Utilization Of Therapeutic Drug Monitoring Research Articles

Therapeutic drug monitoring of perampanel: Clinical utility and impact of co-medication on pharmacokinetic variability

BackgroundPerampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER. MethodWe analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups. ResultsOverall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration. ConclusionPER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments.

Early Target Attainment With Continuous Infusion Meropenem and Piperacillin/Tazobactam and Utilization of Therapeutic Drug Monitoring in Critically Ill Patients: A Retrospective Cohort Study From 2017 to 2020.

We analyzed the attainment of early pharmacological targets of continuous infusion meropenem and piperacillin/tazobactam and the use and effect of a real-time therapeutic drug monitoring (TDM) program on subsequent dosing and target attainment in patients who are critically ill. This was a single-center, retrospective study among patients hospitalized in the intensive care unit in a Swiss tertiary care hospital from 2017 to 2020. The primary outcome was target attainment [100% tT ≥ 4xECOFF (Pseudomonas aeruginosa)] of continuous infusion meropenem and piperacillin/tazobactam within 72 hours after initiation of treatment. A total of 234 patients were included. Median first meropenem (n = 186 of 234) and piperacillin (n = 48 of 234) concentration was 21 mg/L (interquartile range [IQR], 15.6-28.6) and 100.7 mg/L (IQR, 64.0-160.2), respectively. Pharmacological target was attained in 95.7% (95% confidence interval [CI], 91.7-98.1) of patients receiving meropenem and 77.0% (95% CI, 62.7-87.9) treated with piperacillin/tazobactam. In the univariable and multivariable logistic regression, body weight and estimated glomerular filtration rate were negatively associated with target attainment. Subsequently, meropenem dosage was decreased or stopped in 35 of 186 (18.8%) and 89 of 186 (47.9%) patients, respectively, and increased in 2 of 186 (1.1%) patients. Continuous infusion meropenem and piperacillin/tazobactam yielded excellent and moderate early pharmacological target attainment in critically ill patients, respectively. The TDM was mainly used to decrease meropenem dosage.

Therapeutic drug monitoring in inflammatory bowel disease: implementation, utilization, and barriers in clinical practice in Scandinavia

Background and aims Therapeutic drug monitoring (TDM) may optimize biologic and thiopurine therapies in inflammatory bowel disease (IBD). The study aimed to investigate implementation and utilization of TDM in Scandinavia. Methods A web-based questionnaire on the use of TDM was distributed to Scandinavian gastroenterologists via the national societies. Results In total, 297 IBD physicians prescribing biologic therapies, equally distributed between community and university hospitals, were included (response rate 42%) (Norway 118 (40%), Denmark 86 (29%), Sweden 50 (17%), Finland 33 (11%), Iceland 10 (3%)). Overall, TDM was applied during biologic therapies by 87%, and for TNF-inhibitors >90%. Among the users, reactive and proactive TDM were utilized by 90% and 63%, respectively. Danish physicians were significantly less inclined to use TDM compared to other Scandinavian countries; (58% vs 98%); OR 0.03 [0.01–0.09], p < 0.001). Reactive TDM was commonly applied at primary (74%) and secondary (99%) treatment failure. Proactive TDM was used by 80% during maintenance therapy and 56% during induction and more commonly utilized in Norway (p < 0.001), and by physicians managing >10 IBD patients/week (p = 0.005). TDM scenarios were interpreted in accord with available evidence but with discrepancies for proactive TDM. The main barriers to TDM were lack of guidelines (51%) and time lag between sampling and results (49%). TDM of thiopurines was routinely used by 87%. Conclusion TDM of biologic and thiopurine therapies has been broadly implemented into clinical practice in Scandinavia. However, physicians call for TDM guidelines detailing indications and interpretations of test results along with improved test response times.

A Case of Suspected Lacosamide-induced Paroxysmal Atrial Fibrillation and Bradycardia-tachycardia Syndrome and Utilization of Therapeutic Drug Monitoring

A Case of Suspected Lacosamide-induced Paroxysmal Atrial Fibrillation and Bradycardia-tachycardia Syndrome and Utilization of Therapeutic Drug Monitoring

Blood Levels to Optimize Antipsychotic Treatment in Clinical Practice: A Joint Consensus Statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie.

The quantification of antipsychotic levels in blood, also known as therapeutic drug monitoring (TDM), is a potentially useful tool of modern personalized therapy that can be applied to augment antipsychotic use and dosing decisions. The application of TDM for antipsychotics can be helpful in numerous challenging clinical scenarios, such as lack of therapeutic response, relapse, or adverse drug reactions (ADRs) related to antipsychotic treatment. The benefits of TDM may be particularly evident in the treatment of highly vulnerable patient subgroups, such as children, adolescents, pregnant women, and the elderly. The main aim of this article is to aid clinicians who routinely prescribe antipsychotics to successfully apply TDM in routine clinical practice in order to help optimize the efficacy and safety of those antipsychotics. Participants were clinicians and researchers, members of the American Society of Clinical Psychopharmacology, and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association of Neuropsychopharmacology and Pharmacopsychiatry). TDM literature on antipsychotics was critically reviewed to provide a condensed clinical decision-making algorithm with therapeutic reference ranges for blood antipsychotic levels, within which patients are most likely to respond and tolerate treatment, although TDM is not equally recommended/supported for all antipsychotics. A preliminary draft was prepared and circulated to the writing group members. Consensus was achieved in all cases, and resulting recommendations focused on following areas: steady-state and sampling time, levels of recommendations, indications, therapeutic reference ranges and laboratory alert levels, practical issues, and interpretation, as well as limitations. The utilization of TDM as a tool for problem solving in antipsychotic treatment offers a unique method to improve safety and efficacy. This consensus statement summarizes essential information on the routine use of TDM for antipsychotics and encourages clinicians to perform TDM with the appropriate indications as part of the clinical decision-making process.

Therapeutic Drug Monitoring of Targeted Anticancer Protein Kinase Inhibitors in Routine Clinical Use: A Critical Review.

Therapeutic response to oral targeted anticancer protein kinase inhibitors (PKIs) varies widely between patients, with insufficient efficacy of some of them and unacceptable adverse reactions of others. There are several possible causes for this heterogeneity, such as pharmacokinetic (PK) variability affecting blood concentrations, fluctuating medication adherence, and constitutional or acquired drug resistance of cancer cells. The appropriate management of oncology patients with PKI treatments thus requires concerted efforts to optimize the utilization of these drug agents, which have probably not yet revealed their full potential. An extensive literature review was performed on MEDLINE on the PK, pharmacodynamics, and therapeutic drug monitoring (TDM) of PKIs (up to April 2019). This review provides the criteria for determining PKIs suitable candidates for TDM (eg, availability of analytical methods, observational PK studies, PK-pharmacodynamics relationship analysis, and randomized controlled studies). It reviews the major characteristics and limitations of PKIs, the expected benefits of TDM for cancer patients receiving them, and the prerequisites for the appropriate utilization of TDM. Finally, it discusses various important practical aspects and pitfalls of TDM for supporting better implementation in the field of cancer treatment. Adaptation of PKIs dosage regimens at the individual patient level, through a rational TDM approach, could prevent oncology patients from being exposed to ineffective or unnecessarily toxic drug concentrations in the era of personalized medicine.

Pharmacokinetic/pharmacodynamic variations during sepsis/septic shock

Sepsis, a heterogeneous syndrome, is usually associated with uncontrolled body response to a systemic infection leading to dysregulated pro- and anti-inflammatory cascades.1 This, subsequently, leads to immune suppression, tissue damage, and organ failure. With time, the natural body compensation is lost and a state of shock, characterized by profound hypotension and abnormal cellular metabolism, ensues. Sepsis and septic shock are thus considered major challenges in critical care management due to the high rates of complications, including morbidity and mortality. Successful management of sepsis/septic shock necessitates implementation of urgent treatment measures targeting the underlying infection, as well as improving patient's hemodynamics.2 Treatment measures include administration of antimicrobials, vasoactive drugs, sedatives, analgesics, along with others with the aim of achieving effective, yet safe concentrations of different administered medications at the targeted site of action.3 However, this aim of efficient medication dosing attainment can be challenging in critically ill septic patients. The host response to sepsis is usually associated with tremendous changes of different physiological processes.3,4 Different studies have shown that such pathophysiological alterations were linked to dysregulations in both pharmacokinetic (PK) and pharmacodynamic (PD) properties of different administered medications and thus result in complicated drug dosing.3,4 Pharmacokinetics of a given therapy is usually linked to the administered dose and the corresponded changes of concentrations inside the body with time, whereas pharmacodynamics describes the resultant relation between the obtained drug concentration and its pharmacological effect. In-vivo efficacy of an administered medication is largely driven by its intrinsic PK and PD properties. Variations in PK/PD are not always universal or easily predictable, and different aspects can affect the overall discrepancies. Those aspects include disease, patient and drug related factors.5 For instance, the alterations of PK/PD properties seen with sepsis can be different from those seen with septic shock. A similar thing applies to the drug properties where the therapeutic concentrations of a lipophilic medication might be less prone to changes as compared to a hydrophilic therapy. Likewise, the co-existence of different conditions that influence overall medications' pharmacokinetics can complicate proper prediction of therapeutic concentrations. This is frequently encountered in critically ill patients presenting with sepsis/septic shock and requiring the use of renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO), plasmapheresis, or even all in certain individuals.A deep understanding of various pathophysiologic changes seen in critically ill patients and their effects on the overall drug PK/PD is thus essential. This ensures that personalized dosing regimens are tailored to each patient to achieve an optimized therapy rather than using a “one size fits all” model of drug dosing. The implementation of personalized tailored therapy based on patient specific parameters, along with the utilization of therapeutic drug monitoring can successively give rise not only to improved clinical efficacy but also to decreased toxicity and antimicrobial resistance. Subsequently this would result in improved patient outcomes and survival.

A nationwide utilization survey of therapeutic drug monitoring for five antibiotics in South Korea.

PurposeThe current status of therapeutic drug monitoring (TDM) assay utilization by clinical laboratories in South Korea remains little known. We investigated the TDM status of five antibiotics known for nephrotoxicity (vancomycin, amikacin, gentamicin, tobramycin, and teicoplanin) for the improvement of TDM in South Korea among patients with infectious diseases using a cross-sectional nationwide survey.Patients and methodsWe developed an online questionnaire and collected responses using a user-friendly web-based platform. The survey included questions about laboratory characteristics, implementation and operation of drug assays, implementation and operation of TDM consulting services, patient needs, and barriers to providing better TDM service including expectations and concerns about other platform-based drug assays.ResultsAmong a total of 235 clinical laboratories, 112 (47.7%) responded, and 62 of the responding laboratories (55.4%) possessed drug assay facilities. Only 41.2% to 58.1% of respondents were providing TDM consulting services for each antibiotic. Respondents indicated that there are unmet needs regarding drug assays and TDM consultation as well as barriers to TDM utilization including high operating costs, lack of knowledge about TDM, lack of user-friendly software, lack of medical and laboratory information systems that can access patient information critical for TDM dose calculation, and reimbursement issues.ConclusionThis study, the first nationwide survey addressing these questions, showed that there are barriers against the utilization of TDM in South Korea. These barriers may be addressed by improving drug assays and TDM consulting services with the goals of new analytical method development, better interpretation of results, consultation services, and quality control.

Tu1828 – Enhancing Utilization of Therapeutic Drug Monitoring in Inflammatory Bowel Disease Correlates with Improved Outcomes

Tu1828 – Enhancing Utilization of Therapeutic Drug Monitoring in Inflammatory Bowel Disease Correlates with Improved Outcomes

Therapeutics for Inflammatory Bowel Diseases in Children and Adolescents: A Focus on Biologics and an Individualized Treatment Paradigm.

Pharmacologic treatment of children and adolescents with inflammatory bowel diseases (IBD) [Crohn's disease and ulcerative colitis] requires consideration of disease and medication effects on growth and nutrition, the importance of durability of biologics, and concerns for long-term sequelae of disease and therapies. Achieving early remission in children with Crohn's disease correlates with improved outcomes and therefore allows a window of opportunity for maximizing growth. Thus, there is a great need to treat children and adolescents with the right drug at the right time while achieving adequate exposure. Improved understanding of disease phenotypes, disease natural history, and risk stratification will play a critical role in treatment selection for children, particularly as more therapeutic options become available. Here we summarize data supporting newer concepts of treating the individual child with IBD through targeted early biologic treatment, including utilization of therapeutic drug monitoring to optimize treatment effects and the use of early antitumor necrosis factor (TNF)-α therapies to mitigate long-term sequelae of the disease. Recent inception cohort studies provide important data regarding the risk stratification of children and adolescents with IBD, which support a move toward a personalized therapeutic approach to IBD in children and adolescents.

Development of a limited‐sampling model for prediction of doxorubicin exposure in dogs

Understanding the relationship between drug dose and exposure (pharmacokinetics, PK) and the relationship between exposure and effect (pharmacodynamics) is an important component of pharmacology when attempting to predict clinical effects of anticancer drugs. PK studies can provide a better understanding of these relationships; however, they often involve intensive sampling over an extended period of time, resulting in increased cost and decreased compliance. Doxorubicin (DOX), one of the most widely used antineoplastic agents in veterinary cancer therapy, is characterized by large interpatient variability in overall drug exposure and the development and degree of myelosuppression following equivalent dosages. We have developed and validated a limited-sampling strategy for DOX, in which three blood samples are obtained over 1 h post-treatment, that accurately predicts patient exposure. This strategy could allow for refining of dosing variables and utilization of therapeutic drug monitoring to ensure optimized dosing.

Predictability of individualized dosage regimens of carbamazepine and valproate mono- and combination therapy

Many investigators agree that appropriate rational utilization of therapeutic drug monitoring (TDM) with Bayesian feedback dosage adjustment facilitates epilepsy treatment with carbamazepine (CBZ) and/or valproate (VPA) by increasing the seizure control and safety, as well as by reducing treatment costs. In previous works we have developed and used in clinical practice population pharmacokinetic (PK) models of different dosage forms for VPA and post-induction CBZ behaviour, as well as for combined therapy with CBZ plus another 'old' antiepileptic drug (AED). An important step of external validation is to evaluate how well a procedure of Bayesian individualizing AED dosage regimens based on a proposed population PK model and sparse TDM data 'works', and how helpful it is in real practical clinical settings. The aim of this study was to evaluate the predictability of individualized dosage regimens for monotherapy with CBZ in the post-induction period or with VPA, as well as for CBZ and VPA given as combination therapy based on TDM data of epileptic patients and the earlier developed population models. Four groups of TDM data were analysed using the USC*PACK software for PK/PD analysis: 556 predictions for adult epileptic patients on CBZ monotherapy, 662 predictions for VPA monotherapy, 402 predictions of CBZ serum levels and 430 predictions of VPA serum levels for adult epileptic patients on CBZ+VPA combination therapy. Statistical characteristics of the prediction errors (PE) and weighted PE were used to estimate bias and precision of predictions. Intraindividual and interoccasional variability of predictions were also estimated. This study demonstrated that in most cases of CBZ and VPA monotherapy and combination therapy, predictions of future AED concentrations based on the earlier developed population PK models, TDM data and patient-specific maximum a posteriori probability Bayesian posterior parameter values provided clinically acceptable estimates. Statistical analysis of the residuals demonstrated that the distributions of residual and weighted residual were close to the normal distribution (Kolmogorov-Smirnov test, P > 0·05) and their mean values did not differ statistically significant from zero (no statistically significant bias, P > 0·05) for all groups of predictions. The observed decreased quality of predictions of VPA concentrations during VPA+CBZ combination therapy, especially when CBZ dosages were changed, might well be explained by their PK interactions. For all groups, in linear regression analysis, the observed trend of decreasing of the prediction quality over various future prediction time horizons was considered statistically significant (P < 0·05). Prediction of serum levels further in future was less precise than those closer to the present for a 1·5- to 3·5-year observation period. No bias in predictions was associated with the time horizons. Our validation results suggest good predictive performance of the population models developed earlier, and quite acceptable predictions of future AED serum levels for individualized dosage regimens of CBZ and VPA therapy in real clinical settings.

Therapeutic Drug Monitoring: Appropriateness and Clinical Utility in Neuropsychiatry Practice

A retrospective study was conducted to assess the appropriateness of the utilization of therapeutic drug monitoring (TDM) services with regards to antiepileptic drugs (AEDs) at a tertiary care hospital, and analysis of 5094 samples of the carbamazepine (CBZ), phenytoin (PHT), valproic acid (VAP), and phenobarbitone (PB) was undertaken. Maximum requisitions were received for CBZ (54.92%) followed by PHT (27.05%), VAP (14.40%), and PB (3.61%). About 2.12% requisitions were received for patients taking unlabeled AEDs. Reasons for TDM were routine monitoring (36.3%), adverse drug reactions (ADRs) (17.2%), relapse (30.7%), no response (3.35%), and irregular treatment (2.24%) and not mentioned (10.5%). Majority of the samples (69%) were drawn for measuring trough levels; however, in 22% time of last dose was not mentioned and 9.64% were for peak or random levels. In all, 6.9% requisitions for TDM were sent before steady-state levels, and in 15.5% duration of therapy was not mentioned. Blood levels within therapeutic range were found with CBZ (63%) followed by PB (56.52%), VAP (45.99%), and PHT (42.52%). Blood levels were above therapeutic range in 45.69%, 29%, and 21.73% patients taking VAP, PHT, and PB, respectively. Unsuspected poor compliance was uncovered in 11.8%, 41.2%, and 29.3% requisitions sent with ADR, relapse, and routine monitoring as reason for drug levels, respectively. Only half of all AED measurement requisitions were complete and met the criteria for appropriate AED-level determination. Incomplete requisitions lead to difficulty in uniform interpretation of results and thus add to unnecessary costs.

Utilization of Digoxin and Theophylline Assays in the Eastern Province

The utilization of therapeutic drug monitoring (TDM) for serum digoxin and theophylline was assessed with respect to the indication, time of sample collection and contribution to patient care. A total of 585 serum drug level determinations of digoxin (275) and theophylline (328) were done in a four month period. Reasons for requests were subtherapeutic response (27.5%), suspected toxicity (3.8%), baseline data (26.7%), patients at risk for toxicity (7.7%), and for the remaining 34.4% of orders, no reason was stated. The highest number of requests 246 (42.1%) were from the inpatient ward (INP), followed by emergency room (ER) 32.6%, outpatient department (OPD) 13% and intensive care unit (ICU) 12.3%. Repeated assays accounted for 363 determinations of which 55.9% had levels similar to the previous ones. In this study, we found a high incidence of inappropriateness in patient selection (34.4%), time of serum sample collection (28.4%), and dosage adjustment (46.8%). However, when these audit criteria were analyzed together, the overall appropriateness was as low as 33.5%. This indicated that serum drug monitoring was poorly utilized and did not contribute much to the patient's care. This results in an estimated financial loss per year (for inappropriate use of digoxin and theophylline levels) of about 37,344 Saudi Riyals (US $9,956.00). Corrective educational programs for the staff, based on standard guidelines for TDM, have been initiated and this study is a baseline for future prospective audits.

Italian collaborative study on the utilization of therapeutic drug monitoring in hospital departments. Italian Collaborative Group on Therapeutic Drug Monitoring.

A population base of 6,367 in-patients from 28 general hospital wards was included in a nation-wide project aimed at documenting the extension and criteria of therapeutic drug monitoring (TDM). On randomly selected index days over a 3-month period details of age, clinical status, renal and liver function, diseases, drug therapies, and drug monitoring of all in-patients of eight different clinical specialties were recorded and analyzed. A total of 648 requests for 387 patients (16.3% of the population given drugs for which TDM was available in the hospital) was traced. Digoxin was the most frequently monitored drug (481 requests for 289 patients), accounting for 74% of the overall requests. This finding is consistent with the yearly activity of the laboratories of the same hospitals, which documented that 63% of the whole in-hospital analytical work (29,396 out of 46,692 requests) concerned digoxin. From a more qualitative point of view, data are provided that document a largely inappropriate use of TDM, which was employed only for 20% of patients who might have benefited from it.