Dose Individualization of Cefepime for Febrile Neutropenia in Patients With Lymphoma or Multiple Myeloma: Implications for Therapeutic Drug Monitoring.

BACKGROUND: Optimal cefepime dosing is a challenge because of its dose-dependent neurotoxicity. This study aimed to determine individualized cefepime dosing for febrile neutropenia in patients with lymphoma or multiple myeloma. METHODS: This prospective study enrolled 16 patients receiving cefepime at a dose of 2 g every 12 hours. Unbound concentrations were determined at 0.5 hours, 7.2 hours [at the 60% time point of the 12 hours administration interval (C7.2h)], and 11 hours (trough concentration) after the first infusion (rate: 2 g/h). The primary and secondary end points were the predictive performance of the area under the unbound concentration-time curve (AUC unbound ) and the effect of unbound cefepime pharmacokinetic parameters on clinical response, respectively. RESULTS: The mean (SD) AUC unbound was 689.7 (226.6) mcg h/mL, which correlated with C7.2h (R 2 = 0.90), and the Bayesian posterior AUC unbound using only the trough concentration (R 2 = 0.66). Although higher exposure was more likely to show a better clinical response, each parameter did not indicate a statistical significance between positive and negative clinical responses ( P = 0.0907 for creatinine clearance (Ccr), 0.2523 for C7.2h, 0.4079 for trough concentration, and 0.1142 for AUC unbound ). Cutoff values were calculated as 80.2 mL/min for Ccr (sensitivity: 0.889, specificity: 0.714), 18.6 mcg/mL for C7.2h (sensitivity: 0.571, specificity: 1.000), and 9.2 mcg/mL for trough concentration (sensitivity: 0.571, specificity: 1.000). When aiming for a time above 100% the minimum inhibitory concentration, both continuous infusion of 4 g/d and intermittent infusion of 2 g every 8 hours achieved a probability of approximately 100% at a minimum inhibitory concentration of 8 mcg/mL. CONCLUSIONS: Therapeutic drug monitoring by sampling at C7.2h or trough can facilitate rapid dose optimization. Continuous infusion of 4 g/d was recommended. Intermittent dosing of 2 g every 8 hours was alternatively suggested for patients with a Ccr of 60-90 mL/min.

Therapeutic drug monitoring of ceftazidime/avibactam: why one leg is not enough to run.

BACKGROUND: Therapeutic drug monitoring (TDM) is becoming an increasingly recommended approach for assessing optimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ceftazidime/avibactam. Some authors hypothesized that the PK/PD target attainment of ceftazidime/avibactam could be assessed by means of the TDM of solely ceftazidime, since avibactam concentrations might be extrapolated based on the fixed 4:1 ceftazidime-to-avibactam ratio present in the vial. The reliability of this hypothesis could be called into question if a wide interindividual variability in the ceftazidime-to-avibactam ratio would exist among patients. This study aimed to assess the distribution of the individual ceftazidime-to-avibactam ratios in relation to renal function in a cohort of adult patients who were treated with continuous infusion ceftazidime/avibactam and underwent TDM of both ceftazidime and avibactam. METHODS: Individual ceftazidime-to-avibactam ratio was calculated at each TDM assessment. Receiving operating characteristics (ROC) curve analysis was performed for testing the potential impact of renal function on ceftazidime-to-avibactam ratio variability. RESULTS: A total of 188 TDM assessments were collected from 107 patients. The ceftazidime-to-avibactam ratios ranged from 1.29:1 to 13.46:1. Seventy-seven out of 188 ceftazidime-to-avibactam ratios (41.0%) were >5:1, and 36 (19.1%) were >6:1. Patients without renal dysfunction had significantly higher proportions of ceftazidime-to-avibactam ratio >5:1 (59.3% versus 23.8%; P < 0.001) and >6:1 (32.1% versus 6.3%; P < 0.001) compared with those with mild-to-severe renal dysfunction. CONCLUSIONS: The findings may strengthen the contention that for properly assessing the PK/PD target attainment of ceftazidime/avibactam, both ceftazidime and avibactam concentrations should be measured, given the unpredictability of the ceftazidime-to-avibactam ratio occurring among patients.

Ceftazidime Plasma Concentrations and Neurotoxicity: The Importance of Therapeutic Drug Monitoring in Patients Undergoing Different Modalities of Renal Replacement Therapy. A Grand Round.

ABSTRACT: Ceftazidime-avibactam (CTZ-AVM) is a novel cephalosporin/beta-lactamase inhibitor with broad-spectrum activity against multidrug-resistant Pseudomonas aeruginosa . Ceftazidime-induced neurotoxicity is a well-described adverse effect, particularly in patients with renal insufficiency. However, appropriate dosing of ceftazidime-avibactam in patients undergoing renal replacement therapy (RRT) is sparsely investigated, and therapeutic drug monitoring to guide dosing remains lacking. Furthermore, when dose adjustment for impaired renal function is based on CTZ-AVM product information, inferior cure rates have been obtained compared with those with the standard therapy for intra-abdominal infections. Maintaining an effective dose while avoiding toxicity in these patients is challenging. Here, the authors describe the case of a critically ill patient, undergoing 2 modalities of RRT, who developed ceftazidime-induced neurotoxicity as confirmed using ceftazidime therapeutic drug monitoring. This case illustrates a therapeutic drug monitoring-based approach for guiding ceftazidime-avibactam dosing in this context and in diagnosing the cause of neurological symptoms and signs.

Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma.

BACKGROUND: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. METHODS: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. RESULTS: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg·h/mL or CPT-11 AUC values below 10 mcg·h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC ≥28 mcg·h/mL [HR = 0.251, 95% CI 0.096-0.656; p = 0.005] and CPT-11 AUC <10 mcg·h/mL [HR = 0.189, 95% CI 0.073-0.486, p = 0.001]. CONCLUSIONS: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma.

Should the trough concentration of vancomycin be abandoned in therapeutic drug monitoring? A multicentre, retrospective study of critically ill patients without any form of dialysis.

BACKGROUND: There are conflicts in guideline recommendations about the value and range of vancomycin trough concentration during therapeutic drug monitoring (TDM). This multicentre, retrospective study was conducted to explore the usefulness of trough concentration in specific patients who were critically ill and without any form of dialysis. METHODS: Patient information from five centres was retrospectively collected and the 24-hour area under the curve (AUC) was estimated by a Bayesian method. Patients were categorised into four groups according to trough concentration: < 10, 10-15, 15-20 and > 20 mg/L, and the corresponding AUC was analysed. A multivariable logistic regression model was used to investigate the relationship between trough concentration and AUC. RESULTS: Overall, 645 trough concentrations available from 416 patients were included in this study. The results indicated that the AUC was always < 400 mg/L∙h or > 600 mg/L∙h in the < 10 or > 20 mg/L groups, whereas the ratios of vancomycin AUC target attainment (400-600 mg/L∙h) were 48.8% and 92.3% in the 10-15 mg/L and 15-20 mg/L groups, respectively. Augmented renal clearance, low daily dose and non-q12h administration were found to be independent risk factors associated with AUC target non-attainment for patients with trough concentrations of 10-15 mg/L. CONCLUSION: Vancomycin trough concentration is a good marker of AUC for critically ill adults without any form of dialysis. However, AUC-guided TDM may be needed for patients with trough concentrations of 10-15 mg/L, especially for those with risk factors.

A HPLC-DAD method to facilitate large-scale therapeutic drug monitoring of dalbavancin.

Dalbavancin, a long-acting lipoglycopeptide antibiotic targeting susceptible Gram-positive bacteria, is WHO critically important antibiotic, increasingly used in critical situations such as osteoarticular infections. To ensure its effectiveness and its safety, the therapeutic drug monitoring (TDM) of dalbavancin is strongly recommended. In the absence of an available minimum inhibitory concentration (MIC), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommends a breakpoint of 0.125 mg/L for Staphylococcus aureus, corresponding to a trough target concentration of 25 mg/L. Nowadays, the TDM is usually performed using a high-performance liquid chromatography (HPLC) method coupled with a tandem mass spectrometry. However, this expensive and specialized equipment and reagents may be difficult to acquire for non-specialized laboratories. The use of HPLC coupled with diode array detector (DAD) facilitates TDM with a lower cost, while preserving the reliability of the results. Our aim was to provide a sensitive and specific method, relying on HPLC-DAD for extending the TDM of dalbavancin beyond non-specialized labs, therefore maximizing its efficiency and Benefit/risk ratio. Our method complied with the European Medicines Agency guidelines of bioanalytical validation. Irrespective of the concentrations of dalbavancin, the coefficient of variation < 10% confirmed the reliability of this analytical method, with a calibration curve ranging from 5 to 100 mg/L. No interferences nor carryover was observed. Our HPLC-DAD method, combined with a simple extraction, provides a widely usable, inexpensive and easy-to-implement new asset for the TDM of Dalbavancin.

Amoxicillin therapeutic drug monitoring for endocarditis: A comparative study (EI-STAB).

INTRODUCTION: International guidelines recommend high doses of ß-lactams for most cases of infective endocarditis (IE). Therapeutic drug monitoring (TDM) is increasingly used to adjust ß-lactam dose based on plasma concentrations, although there are no comparative studies to support this practice. The benefit of amoxicillin TDM during IE was evaluated. METHODS: An observational, retrospective, cohort study of adults treated with high-dose amoxicillin for enterococcal or streptococcal IE was conducted in two referral centers. Patients with, or without TDM were compared. The primary outcome was mean daily amoxicillin dose. RESULTS: A total of 206 cases of streptococcal (n=140, 68%) or enterococcal (n=66, 32%) IE were included. IE occurred on prosthetic valves in 77 (37%) cases, and on intracardiac devices in 28 (14%) cases. Aortic valve was involved in 136 (66%) cases. There were 154 men (75%), mean age was 70 ± 14 years, valve surgery was performed in 81/206 (39%) patients, and in-hospital mortality was 8% (17/206). All patients in the TDM group and most patients in the group without TDM received amoxicillin as continuous infusion. Amoxicillin TDM was performed for 114 patients (55.3%), with a mean of 4.7 ± 2.3 measures per patient, a mean plasma steady-state concentration of 41.2 ± 19 mg/L, most (82/114, 72%) being within the therapeutic target (20-80 mg/L). Mean amoxicillin dose was lower in patients with TDM (10.0 ± 3.3 g/day) than those without TDM (11.3 ± 2.0 g/day) (P=0.003). CONCLUSION: Amoxicillin TDM was associated with a reduction in daily doses, with no impact on adverse events and prognosis. Individualized treatment of IE through TDM may contribute to decreased use of antibiotics.

Methotrexate Drug Monitoring From Central Access: Can Blood Sample Collection From Central Venous Access Replace Peripheral Venipuncture in Adults?

BACKGROUND: Intravenous high-dose methotrexate (MTX ≥ 1 g/m 2 ) is frequently used in patients with cerebral lymphoma or other malignancies. In addition to its potent efficacy, it is known to have pronounced toxicity and life-threatening side effects. Regular-level monitoring at short and defined intervals is mandatory. This study aimed to evaluate the possibility of replacing peripheral blood sampling with blood samples from central venous catheters for therapeutic monitoring of MTX in adults. METHODS: A total of 6 patients and 7 cycles of chemotherapy (6 females; 5 with cerebral non-Hodgkin lymphoma and 1 with osteosarcoma, median age 51 years; range 33-62 years) were included. An immunoassay was used for quantitative analysis of MTX levels. The measurement points were obtained in the time intervals of 24, 42, 48, and 72 hours, and afterward, every 24 hours until the level was below <0.1 µmol/L. After flushing with 10 mL of saline solution and discarding 10 mL of venous blood, blood was drawn from the central venous access through which MTX had previously been administered. Simultaneously, MTX levels were obtained from peripheral venipuncture. RESULTS: Methotrexate levels from central venous access and MTX levels from peripheral venipuncture showed a significant correlation (r = 0.998; P < 0.01; n = 35). During withdrawal from the central access group, 17 values showed a lower MTX level, 10 showed a higher level, and 8 showed no difference. However, the MTX level difference was not significant ( P = 0.997, linear mixed model). No increase in the dose of calcium folinate was necessary based on the collected MTX levels. CONCLUSIONS: In adults, MTX monitoring from central venous access is not inferior to monitoring from peripheral venipuncture. Repeated venipuncture to measure MTX levels can be replaced after establishing standardized instructions for proper sampling by a central venous catheter.

Drug monitoring detects under- and overdosing in patients receiving 5-fluorouracil-containing chemotherapy-results of a prospective, multicenter German observational study.

INTRODUCTION: Body surface area (BSA)-based dosing of 5-fluorouracil (5-FU) results in marked inter-individual variability in drug levels, whereas determination of plasma 5-FU concentration and area under the curve (AUC) is a more precise dosing method but has not been integrated into clinical routine. We conducted a multicenter, prospective study to study 5-FU AUC distributions and assess clinical factors predicting therapeutic dosing in patients receiving BSA-dosed 5-FU. METHODS: Between June 2017 and January 2018, a total of 434 patients receiving continuous, infusional BSA-dosed 5-FU from 37 sites in Germany were included. Plasma 5-FU concentration and AUC were measured in venous blood samples at steady state. The primary objective was to determine 5-FU AUC distributions in relation to the target range, which is defined as 20-30 mg × h/l. The second objective was to explore clinical parameters that correlate with achievement of 5-FU AUC target range. RESULTS: The primary tumor was mainly located in the gastrointestinal tract (96.3%), with colorectal cancer being the most common (71.2%) tumor entity. 5-FU was administered as monotherapy (8.1%) or as part of FOLFOX (33.2%), FOLFIRI (26.3%), or other regimens (12.4%). Treatment setting was adjuvant (31.3%) or metastatic (64.5%). The median AUC was 16 mg × h/l. Only 20.3% of patients received 5-FU treatment within the target range, whereas the majority of patients (60.6%) were underdosed and 19.1% of patients were overdosed. In the univariate logistic regression, treatment setting was the only clinical parameter that significantly correlated with achievement of the target range. Patients treated in the metastatic setting had a 2.1 (95% confidence interval 1.186-3.776, P = 0.011) higher odds to reach the target range compared with patients treated in the adjuvant setting. CONCLUSIONS: The majority of patients received suboptimal doses of 5-FU using BSA dosing. Therapeutic drug monitoring of 5-FU is an option for optimized individualized cancer therapy and should be integrated into the clinical practice.

Switching from intravenous to subcutaneous vedolizumab maintenance treatment in patients with inflammatory bowel disease followed by therapeutic drug monitoring.

OBJECTIVE: Vedolizumab (VDZ) for subcutaneous (SC) administration has recently become available. We aimed to assess feasibility, safety and clinical outcome when switching from intravenous (IV) to SC VDZ maintenance treatment in a real world cohort of patients with inflammatory bowel disease (IBD) followed by therapeutic drug monitoring (TDM). METHODS: Eligible IBD patients were switched from IV to SC treatment and assessed six months prior to switch, at baseline and six, twelve and twenty-six weeks after switch. Primary outcome was proportion of patients on SC treatment after 26 weeks. Secondary outcomes included adverse events (AEs), clinical disease activity, biochemical markers, treatment interval, serum-VDZ (s-VDZ), preferred route of administration and health-related quality of life. RESULTS: In total, 108 patients were switched. After 26 weeks, 100 patients (92.6%) were still on SC treatment and median s-VDZ was 47.6 mg/L (IQR 41.3 - 54.6). The most frequent AE was injection site reaction (ISR), reported by 20 patients (18.5%). There were no clinically significant changes in disease activity, biochemical markers and quality of life. The proportion of patients preferring SC administration increased from 28.0% before switch to 59.4% after 26 weeks (p < 0.001). CONCLUSIONS: Nine out of ten patients still received SC treatment after 26 weeks. No change in disease activity occurred, and levels of serum VDZ increased. Although almost one fifth of patients experienced ISRs, a higher proportion favored SC administration at 26 weeks. This study demonstrates that SC maintenance treatment is a safe and feasible alternative to IV treatment.

Utility of Therapeutic Drug Monitoring in Identifying Clinically Significant Interactions Between St. John's Wort and Prescription Drugs.

BACKGROUND: The general population widely uses herbal medicines, as they are regarded as effective and safe. St. John's wort, which is an effective herbal antidepressant, exhibits both pharmacokinetic and pharmacodynamic interactions with several drugs. The aim of this review was to highlight the clinically significant interactions of St. John's wort with drugs that require to be monitored to assess their therapeutic effect. METHODS: Published literature was searched using electronic databases, such as MEDLINE, PubMed, and Elsevier ScienceDirect using terms such as "herbal medicine," "herbal toxicity," "legislation herbal medicine," "drug-herb interactions," "St. John's wort," and "St. John's wort-drug interactions." Searches were limited to the English language, and there was no restriction on the date of publication. RESULTS: St. John's wort exhibits a number of pharmacokinetic and pharmacodynamic interactions with drugs. The most dangerous interactions occurred when used concurrently with the immunosuppressants, cyclosporine, and tacrolimus (treatment failure or organ rejection) or warfarin (treatment failure resulting in thromboembolic events) or antiretroviral agents (treatment failure and the emergence of new viral variants that are resistant to conventional drugs). CONCLUSIONS: Patients should consult their health care providers before consuming herbal supplements, especially St. John's wort, to avoid potentially dangerous drug-herb interactions.

Pharmacokinetics/pharmacodynamics and therapeutic drug monitoring of ceftazidime/avibactam administered by continuous infusion in patients with MDR Gram-negative bacterial infections.

BACKGROUND: Therapeutic drug monitoring (TDM) of ß-lactams in critically ill patients has been correlated with better clinical outcomes. Evidence on TDM of newer ß-lactams such as ceftazidime/avibactam administered by continuous infusion (CI) is very limited. OBJECTIVES: To describe our experience with TDM of ceftazidime/avibactam and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in patients with MDR bacterial infections. Clinical outcomes of ceftazidime/avibactam administered by CI were also assessed. METHODS: Patients treated with ceftazidime/avibactam administered by CI and undergoing TDM of ceftazidime plasma concentrations were included. Blood samples were obtained as part of the TDM program. The PK/PD therapeutic target of ceftazidime/avibactam was defined as 100%fT > 4 × MIC of the causative pathogen, and 100%fT > 10 × MIC was considered overexposure. Dose changes were made according to the TDM results. RESULTS: Thirty-one patients were included. Ceftazidime/avibactam total daily doses ranged from 1 g/0.25 g to 6 g/1.5 g. Twenty-six patients (83.9%) achieved a 100%fT > 4 × MIC, 15 (48.4%) of which were overexposed (100%fT > 10 × MIC). Dose reduction was suggested in 16/28 (57.1%) patients and dose maintenance in 12/28 (42.9%). Overall clinical cure was observed in 21 (67.7%) patients, and 18 of these (85.7%) achieved a 100%fT > 4 × MIC. CONCLUSIONS: Administering ceftazidime/avibactam by CI enabled the desired PK/PD target to be achieved in a large proportion of patients, even at lower doses than those recommended for a 2 h extended infusion. We suggest that the use of CI with TDM may be a useful tool for reducing initial doses, which could help to reduce antimicrobial-related adverse effects and treatment costs.

A new UHPLC-MS/MS method for cannabinoids determination in human plasma: A clinical tool for therapeutic drug monitoring.

Cannabinoid derivates have been largely used for different medical purpose. In the literature, several methods capable of separating THC and its principles metabolites are described, although Δ8- and Δ9-THC separation has not been completely achieved. THC metabolism has not been fully understood and metabolites plasma distribution in healthy and pathological patients remains to further deepen. The aim of this study was the validation of UHPLC-MS/MS method for the quantification of 10 cannabinoids in human plasma, as important tool for improving clinical efficacy of cannabis administration. Obtained results were in accordance with recommendations of ICH Harmonised Guideline for bioanalytical method validation, showing a good linearity, optimal accuracy as well as satisfactory results in terms of intra-day and inter-day precision and matrix effect. Furthermore, blood sampling study was performed to investigate the better collection method. Optimal separation of Δ-9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC) was obtained. The present method showed optimal linearity and satisfactory results in terms of specificity and selectivity. Recovery was between 92.0% and 96.5% for all analytes. The matrix-effect showed good performance; no carry over was observed. Cannabinoid metabolites present in higher plasma concentrations were: 11-Hydroxy-Δ9-tetrahydrocannabinol, 11-Nor-9carboxy-Δ9-tetrahydrocannabinol and THC-COOH-glucuronide. Method performance makes it suitable for routine purposes and a potential tool for therapeutic ranges definition. The present work will be used to test several samples in a long-term clinical study, paving the way for further future works.

Critical assessment of the revised guidelines for vancomycin therapeutic drug monitoring.

BACKGROUND: The revised vancomycin guidelines recommend replacing trough-only with trough or peak/trough Bayesian and first-order equations monitoring, citing their better AUC predictions and poor AUC-trough R2. Yet, evidence suggesting good AUC-trough correlation has been overlooked, and the optimality of peak/trough samples has been doubted. The guidelines recommend Bayesian programs implement richly-sampled PopPK priors despite their scarcity. Therefore, whether complex Bayesian and sample-demanding first-order equations can bring significant advantages to the practice over simple trough-only monitoring is worth weighing. OBJECTIVES: The primary aim is to compare the predictive performance of the AUC monitoring methods. Then, we investigate the impact of not adhering to trough sampling on the Bayesian-based predictions. Moreover, we report the nature of PopPK priors used in Bayesian programs to assess the applicability of the guideline recommendations. METHODS: We calculated the predictive performance of the monitoring methods using a standard PopPK modeling and simulation approach. We thoroughly explored the prior PK models implemented in Bayesian programs. RESULTS: Predictive performances of the monitoring methods were comparable at steady-state relative to the number of samples. Contrary to the recommendation, Bayesian trough monitoring did not result in better predictive performances compared to using random levels. Very few programs implemented richly-sampled priors. CONCLUSION: All the monitoring methods can be, relatively, reliable at steady-state, if properly implemented. Although only Bayesian-based monitoring can be used pre-steady-state, its predictive performance can be modest. Trough-only monitoring is the simplest approach. Constraints regarding trough sampling times could be relaxed. The scarcity of richly-sampled Bayesian priors questions the applicability of the revised guidelines recommendation.

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Dose Individualization of Oral Multi-Kinase Inhibitors for the Implementation of Therapeutic Drug Monitoring.

Oral multi-kinase inhibitors have transformed the treatment landscape for various cancer types and provided significant improvements in clinical outcomes. These agents are mainly approved at fixed doses, but the large inter-individual variability in pharmacokinetics and pharmacodynamics (efficacy and safety) has been an unsolved clinical issue. For example, certain patients treated with oral multi-kinase inhibitors at standard doses have severe adverse effects and require dose reduction and discontinuation, yet other patients have a suboptimal response to these drugs. Consequently, optimizing the dosing of oral multi-kinase inhibitors is important to prevent over-dosing or under-dosing. To date, multiple studies on the exposure-efficacy/toxicity relationship of molecular targeted therapy have been attempted for the implementation of therapeutic drug monitoring (TDM) strategies. In this milieu, we recently conducted research on several multi-kinase inhibitors, such as sunitinib, pazopanib, sorafenib, and lenvatinib, with the aim to optimize their treatment efficacy using a pharmacokinetic/pharmacodynamic approach. Among them, sunitinib use is an example of successful TDM implementation. Sunitinib demonstrated a significant correlation between drug exposure and treatment efficacy or toxicities. As a result, TDM services for sunitinib has been covered by the National Health Insurance program in Japan since April 2018. Additionally, other multi-kinase targeted anticancer drugs have promising data regarding the exposure-efficacy/toxicity relationship, suggesting the possibility of personalization of drug dosage. In this review, we provide a comprehensive summary of the clinical evidence for dose individualization of multi-kinase inhibitors and discuss the utility of TDM of multi-kinase inhibitors, especially sunitinib, pazopanib, sorafenib, and lenvatinib.

New Insight Concerning Therapeutic Drug Monitoring-The Importance of the Concept of Psychonephrology.

Recently, the concept of psychonephrology was developed and has been recognized as a field of study that focuses on nephrology and mental health fields, such as psychiatry and psychosomatic medicine. Indeed, patients with chronic kidney disease frequently suffer from mental problems as the disease stage progresses. Most psychotropic drugs are hepatically metabolized, but some are unmetabolized and eliminated renally. However, renal disease may affect the pharmacokinetics of many psychotropic drugs, as the decreased renal function not only delays the urinary excretion of the drug and its metabolites but also alters various pharmacokinetic factors, such as protein-binding, enterohepatic circulation, and activity of drug-metabolizing enzymes. Therefore, when prescribing drug therapy for patients with both renal disease and mental issues, we should consider reducing the dosage of psychotropic drugs that are eliminated mainly via the kidney and also carefully monitor the blood drug concentrations of other drugs with a high extrarenal clearance, such as those that are largely metabolized in the liver. Furthermore, we should carefully consider the dialyzability of each psychotropic drug, as the dialyzability impacts the drug clearance in patients with end-stage renal failure undergoing dialysis. Therapeutic drug monitoring (TDM) may be a useful tool for adjusting the dosage of psychotropic drugs appropriately in patients with renal disease. We herein review the pharmacokinetic considerations for psychotropic drugs in patients with renal disease as well as those undergoing dialysis and offer new insight concerning TDM in the field of psychonephrology.

Feasibility of therapeutic drug monitoring of sorafenib in patients with liver or thyroid cancer.

INTRODUCTION: Sorafenib is a tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid carcinoma, and desmoid fibromatosis. As high inter-individual variability exists in exposure, there is a scientific rationale to pursue therapeutic drug monitoring (TDM). We investigated the feasibility of TDM in patients on sorafenib and tried to identify sub-groups in whom pharmacokinetically (PK) guided-dosing might be of added value. METHODS: We included patients who started on sorafenib (between October 2017 and June 2020) at the recommended dose of 400 mg BID or with a step-up dosing schedule. Plasma trough levels (Ctrough) were measured at pre-specified time-points. Increasing the dose was advised if Ctrough was below the target of 3750 ng/mL and toxicity was manageable. RESULTS: A total of 150 samples from 36 patients were collected. Thirty patients (83 %) had a Ctrough below the prespecified target concentration at a certain time point during treatment. Toxicity from sorafenib hampered dosing according to target Ctrough in almost half of the patients. In 11 patients, dosing was adjusted based on Ctrough. In three patients, this resulted in an adequate Ctrough without additional toxicity four weeks after the dose increase. In the remaining eight patients, dose adjustment based on Ctrough did not result in a Ctrough above the target or caused excessive toxicity. CONCLUSIONS: TDM for sorafenib is not of added value in daily clinical practice. In most cases, toxicity restricts the possibility of dose escalations.

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

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

Therapeutic Drug Monitoring and Prolonged Infusions of Ceftolozane/Tazobactam for MDR/XDR Pseudomonas aeruginosa Infections: An Observational Study.

BACKGROUND AND OBJECTIVE: Prolonged infusion of ceftolozane/tazobactam (C/T) is a strategy used to increase achievement of pharmacokinetic/pharmacodynamic targets for the treatment of multi- or extensively drug-resistant MDR/XDR Gram-negative microorganisms. The objective of this study was to describe our therapeutic drug monitoring (TDM) experience of C/T administered by prolonged infusion or intermittent infusion to patients with MDR/XDR Pseudomonas aeruginosa infections. Our outcomes of interest were pharmacokinetic/pharmacodynamic target achievement and clinical cure. METHODS: Patients with MDR/XDR P. aeruginosa infections treated with C/T were enrolled between February 2018 and February 2020. Blood samples were obtained as part of a TDM program. The pharmacokinetic/pharmacodynamic therapeutic target of C/T was defined as 100% of the duration of the dosing interval that free concentrations are above the minimum inhibitory concentration (MIC) (100 %ƒT ≥ MIC) of the causative pathogen. Dose changes were performed according to TDM results. RESULTS: Forty patients were included: 13 (32.5%) with a proven MDR and 27 (67.5%) with a XDR P. aeruginosa infection. C/T was administered by prolonged infusion in 32 (80%) patients and by intermittent infusion in 8 (20%) patients. Lower doses were administered in the prolonged infusion compared to the intermittent infusion group [3 (9.4%) vs. 5 (62.5%] patients received a dose of 9 g/day (ceftolozane 2 g + tazobactam 1 g, every 8 h; p = 0.004). All patients achieved the pharmacokinetic/pharmacodynamic target and C/T concentrations exceeded 10 × MIC in > 50% of patients in both groups. TDM-recommended dose reductions occurred in 19 (47.5%) patients, being 16 (84.2%) in the prolonged infusion group. A high proportion of patients achieved clinical cure (82.5%). CONCLUSIONS: The administration of C/T by prolonged infusion with TDM-guided dosing allowed the achievement of a pharmacokinetic/pharmacodynamic target even at lower doses. C/T showed a high efficacy for treating MDR/XDR P. aeruginosa infections.