Use Of Therapeutic Drug Monitoring Research Articles

"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.

Case Report: Cefepime Induced Neurotoxicity Following a Change in Infusion Time

Purpose: Cefepime is an antibiotic associated with cefepime induced neurotoxicity (CIN), particularly in those with reduced renal function, or in cases of inappropriate medication dosing. This report describes a case of CIN associated with a change in infusion duration from 180 to30 minutes, which to the best of our knowledge has not been previously reported in the literature. Summary: A 73-year old male was treated with extended infusion cefepime over 180 minutes while hospitalized with recurrent pneumonia. On discharge, cefepime was continued as outpatient parenteral antimicrobial therapy (OPAT) administered over 30 minutes. The patient began to experience symptoms of neurotoxicity after 1 day of receiving OPAT, which subsequently led to a readmission as neurological symptoms worsened. Cefepime was discontinued and symptoms resolved within 48 hours. Renal function was stable throughout treatment and no other causes for neurotoxicity were noted. Conclusion: This is a unique case of CIN secondary to shortened infusion time, which is clinically relevant, particularly during transitions of care. Further investigation, including more widespread use of therapeutic drug monitoring will be beneficial to further elucidate the relationship between infusion time and CIN development.

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

Guideline for the use of therapeutic drug monitoring of antipsychotics to individualize the selection of therapy in the treatment of exacerbation of schizophrenia

Significant individual variability in the concentration of antipsychotics (AP) and its impact on both the efficacy and safety of therapy has been shown in many studies. In this regard, the use of therapeutic drug monitoring (TDM) of AP seems to be a clinically relevant method for the individualization of psychopharmacotherapy in the treatment of exacerbations of schizophrenia. The purpose of this work was to develop recommendations on the use of TDM AP for the individualization of therapy for exacerbation of schizophrenia. Materials and methods. To develop recommendations, a literature search was performed on the Medline, Google Scolar and Elibrary databases and the materials of the dissertation of Potanin S.S. "The role of therapeutic drug monitoring of antipsychotics in the individualization of therapy for exacerbations of paroxysmal-progredient schizophrenia" were used. Results. The conducted literature search made it possible to classify AP according to the degree of expediency of TDM, to determine the optimal therapeutic concentrations for each drug, indications for TDM, and to develop a structured decision-making algorithm depending on the results obtained. The main indications for TDM AP in the treatment of exacerbation of schizophrenia are signs of impaired drug compliance, insufficient efficacy of therapy, pronounced dose-dependent side effects, and the addition of concomitant therapy that can significantly affect the concentration of AP. According to the results obtained, TDM is strongly recommended for clozapine, olanzapine and amisulpride, recommended for risperidone, paliperidone, aripiprazole, quetiapine, haloperidol, ziprasidone, perphenazine, sertindole, trifluoperazine, sulpiride and chlorpromazine, for other antipsychotics TDM may be useful in selected cases. A detailed decision-making algorithm is presented in the form of a table and is based on both the clinical situation and the results of TDM AP. Conclusion. Thus, TDM AP seems to be one of the most relevant and potentially close to the introduction into everyday practice methods of individualization of therapy for exacerbation of schizophrenia.

Development and validation of enzyme-linked immunosorbent assays for the measurement of infliximab and anti-drug antibody levels

Infliximab and its anti-drug antibody (ADA) serum concentrations exhibit a strong correlation with clinical response and loss of response. The use of therapeutic drug monitoring to measure the concentration of infliximab and ADA can facilitate clinical decision-making, helping patients attain optimal therapeutic effects. However, there are still limitations to the existing infliximab and its ADA detection methods. Therefore, this study aimed to develop and validate enzyme-linked immunosorbent assay (ELISA)-based methods for measuring infliximab and its ADA levels in human plasma according to the general recommendations for immunoassays. Free infliximab is bound by recombinant TNF-α and detected using HRP-labeled anti-human antibody. The ADA is captured by on-plate-coated infliximab and recognized by biotin-labeled infliximab. Two bridging ELISA assays were developed and after assay optimization and validation, these assays have been applied in ten patients with inflammatory bowel disease (IBD). In infliximab detection assay, a standard curve ranging from 0.10 μg/mL to 8.0 μg/mL with great precision and accuracy has been established. Drug tolerance of the ADA assay was that 100 ng/mL ADA could tolerate at least 5.0 μg/mL infliximab in the plasma using a commercially available monoclonal anti-infliximab antibody as the positive control. The ADA screening and confirmatory assays achieved a sensitivity of 36.74 ng/mL and 37.15 ng/mL, respectively. All other assay characteristics met the requirements. The mean concentration of infliximab in eight patients with IBD was 7.88 (1.87–21.1) μg/mL, and the ADA levels were all negative. Moreover, the concentrations of infliximab in the remaining two patients were below the LLOQ and the ADAs were positive. Thus, accurate and sensitive ELISA methods have been developed and validated for the detection of infliximab and its ADA concentrations and have been successfully applied to clinical therapeutic drug monitoring.

Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation.

This review describes current knowledge of ganciclovir (GCV) and valganciclovir (ValGCV) pharmacokinetic/pharmacodynamic characteristics, highlighting the likely contribution from host genetic factors to interpatient variability. The evidence and challenges surrounding optimization of drug dosing through therapeutic drug monitoring (TDM) are examined, with recommendations made. Pharmacokinetic studies of current dosing guidelines have shown high interindividual and intraindividual variability of GCV concentrations. This is sometimes associated with a slow decline in cytomegalovirus (CMV) viral load in some transplant recipients. A high incidence of GCV-associated myelosuppression has limited the use of this drug in the transplant setting. Patient groups identified to benefit from GCV TDM include pediatric patients, cystic fibrosis with lung transplantation, obese with kidney transplantation, and patients with fluctuating renal function or on hemodialysis. The emergence of refractory resistant CMV, particularly in immune compromised patients, highlights the importance of appropriate dosing of these antivirals. Host genetic factors need to be considered where recently, two host genes were shown to account for interpatient variation during ganciclovir therapy. Therapeutic Drug Monitoring has been shown to improve target antiviral-level attainment. The use of TDM may guide concentration-based dose adjustment, potentially improving virological and clinical outcomes. However, evidence supporting the use of TDM in clinical practice remains limited and further study is needed in the transplant cohort. Further studies examining novel biomarkers are needed to guide target concentrations in prophylaxis and treatment. The use of TDM in transplant recipients is likely to improve the clinical efficacy of current antivirals and optimize outcomes in transplant recipients.

Pharmacokinetics of Four Tyrosine Kinase Inhibitors in Adult and Paediatric Chronic Myeloid Leukaemia Patients.

Tyrosine kinase inhibitors work by blocking the tyrosine kinases responsible for the dysregulation of intracellular signalling pathways in tumour cells. This study looked at the impact of age and sex on the levels of imatinib, dasatinib, nilotinib, and ponatinib in plasma and cerebrospinal fluid samples of patients with chronic myeloid leukaemia. Imatinib and dasatinib were used to treat the majority of the enrolled patients, and most of them were paediatrics. A total of 82.4% of the patients were men; however, sex-related differences in the drugs' pharmacokinetics were not found. Age and imatinib plasma concentration were found to be inversely correlated. The dasatinib concentrations in plasma were found to be substantially lower than those found in cerebrospinal fluid, particularly in paediatrics. Analysing the obtained data, we can state that therapeutic drug monitoring is a useful method for adjusting a patient's treatment schedule that depends on drug concentrations in biological fluids. The use of therapeutic drug monitoring in conjunction with tyrosine kinase inhibitors for the treatment of chronic myeloid leukaemia is supported by a number of sources of evidence. As a result, as the research develops, the tyrosine kinase inhibitor therapeutic drug monitoring classification needs to be refined in terms of factors like sex and age.

A supervised machine-learning approach for the efficient development of a multi method (LC-MS) for a large number of drugs and subsets thereof: focus on oral antitumor agents.

Accumulating evidence argues for a more widespread use of therapeutic drug monitoring (TDM) to support individualized medicine, especially for therapies where toxicity and efficacy are critical issues, such as in oncology. However, development of TDM assays struggles to keep pace with the rapid introduction of new drugs. Therefore, novel approaches for faster assay development are needed that also allow effortless inclusion of newly approved drugs as well as customization to smaller subsets if scientific or clinical situations require. We applied and evaluated two machine-learning approaches i.e.,a regression-based approach and an artificial neural network (ANN) to retention time (RT) prediction for efficient development of a liquid chromatography mass spectrometry (LC-MS) method quantifying 73 oral antitumor drugs (OADs) and five active metabolites. Individual steps included training, evaluation, comparison, and application of the superior approach to RT prediction, followed by stipulation of the optimal gradient. Both approaches showed excellent results for RT prediction (mean difference ± standard deviation: 2.08 % ± 9.44 % ANN; 1.78 % ± 1.93 % regression-based approach). Using the regression-based approach, the optimum gradient (4.91 % MeOH/min) was predicted with a total run time of 17.92 min. The associated method was fully validated following FDA and EMA guidelines. Exemplary modification and application of the regression-based approach to a subset of 14 uro-oncological agents resulted in a considerably shortened run time of 9.29 min. Using a regression-based approach, a multi drug LC-MS assay for RT prediction was efficiently developed, which can be easily expanded to newly approved OADs and customized to smaller subsets if required.

Usefulness of Therapeutic Drug Monitoring to Manage Clindamycin-Rifampicin Interaction in a Patient with Diabetic Foot Osteomyelitis.

Usefulness of Therapeutic Drug Monitoring to Manage Clindamycin-Rifampicin Interaction in a Patient with Diabetic Foot Osteomyelitis.

Use of a common spreadsheet program to demonstrate the ability of Bayesian forecasting to estimate the pharmacokinetic parameters of antibiotics.

Recent guidelines for vancomycin have incorporated the use of Bayesian forecasting, reinforcing the need to inform students in pharmacy and clinical pharmacology of its use in therapeutic drug monitoring. The goal was to devise a PharmD research project that could demonstrate to students through simulation and data generation the utility of the Bayesian approach in estimating the pharmacokinetics of gentamicin and vancomycin. A series of steps were devised using Microsoft Excel to simulate patient data based on study-derived means and variances, pharmacokinetic modelling, random selection of sparse blood samples, introduce random error into the selected concentrations based on assay variability measure, and finally, inputting of the information into an add-in computer program to find the pharmacokinetic estimates using Bayesian forecasting. Excellent correlations were seen between Bayesian estimates and true clearances. Lower assay variability tended to provide better estimates than larger assay variability for gentamicin, and for vancomycin, selecting a sample during the distribution phase and near the trough values tended to provide estimates with less bias and greater precision. The approach used was able to demonstrate all aspects involved in Bayesian forecasting, and the results supported its use for these antibiotics.

Therapeutic drug monitoring and the therapeutic reference range of levetiracetam for Chinese patients: Problems and issues.

Levetiracetam (LEV) is widely used in the clinical monotherapy or multi-drug combination treatment of seizures due to its good tolerability and efficacy. Due to a lack of large-scale clinical studies, the relationship between levetiracetam concentrations, disease activity and adverse is unclear, limiting the usefulness of therapeutic drug monitoring (TDM) based LEV plasma levels. This study was intended to investigate factors influencing the pharmacokinetics of and the appropriate reference range of LEV concentration using available LEV TDM data. A rapid, accurate and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) method was established to determine LEV plasma concentrations. In this study, the levetiracetam plasma concentration monitoring data from 352 samples (taken from 248 patients) were used to explore the relationship between levetiracetam dose, age, combined administration with other antiseizure medications in patients with epilepsy. Age and combined administration emerged as important affecting factors for the correlation of LEV concentration and dose. The correlation between concentration and dose was better in monotherapy. Combined administration may affect LEV concentration, especially when LEV is combined with oxcarbazepine, which might decrease the LEV concentration. These findings emphasize the need to monitor LEV routinely LEV, especially among children and older adults when other antiseizure comedications are prescribed in the treatment regimen. LEV TDM is a well-established tool for the management of patients with epilepsy.

International survey of antibiotic dosing and monitoring in adult intensive care units

BackgroundIn recent years, numerous dosing studies have been conducted to optimize therapeutic antibiotic exposures in patients with serious infections. These studies have led to the inclusion of dose optimization recommendations in international clinical practice guidelines. The last international survey describing dosing, administration and monitoring of commonly prescribed antibiotics for critically ill patients was published in 2015 (ADMIN-ICU 2015). This study aimed to describe the evolution of practice since this time.MethodsA cross-sectional international survey distributed through professional societies and networks was used to obtain information on practices used in the dosing, administration and monitoring of vancomycin, piperacillin/tazobactam, meropenem and aminoglycosides.ResultsA total of 538 respondents (71% physicians and 29% pharmacists) from 409 hospitals in 45 countries completed the survey. Vancomycin was mostly administered as an intermittent infusion, and loading doses were used by 74% of respondents with 25 mg/kg and 20 mg/kg the most favoured doses for intermittent and continuous infusions, respectively. Piperacillin/tazobactam and meropenem were most frequently administered as an extended infusion (42% and 51%, respectively). Therapeutic drug monitoring was undertaken by 90%, 82%, 43%, and 39% of respondents for vancomycin, aminoglycosides, piperacillin/tazobactam, and meropenem, respectively, and was more frequently performed in high-income countries. Respondents rarely used dosing software to guide therapy in clinical practice and was most frequently used with vancomycin (11%).ConclusionsWe observed numerous changes in practice since the ADMIN-ICU 2015 survey was conducted. Beta-lactams are more commonly administered as extended infusions, and therapeutic drug monitoring use has increased, which align with emerging evidence.

Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring.

Antiseizure medications (ASMs) are the cornerstone of treatment for patients with epilepsy. Several new ASMs have recently been introduced to the market, making it possible to better tailor the treatment of epilepsy, as well as other indications (psychiatry and pain disorders). For this group of drugs there are numerous pharmacological challenges, and updated knowledge on their pharmacodynamic and pharmacokinetic properties is, therefore, crucial for an optimal treatment outcome. This review focuses on educational approaches to the following learning outcomes as described by the International League Against Epilepsy (ILAE): To demonstrate knowledge of pharmacokinetics and pharmacodynamics, drug interactions with ASMs and with concomitant medications, and appropriate monitoring of ASM serum levels (therapeutic drug monitoring, TDM). Basic principles in pharmacology, pharmacokinetic variability, and clinically relevant approaches to manage drug interactions are discussed. Furthermore, recent improvements in analytical technology and sampling are described. Future directions point to the combined implementation of TDM with genetic panels for proper diagnosis, pharmacogenetic tests where relevant, and the use of biochemical markers that will all contribute to personalized treatment. These approaches are clinically relevant for an optimal treatment outcome with ASMs in various patient groups.