cAUCs were compared between (1) without TDM (hypothetical, e.g. four times AUC-day1), (2) actual TDM (fixed clearance over time), and (3) TDM with an adapted PK model (taking into account age and temporal changes in busulfan clearance). Potential determinants of clearance alterations were modeled using linear regression. ResultsIn the total patient population (n=239), substantially more patients attained their busulfan target (76.2%) with TDM (adapted PK model) as compared to when no TDM would have been performed (49.8%, rate ratio 1.53, 95% confidence interval 1.21-1.93). Moreover, TDM resulted into a significantly lower variation in cAUC (-41%, p<0.001). Age (p<0.001) and use of paracetamol (p=0.025) and anticonvulsants (p=0.044) were identified as independent predictors for decline in busulfan clearance over time. ConclusionsTDM is of added value in preventing severe under and over exposure of busulfan in patients undergoing allo-HCT. We strongly advocate the use of PK model aided TDM anticipating a decrease in busulfan clearance. This particularly applies to adults and individuals taking paracetamol or anticonvulsants, given the more pronounced decline in busulfan clearance observed in this subset of patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients.

Belatacept (Nulojix; Bristol-Myers Squibb, New York, NY) is a biological immunosuppressive drug used for the prophylaxis of acute rejection after renal transplantation. Few studies have described belatacept pharmacokinetics, and the effect of therapeutic drug monitoring has not been investigated. We have developed a drug-capture assay (using drug target) to measure belatacept in serum and applied this assay in a pharmacokinetic study in renal transplant recipients. CD80 was used to trap belatacept onto streptavidin-coated wells. Captured drug was quantified using Eu-labeled protein A and time-resolved fluorescence. The assay was applied in a pilot pharmacokinetic study in renal transplanted patients receiving belatacept infusions. Belatacept serum concentrations were determined at several time points between belatacept infusions. A simple population pharmacokinetic model was developed to visualize measured and predicted belatacept serum concentrations. The assay range was 0.9-30 mg/L with accuracy within 91%-99% and coefficients of variation ranging from 1.2% to 3.6%. Predilution extended the measurement range to 130 mg/L with an accuracy of 90% and coefficients of variation of 3.8%. Samples were stable during storage at 4°C for 15 days and during 2 freeze-thaw cycles. Belatacept concentrations were determined in a total of 203 serum samples collected during 26 infusion intervals from 5 renal transplant recipients. The population pharmacokinetic model visualized both measured and predicted concentrations. We have developed an automated, accurate, and precise assay for the determination of belatacept serum concentrations. The assay was successfully applied in a pharmacokinetic study in renal transplant recipients receiving belatacept infusions.

Clinical Outcomes With Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Systematic Review With Meta-Analysis.

We undertook a systematic review and meta-analysis examining the effectiveness of therapeutic drug monitoring [TDM] to improve clinical outcomes in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha [anti-TNF] drugs. We searched MEDLINE, Epub Ahead of Print, EMBASE and Cochrane up to October 2017 for randomized trials [RCTs] and cohort studies comparing proactive or reactive TDM to each other or empiric care. Outcomes included clinical remission [primary], clinical relapse, endoscopic remission, anti-TNF response durability, cost and adverse events [secondary]. Pooled odds ratios and mean differences were calculated. The search identified nine studies [three RCTs, six observational], focused on infliximab maintenance therapy in adults. Neither proactive nor reactive TDM was associated with superior clinical remission rates compared to empiric dose optimization. However, evidence of a cost benefit, particularly for reactive TDM vs empiric care, was identified. In several studies, TDM, particularly proactive TDM, was associated with favourable outcomes related to durability of anti-TNF response, such as lower drug discontinuation rates compared to empiric care and reactive TDM, and lower relapse rates compared to empiric care. No consistent benefit was found for endoscopic or surgical outcomes. The existing limited evidence does not support an association between any TDM strategy and superior clinical remission rates but does support a cost savings benefit [particularly for reactive TDM] and suggests a potential benefit for anti-TNF durability [particularly proactive TDM]. Additional, longer-term studies are needed, particularly to further investigate proactive TDM, and to generate data on other anti-TNF agents, the induction period and paediatric populations.