Use Of Therapeutic Drug Monitoring Research Articles

Therapeutic drug monitoring for antimicrobial agents for people living with HIV (TAP)

Background Antimicrobial resistance (AMR) is a growing health concern, particularly in Africa, and is predicted to be the leading cause of death after cancer by 2050. Factors like overuse or inappropriate use of antibiotics, contribute to this crisis. People living with HIV (PLWH) are particularly vulnerable to AMR with potential drug-drug interactions between antiretroviral and antimicrobial agents against common organisms like Mycobacterium tuberculosis. There is limited data on the concentrations of commonly used antimicrobial agents in people living with HIV in resource-limited settings. Therapeutic Drug Monitoring (TDM) offers a promising approach to optimize antibiotic dosing and improve treatment outcomes for those with sub-optimal drug concentrations. TDM has been recommended for PLWH on anti-tuberculosis treatment due to sub-optimal drug concentrations found in a significant proportion of those with TB. Objectives The main objectives of this study are to determine the concentrations of selected antimicrobial agents in people living with HIV requiring antimicrobial therapy and to assess the utility of therapeutic drug monitoring in achieving therapeutic targets for PLWH receiving rifampicin and isoniazid for the treatment of tuberculosis Methods This prospective observational study will enroll adult PLWH receiving amoxicillin, azithromycin, ciprofloxacin, rifampicin, isoniazid, or ceftriaxone. Concentrations of these antibiotics will be measured locally using validated liquid chromatography mass spectrometry methods and high-performance liquid chromatography with ultraviolet detection. TDM with dose adjustment will be performed in a subset of participants on TB treatment. Pharmacokinetic parameters will be estimated using non-linear mixed effects models. Results This study was reviewed and approved by the research and ethics committee in February 2024. Enrolment is projected to begin by August 2024. Conclusions We anticipate that the findings from this research will characterize pharmacokinetic and pharmacodynamics relationships to predict treatment response for optimal antimicrobial therapeutic and anti-tuberculosis dosing among people living with HIV (PLWH). Clinical registration The study is registered with Pan African Clinical Trials Registry, registration number PACTR202409710100607, registration date 07 August 2024, pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=31764

Importance of sex-dependent differences for dosing selection and optimization of chemotherapeutic drugs.

Background Despite major advances in cancer treatment in the past years, there is a need to optimize chemotherapeutic drugs dosing strategies to reduce toxicities, suboptimal responses, and the risk of relapse. Most cancer drugs have a narrow therapeutic index with substantial pharmacokinetics variability. Yet, current dosing approaches do not fully account for the complex pathophysiological characteristics of the patients. In this regard, the effect of sex on anticancer chemotherapeutic drugs disposition is still underexplored. In this article, we review sex differences in chemotherapeutic drug pharmacokinetics, we suggest a novel approach that integrates sex into the traditional a priori body-surface-area (BSA) dosing selection model and finally, we provide an overview of the potential benefits of a broader use of therapeutic drug monitoring (TDM) in oncology. Summary To date, anticancer chemotherapeutic drugs dosing is most often determined by BSA, a method widely used for of its ease-of-practice, despite criticism for not accounting for individual factors, notably sex. Anatomical, physiological, and biological differences between males and females can affect pharmacokinetics, including drug metabolism and clearance. At equivalent doses, females tend to display higher circulating exposure and more organ toxicities, which has been formally demonstrated at present for about 20% of chemotherapeutic drugs. An alternative could be the Sex-Adjusted-BSA (SA-BSA), incorporating a 10% increase in dosing for males and a 10% decrease for females, though this approach still lacks formal clinical validation. Another strategy to reduce treatment-related toxicity and potentially enhance clinical outcomes could be a more widespread use of therapeutic drug monitoring (TDM), for which a benefit has been demonstrated for 5-fluorouracil, busulfan, methotrexate or thiopurines.

Antibiotic-Induced Immunosuppression-A Focus on Cellular Immunity.

Antibiotics are the fundamental treatment for bacterial infections. However, they are associated with numerous side effects. Their adverse effects on the immune system are increasingly recognised, with several mechanisms identified. In this review, we focus on their direct effects on cellular immunity. We review the effects of antibiotics on mitochondrial function and how they impair specific immune cell functions including chemotaxis, phagocytosis, cytokine production, antigen presentation, and lymphocyte proliferation. Findings are described in a multitude of in vivo and in vitro models. However, their impact on patient immunity and clinical outcomes requires further research. Awareness of the potential adverse effects of antibiotics may improve antimicrobial stewardship. The use of therapeutic drug monitoring may help to reduce dose-dependent effects, which warrants further research.

Review article: Optimisation of biologic (monoclonal antibody) therapeutic response in inflammatory bowel disease.

There are a plethora of therapeutic options for the management of inflammatory bowel disease (IBD). Despite this, clinical outcomes with standard dosing often fall short of established targets. While efforts centre on developing novel therapies, there is an ongoing need to optimise the use of existing agents. To focus on strategies to optimise response to biologic (monoclonal antibody) therapies in IBD, including use of therapeutic drug monitoring (TDM). An extensive review of the published literature. TDM is a strategy aimed at enhancing the effectiveness of drugs with variable exposure-response relationships by measuring serum concentrations of biologic therapies and detecting neutralising antibodies. Reactive TDM is performed when therapeutic goals have not been achieved. Tumour necrosis factor alpha (TNF) inhibitors are the treatment class most frequently associated with immunogenicity and loss of response. Immunogenicity can be reduced through avoidance of low serum drug concentrations by dose optimisation or use of concomitant immunomodulator therapy. Subtherapeutic dosing in the absence of antidrug antibodies is best managed by dose escalation or dose interval reduction. Persistent neutralising drug antibodies necessitate switching to an alternative therapy. Proactively ensuring adequate serum trough levels might help sustain treatment durability and prevent loss of response. Newer non-TNF inhibitors demonstrate less robust exposure-response relationships, and TDM may not prove as beneficial. In the treat-to-target paradigm of IBD treatment, optimising treatment effect with dose optimisation, which may involve strategies including TDM, increases the likelihood of achieving clinical remission and may accomplish deeper levels of remission beyond symptom control.

54512 Use of therapeutic drug monitoring to assess drug levels and antibody development in patients with Hidradenitis Suppurativa on Infliximab therapy

54512 Use of therapeutic drug monitoring to assess drug levels and antibody development in patients with Hidradenitis Suppurativa on Infliximab therapy

Association of Plasma Cabozantinib Concentration With Treatment Response and Adverse Events in Japanese Patients With Advanced Renal Cell Carcinoma.

Cabozantinib is highly effective against advanced renal cell carcinoma (RCC). However, approximately 60% of the patients require a dose reduction due to severe adverse events. Although associations between trough concentrations of cabozantinib and its efficacy and safety have been reported in other countries, reports on Japanese patients are unavailable. Therefore, we investigated the association of cabozantinib trough concentration with therapeutic efficacy and adverse events in Japanese patients with RCC and evaluated the usefulness of therapeutic drug monitoring. In this prospective observational study, we measured the trough concentrations of cabozantinib in 10 Japanese patients with RCC enrolled between May 2022 and September 2023. The associations of trough concentration with treatment response, as determined by RECIST 1.1, and the occurrence of grade 2 or higher adverse events were assessed. Trough concentration was higher in patients with controlled cancer than in those with progressive cancer (1024 ± 352 versus 457 ± 216 ng/mL, P = 0.035). In addition, patients with grade 2 or higher adverse events showed a significantly higher trough concentration than those without (1560 ± 513 versus 807 ± 319 ng/mL, P = 0.032). In particular, grade 2 or higher dysgeusia, anorexia, fatigue, and dyspepsia significantly correlated with trough concentrations. This is the first clinical study to demonstrate a correlation between cabozantinib trough concentration, therapeutic efficacy, and adverse events in Japanese patients with RCC. The therapeutic drug monitoring of cabozantinib could be useful for improving therapeutic efficacy and avoiding serious adverse events.

Amikacin Dosing Analysis in Sepsis Treatment: A Pharmacokinetic Study Based on Therapeutic Drug Monitoring

Objectives: The primary purpose of this research was to evaluate the loading dose and maintenance dose of amikacin in the treatment of sepsis from intensive care unit (ICU) patients from May to July 2023 at the dr. Ramelan Naval Central Hospital in Indonesia. The analysis focus on the use of therapeutic drug monitoring (TDM) results to improve efficacy and safety of amikacin therapy. Material and Methods: A total of 8 sepsis patients received amikacin for 5 days. The loading dose was administered regardless of the renal function and was calculated of 7.5mg / kg body weight, administered intravenously as a bolus. The subsequent maintenance dose was delivered 4 hours following the loading dose at 15mg / kg body weight by an intermittent drip for 1 hour. The TDM measurement was conducted twice on the third day, with sampling conducted at 1.5 and 4 hours following the administration of the third amikacin maintenance dose. Results: The TDM results revealed that the amikacin t½ elpatients demonstrated Cpmax/MIC indices exceeding 8, while three patients exhibited AUC0-24h/MIC indices surpassing 75. The data showed variabilities in pharmacokinetic characteristics of amikacin in the sepsis patients due to comorbidities specifically patient’s creatinine clearance. Conlusion: The dose administered at efficacious doses attaining the desired PK/PD target while minimizing the risk of toxicity The findings of pharmacokinetic parameters on septis patient in Indonesia give valuable insights into the potential of amikacin therapy to enhance the possibility of achieving an effective treatment.

Antibiotic dose optimisation in the critically ill: targets, evidence and future strategies.

To highlight the recent evidence for antibiotic pharmacokinetics and pharmacodynamics (PK/PD) in enhancing patient outcomes in sepsis and septic shock. We also summarise the limitations of available data and describe future directions for research to support translation of antibiotic dose optimisation to the clinical setting. Sepsis and septic shock are associated with poor outcomes and require antibiotic dose optimisation, mostly due to significantly altered pharmacokinetics. Many studies, including some randomised controlled trials have been conducted to measure the clinical outcome effects of antibiotic dose optimisation interventions including use of therapeutic drug monitoring. Current data support antibiotic dose optimisation for the critically ill. Further investigation is required to evolve more timely and robust precision antibiotic dose optimisation approaches, and to clearly quantify whether any clinical and health-economic benefits support expanded use of this treatment intervention. Antibiotic dose optimisation appears to improve outcomes in critically ill patients with sepsis and septic shock, however further research is required to quantify the level of benefit and develop a stronger knowledge of the role of new technologies to facilitate optimised dosing.

Use of the DMAIC Lean Six Sigma quality improvement framework to improve beta-lactam antibiotic adequacy in the critically ill.

Beta-lactam antibiotics are widely used in the intensive care unit due to their favorable effectiveness and safety profiles. Beta-lactams given to patients with sepsis must be delivered as soon as possible after infection recognition (early), treat the suspected organism (appropriate), and be administered at a dose that eradicates the infection (adequate). Early and appropriate antibiotic delivery occurs in >90% of patients, but less than half of patients with sepsis achieve adequate antibiotic exposure. This project aimed to address this quality gap and improve beta-lactam adequacy using the Define, Measure, Analyze, Improve, and Control Lean Six Sigma quality improvement framework. A multidisciplinary steering committee was formed, which completed a stakeholder analysis to define the gap in practice. An Ishikawa cause and effect (Fishbone) diagram was used to identify the root causes and an impact/effort grid facilitated prioritization of interventions. An intervention that included bundled education with the use of therapeutic drug monitoring (TDM; i.e. drug-level testing) was projected to have the highest impact relative to the amount of effort and selected to address beta-lactam inadequacy in the critically ill. The education and TDM intervention were deployed through a Plan, Do, Study, Act cycle. In the 3 months after "go-live," 54 episodes of beta-lactam TDM occurred in 41 unique intensive care unit patients. The primary quality metric of beta-lactam adequacy was achieved in 94% of individuals after the intervention. Ninety-four percent of clinicians gauged the education provided as sufficient. The primary counterbalance of antimicrobial days of therapy, a core antimicrobial stewardship metric, was unchanged over time (favorable result; P = .73). Application of the Define, Measure, Analyze, Improve, and Control Lean Six Sigma quality improvement framework effectively improved beta-lactam adequacy in critically ill patients. The approach taken in this quality improvement project is widely generalizable to other drugs, drug classes, or settings to increase the adequacy of drug exposure.

The European psychiatric association (EPA) – early career psychiatrists committee survey on trainees’ and early-career psychiatrists’ attitudes towards therapeutic drug monitoring (TDM) use and utility during antipsychotic treatment

Objectives This survey assessed psychiatry residents’/early-career psychiatrists’ attitudes towards the utility of therapeutic drug monitoring (TDM) of antipsychotics. Methods A previously developed questionnaire on attitudes on TDM utility during antipsychotic treatment was cross-sectionally disseminated by national coordinators between 01/01/2022–31/12/2023. The frequency of using TDM for antipsychotics other than clozapine was the main outcome in a linear regression analysis, including sex, clinical setting, caseload, and factors generated by an exploratory factor analysis. Comparisons between residents and early-career psychiatrists, respondents working in in- and outpatient settings, and low-/middle- and high–income countries were performed. Results Altogether, 1,237 respondents completed the survey, with 37.9% having never used TDM for antipsychotics. Seven factors explained 41% of response variance; six of them were associated with frequency of TDM use (p < 0.05). Items with highest loadings for factors included clinical benefits of TDM (factors A and E: 0.7), negative expectations for beliefs of patients towards TDM (factor B: 0.6–0.7), weak TDM scientific evidence (factor C: 0.8), and TDM availability (factor D: −0.8). Respondents from low-/middle-income countries were less likely to frequently/almost always use TDM compared to high-income countries (9.4% vs. 21.5%, p < 0.001). Discussion TDM use for antipsychotics was poor and associated with limited knowledge and insufficient availability.

Drugs with a negative impact on cognitive functions (part 3): antibacterial agents in patients with chronic kidney disease.

The relationship between chronic kidney disease (CKD) and cognitive function has received increased attention in recent years. Antibacterial agents (ABs) represent a critical component of therapy regimens in patients with CKD due to increased susceptibility to infections. Following our reviewing work on the neurocognitive impact of long-term medications in patients with CKD, we propose to focus on AB-induced direct and indirect consequences on cognitive function. Patients with CKD are predisposed to adverse drug reactions (ADRs) due to altered drug pharmacokinetics, glomerular filtration decline, and the potential disruption of the blood-brain barrier. ABs have been identified as a major cause of ADRs in vulnerable patient populations. This review examines the direct neurotoxic effects of AB classes (e.g. beta-lactams, fluoroquinolones, aminoglycosides, and metronidazole) on the central nervous system (CNS) in patients with CKD. We will mainly focus on the acute effects on the CNS associated with AB since they are the most extensively studied effects in CKD patients. Moreover, the review describes the modulation of the gut microbiota by ABs, potentially influencing CNS symptoms. The intricate brain-gut-kidney axis emerges as a pivotal focus, revealing the interplay between microbiota alterations induced by ABs and CNS manifestations in patients with CKD. The prevalence of antibiotic-associated encephalopathy in patients with CKD undergoing intravenous AB therapy supports the use of therapeutic drug monitoring for ABs to reduce the number and seriousness of ADRs in this patient population. In conclusion, elucidating AB-induced cognitive effects in patients with CKD demands a comprehensive understanding and tailored therapeutic strategies that account for altered pharmacokinetics and the brain-gut-kidney axis.

"Getting the Dose Right"-Revisiting the Topic With Focus on Biologic Agents.

Nearly two decades after the Peck and Cross article '"Getting the dose right: facts, a blueprint, and encouragements" was published, a review of dose recommendations for biologics shows that the success in getting the dose right appears to have improved given the relatively low incidence of drug withdrawals and dosing/label changes. However, the clinical experience with monoclonal antibodies (MAbs) following approval has been less than perfect. In inflammatory diseases, the disease burden changes with time and high treatment failure rates have been reported. In addition, the use of concomitant steroids and immunosuppressant drugs with MAbs is common. These concomitant agents have their own safety issues and many immunosuppressant agents are not well-tolerated although they have been shown to reduce the incidence of anti-drug antibodies (ADA). This same complexity is seen in MAbs used in oncology as well, although with these agents the doses appear to be higher than needed, which results in high treatment costs and incidence of adverse events. Given the complexity of MAb pharmacokinetics, which makes providing a detailed description of dose options difficult, product labeling should include the options for alternative dose strategies and potentially include the use of therapeutic drug monitoring with dose individualization which have been shown to improve clinical response and reduce the incidence of ADA. So, while the recommended dosing for biologics seems improved over the issues noted 17 years ago, we still have some work to do.

A Score to Predict the Clinical Usefulness of Therapeutic Drug Monitoring: Application to Oral Molecular Targeted Therapies in Cancer.

Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids to adjust drug dosages. In onco-hematology, TDM guidelines for oral molecular targeted therapies (oMTTs) are varied. This study evaluates a quantitative approach with a score to predict the clinical usefulness of TDM for oMTTs. We identified key parameters for an oMTT's suitability for TDM from standard TDM recommendations. We gathered oMTT pharmacological data, which covered exposure variability (considering pharmacokinetic (PK) impact of food and proton pump inhibitors), technical intricacy (PK linearity and active metabolites), efficacy (exposure-response relationship), and safety (maximum tolerated dose, and exposure-safety relationship). To assess the validity and the relevance of the score and define relevant thresholds, we evaluated molecules with prospective validation or strong recommendations for TDM, both in oncology and in other fields. By September 1, 2021, the US Food and Drug Administration (FDA) approved 67 oMTTs for onco-hematological indications. Scores ranged from 15 (acalabrutinib) to 80 (sunitinib) with an average of 48.3 and a standard deviation of 15.6. Top scorers included sunitinib, sorafenib, cabozantinib, nilotinib, and abemaciclib. Based on scores, drugs were categorized into low (< 40), intermediate (≥ 40 and < 60), and high (≥ 60) relevance for TDM. Notably, negative controls generally scored around or under 40, whereas positive controls had a high score across different indications. In this work, we propose a quantitative and reproducible score to compare the potential usefulness of TDM for oMTTs. Future guidelines should prioritize the TDM for molecules with the highest score.

Clinical consequences of infliximab immunogenicity and the effect of proactive therapeutic drug monitoring: exploratory analyses of the randomised, controlled NOR-DRUM trials

Antidrug antibodies to TNF inhibitors might affect clinical outcomes. Proactive therapeutic drug monitoring allows for early detection of antidrug antibodies and might reduce negative clinical consequences. We aimed to explore how antidrug antibodies to the TNF inhibitor infliximab influence treatment outcomes, and to assess the effect of proactive therapeutic drug monitoring. This was a predefined exploratory analysis of data from the randomised, controlled NOR-DRUM trials. The trials were conducted in rheumatology, gastroenterology, and dermatology departments at 21 Norwegian hospitals. Adult patients (aged 18-75 years) with immune-mediated inflammatory diseases were randomly assigned to proactive therapeutic drug monitoring or standard infliximab dosing in the NOR-DRUM A trial (30-week follow-up) and the NOR-DRUM B trial (52-week follow-up). Antidrug antibodies were assessed with a drug-sensitive assay before each infusion. The outcomes of remission (at week 30), disease worsening (during 52 weeks), infusion reactions, and infliximab discontinuation were assessed according to the presence of antidrug antibodies and use of therapeutic drug monitoring. Between March 1, 2017, and Dec 12, 2019, 616 patients were included in the NOR-DRUM trials, of whom 615 had at least one serum infliximab and antidrug antibody assessment and were included in the present analyses. Mean age was 45 years (IQR 32-56), 305 (50%) patients were women, and 310 (50%) patients were men. Antidrug antibodies were detected in 147 (24%) patients. Remission at week 30 occurred in 25 (35%) of 72 patients with antidrug antibodies and 180 (54%) of 335 without antidrug antibodies (risk ratio 0·62 [95% CI 0·45-0·86]; p=0·0037). In patients with antidrug antibodies compared with patients without antidrug antibodies, higher rates were found for: disease worsening over 52 weeks (0·76 per person-year vs 0· 35 per person-year, hazard ratio [HR] 2·02 [95% CI 1·33-3·07]; p=0·0009), infusion reactions (0·16 per person-year vs 0·03 per person-year, HR 17·02 [6·98-41·47]; p<0·0001), and infliximab discontinuation (1·00 per person-year vs 0·20 per person-year, HR 6·64 [4·84-9·11]; p<0·0001). These associations were more pronounced in patients with high concentrations of antidrug antibodies than in those with low concentrations of antidrug antibodies. Independent of antibody status, therapeutic drug monitoring was associated with a lower risk of disease worsening (HR 0·41 [0·29-0·59]; p=0·0001) or an infusion reaction (HR 0·30 [0·12-0·73]; p=0·0076), and was associated with an increase in the rate of infliximab discontinuation (HR 1·37 [1·02-1·83]; p=0·037). In patients where antidrug antibodies were detected, remission was less likely to be reached and sustained, and infusion reaction or discontinuation of infliximab was more likely. Timely detection of antidrug antibodies by proactive therapeutic drug monitoring facilitated treatment decisions that reduced the negative consequences, both regarding infliximab effectiveness and safety. This highlights the role of proactive therapeutic drug monitoring in optimising infliximab therapy. Inter-regional KLINBEFORSK grants and South-Eastern Norway Regional Health Authority grants.

The Relevance of Integrating CYP2C19 Phenoconversion Effects into Clinical Pharmacogenetics.

CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on the effect size of PC for CYP2C19 functional status. The primary aim of this study was to investigate the impact of PC on CYP2C19 functional status. Two patient cohorts (total n=316; 44.2±15.4 years) were investigated for the functional enzyme status of CYP2C19 applying two different correction methods (PCBousman, PCHahn&Roll) as well as serum concentration and metabolite-to-parent ratio of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone, and quetiapine. There was a decrease in the number of normal metabolizers of CYP2C19 and an increase in the number of poor metabolizers. When controlled for age, sex, and, in the case of amitriptyline, venlafaxine, and risperidone, CYP2D6 functional enzyme status, an association was observed between the CYP2C19 phenotype/functional enzyme status and serum concentration of amitriptyline, sertraline, and escitalopram. PC of CYP2C19 changes phenotypes but does not improve correlations with serum concentrations. However, only a limited number of patients received perturbators of CYP2C19. Studies with large numbers of patients are still lacking, and thus, it cannot be decided if there are minor differences and which method of correction to use. For the time being, PC is relevant in individual patients treated with CYP2C19-affecting drugs, for example, esomeprazole. To ensure adequate serum concentrations in these patients, this study suggests the use of therapeutic drug monitoring.

Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy.

A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols. The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated. A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment. This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

Ustekinumab Drug Levels and Outcomes in Inflammatory Bowel Disease.

Data regarding the utility of therapeutic drug monitoring with ustekinumab (UST) are sparse. Our aim was to determine the correlation of UST levels with outcomes in a cohort of patients with inflammatory bowel disease (IBD). This was a multicenter, retrospective study of all patients with IBD who received UST from January 1, 2014 to March 1, 2022. The primary outcomes were the correlation of UST level with clinical remission (per physician global assessment), endoscopic healing [the absence of ulcers/erosions in Crohn's disease (CD) and Mayo endoscopic score ≤1 for ulcerative colitis (UC)], and normal serum C-reactive protein (CRP) (≤5mg/L). Secondary outcomes included defining optimal UST trough levels associated with favorable outcomes. A total of 71 patients (74.6% with CD; 57.7% female) were included. The median age was 39.5 years [interquartile range (IQR): 26 to 52] and 12.6% were on combination therapy with immunomodulators. Median UST trough levels were significantly higher in patients who achieved endoscopic healing at 5.4µg/mL versus 3.5µg/mL (P=0.035) and normal CRP at 5.5µg/mL versus. 3.1µg/mL (P=0.002). A cutoff UST level of 4.8µg/mL yielded the highest area under the curve (AUC) of 0.73 (95% CI: 0.61-0.80) to predict a normal CRP followed by a cutoff of 3.5µg/mL which yielded an AUC of 0.66 (95% CI: 0.52-0.81) to predict endoscopic healing. UST trough levels were significantly higher in patients who achieved a normal CRP and endoscopic healing. A cutoff UST level of 4.8µg/mL reliably predicted CRP normalization.

VALIDATION OF AN INFLIXIMAB POPULATION PHARMACOKINETIC MODEL FOR MAINTENANCE DOSING IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Abstract INTRODUCTION The use of infliximab has revolutionized the care of pediatric patients with inflammatory bowel disease (IBD); however, infliximab may lose efficacy over time during the maintenance phase and the use of therapeutic drug monitoring has been advocated to improve response rates. A population pharmacokinetic (popPK) model using infliximab concentrations, common clinical biomarkers, and demographic information to predict future infliximab concentrations would be clinically invaluable. Previous popPK models such as the Buurman [1] and Fasanmade [2] exist, but their utility, accuracy, and predictive values have not been clinically validated. This study aims to validate a reliable set of covariates for an infliximab popPK model that will predict maintenance drug concentrations and guide treatment decisions for children with IBD. METHODS This retrospective study included 134 pediatric patients with 503 infliximab trough concentrations between 5 and 21 years of age, seen at the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at UH Rainbow Babies and Children’s Hospital between January 1, 2008 and December 31, 2018. We recorded the patients' therapeutic infliximab trough concentrations and other clinical and demographic factors. In previous work, we refit published popPK models using induction phase data. Here, we refit our originally constructed one-compartment model based on induction phase data, the Cleveland Model, with maintenance phase data to yield the Cleveland Refit model. We then tested six different models: Buurman (B), Buurman Refit (BR), Fasanmade (F), Fasanmade Refit (FR), Cleveland (C), and Cleveland Refit (CR). Each model was evaluated on root mean square error (RMSE), mean percent error (MPE), and accuracy of the predicted infliximab concentration. We defined accuracy as the percentage of samples each model correctly predicted to be on the same side of 5 ug/mL, which is our clinical trough target. RESULTS On the first infliximab concentration following the induction phase, published models refit on induction phase data (BR, FR) have higher accuracy but also higher RMSE than published models. In contrast, the CR model was refit on maintenance phase data and has higher accuracy (71.1% vs 66.7%) and lower RMSE (6.8 vs 7.8 ug/mL) and MPE (-5% vs 10%) than the previous induction-only model. CONCLUSIONS The CR model improved upon the performance of the induction-only models tested on this cohort. This study suggests refit popPK models on a specific patient population work well for predicting maintenance phase infliximab concentrations, and may be useful for personalization of dose of frequency for pediatric patients with IBD. Further validation with external data in a multicenter, prospective study is needed. References 1) https://doi.org/10.1111/apt.13299 2) https://doi.org/10.1016/j.clinthera.2011.06.002

P1164 Early monitoring of ustekinumab concentration after induction is related to clinical remission in ulcerative colitis &amp; Crohn`s disease - STOCUSTE study

Abstract Background Ustekinumab (UST), an anti-interleukin-12/23 antibody, is used to treat moderate to severe inflammatory bowel disease (IBD). The STOCUSTE study includes IBD patients treated with UST at four teaching hospitals in Stockholm to provide long-term follow-up data. We investigated in a real-world setting the utility of therapeutic drug monitoring (TDM) to optimize treatment and correlated the serum concentrationof UST to clinical outcomes. Methods This retrospective study includes patients diagnosed with Crohn’s disease (CD) and ulcerative colitis (UC) treated with UST and followed until withdrawal of treatment for any reason, or until end of study,July 31, 2021. Concentration data and dosing interval were collected at each follow-up (3, 6, 9, 12, 24,36, 48, 60 months) in relation to presence of remission defined as Physician Global Assessment (PGA)= 0. Results In total, 418 patients were included, 322 (48% females) with CD and 96 (46% females) with UC. In 229 patients the UST concentration was analyzed at least once and never in the remaining 188 patients. In general, the UST serum concentrations were above 1 μg/ml. At 3 months follow-up, patients in remission had a significant higher concentration of UST compared to non-remitting patients. (Table 1) in the total cohort, as well as when analyzed separately in UC ad CD. There was no significant difference in UST concentrations at 6 months or later between patients in remission versus non-remission for either IBD diagnosis. Further, TDM was related to higher rates of remission at 3 months of follow-up. Conclusion In this study, early measurement of serum UST (≤3 months) correlated to the clinical response. Serum concentrations at later time points were similar in patients in remission and in patients with active disease. These results from a real-world setting might partly be explained by that serum concentrations were not taken in a systematic manner.

Usefulness of therapeutic drug monitoring with tacrolimus and mycophenolate in kidney transplantation

Usefulness of therapeutic drug monitoring with tacrolimus and mycophenolate in kidney transplantation