Trough Concentration Levels Research Articles

Incidence, clinical classification and risk factors of cyclosporin A-induced liver injury in allogeneic haematopoietic stem cell transplant recipients.

There is limited real-world data on cyclosporin A (CsA)-induced liver injury (CILI). This study aims to investigate the incidence, clinical classification and risk factors of CILI, thereby providing evidence to inform the treatment of CILI. Inpatients receiving haematopoietic stem cell transplantation (HSCT) and treated with CsA were included. Patient information was collected to assess suspicious CILI by the Roussel Uclaf causality assessment method (RUCAM) scale. We evaluated the pattern and severity of CILI. The independent risk factors of CILI were identified by multivariable logistic regression. A total of 216 allogeneic HSCT (allo-HSCT) recipients were included in this study. The incidence of CILI was 15.3% (95% confidence interval [CI]: 10.4%-20.1%). Among these cases, 84.8% displayed a hepatocellular pattern, and 90.9% of CILI was of mild severity. Baseline alanine aminotransferase (ALT) level (OR = 1.030, 95% CI: 1.008-1.053, P = .008) and trough concentration level of CsA (OR = 1.007, 95% CI: 1.002-1.012, P = .009) were identified as independent risk factors for CILI. The incidence of CILI in allo-HSCT recipients is notably high. Recipients with elevated baseline ALT levels and higher exposure to CsA are more susceptible to developing CILI.

The role of proactive therapeutic drug monitoring in guiding infliximab therapeutic optimization in pediatric patients with Crohn's disease: A retrospective study

AbstractTherapeutic drug monitoring (TDM) plays an important role in guiding treatment plan adjustments and clinical outcomes in Crohn's disease. To evaluate the role of TDM‐guided optimization of infliximab dosage in patients with pediatric Crohn's disease. Medical records of patients with pediatric Crohn's disease who were treated with infliximab and had proactive TDM from June 2020 to June 2022 at the Children's Hospital of Chongqing Medical University were included. Baseline influencing factors for infliximab trough concentration (TC) and clinical outcomes before and after the treatment change were analyzed to assess the value of adjusting treatment in the patients. Forty‐six patients (male‐to‐female ratio = 1.55:1, age <18 years) were included. Univariate and multivariate analyses showed that hormone exposure (odds ratio: 0.042, 95% confidence interval: 0.002–0.924, p = 0.044), perianal lesions (5.813, 0.984–34.349, p = 0.052), simplified endoscopic score for Crohn's disease (1.656, 1.065–2.577, p = 0.025), and total protein (TP) (0.851, 0.749–0.967, p = 0.014) were correlated with infliximab TC. Shortening the treatment interval increased the infliximab TC (pre vs. post = 1.69 ± 0.8 vs. 12.03 ± 6.64, p = 0.001, n = 12) after 93.9 ± 37.47 days, decreased the pediatric Crohn's disease activity index and simplified endoscopic score for Crohn's disease, and increased the biochemical remission, clinical remission, endoscopic remission, and endoscopic response rates; however, there was no statistical significance. Hormone exposure, perianal lesions, simplified endoscopic score for Crohn's disease, and TP levels before the first infliximab use affected the infliximab TC. Shortening the treatment interval can improve infliximab TC levels and clinical outcomes.

P553 The safety and efficacy of adalimumab 80mg weekly as maintenance therapy in pediatric Crohn’s Disease

Abstract Background Intensification of adalimumab (ADL) dosing to weekly 40 mg injections, in response to low drug levels, has been shown to provide beneficial outcomes in pediatric patients with Crohn’s disease (CD). Our study aimed to evaluate the safety and efficacy of weekly 80 mg ADL administration in children with CD. Methods In this retrospective cohort study conducted across five Israeli centers, we reviewed the medical records of pediatric CD patients who received a high dose of ADL 80 mg weekly injections between 2016 and 2023. Collected data included demographic characteristics, disease features, laboratory studies, and treatment outcomes. Results Thirty-two children with CD were included: mean age 15.8 (±1.7) years at intensification, 21 male (66%), 18 (56%) with L3 phenotype. The median time to ADL 80 mg intensification from ADL induction was 48.4 weeks (IQR 23.1-122.5). The mean weighted Pediatric Crohn's Disease Activity Index (wPCDAI) was 28.5 (±16.9) at the time of intensification and the median calprotectin and C-reactive protein levels were 937 μg/g (IQR 540-1410) and 1.3 mg/dL (IQR 0.6-5.2), respectively. Clinically active disease was the main reason for ADL intensification (30, 94%). Baseline ADL levels were available in 30 patients (94%) with a median of 3.8 μg/mL (IQR 2.4-7.2). Among these, 23 children (77%) failed to achieve a target of ≥ 7.5 μg/mL. The median follow-up duration from the intensification dose was 91.2 weeks (IQR 53.6-149.1). Corticosteroids were required in 5/32 (15.6%) children, with a median time of 32.3 weeks (IQR 10.7-51.3) from intensification. There was no statistically significant difference in steroid utilization rates between children who achieved a target baseline drug level of ≥ 7.5 μg/mL and those who did not (p=0.934). Thirteen individuals (41%) discontinued ADL treatment, within a median of 24.7 weeks (IQR 11.7-57.1) from intensification. CD-related exacerbation, hospitalization, and surgery rates were 9 (28%), 4 (13%), and 2 (6%), respectively. No statistically significant differences were found in exacerbation (p=0.406), hospitalization (p=0.322), or surgery rates (p=0.427) between children who achieved a baseline ADL trough concentration level of ≥ 7.5 μg/mL and those who did not. Overall, ADL intensification was safe, but 3 (9%) patients developed new-onset psoriasis. Conclusion Our findings support the safety and efficacy of administering ADL at a weekly dosage of 80 mg as maintenance therapy in pediatric patients with moderate to severe CD.

Correlation analysis between camrelizumab trough concentration levels and efficacy or safety in East Asian patients with advanced lung cancer.

Camrelizumab combined with chemotherapy is approved across tumor types. However, only a fraction of patients benefits from immunotherapy, and biomarkers such as the expression of PD-L1, tumor mutational burden, and CXCL11 are expensive and suboptimal specificity for cancer patients. An exposure-response (E-R) relationship has been reported in many immune checkpoint inhibitors (ICIs), and the trough concentrations and other drug exposure metrics are broadly used to guide dosing decisions, assess exposure-outcomes relationships, and ultimately predict outcomes based on those relationships. However, the potential use of trough concentration levels for camrelizumab is still not clear. Blood samples were obtained at trough levels after doses 3 and 4 from 77 patients with advanced lung cancer who received camrelizumab (200mg Q3 W) monotherapy or combined with chemotherapy. We optimized a competitive ELISA method to measure the trough concentration. We found that the trough concentration was steady after 3 dose cycles, and the trough concentration level of camrelizumab was higher in patients who developed immune-related adverse effects (irAEs) than in those who did not (P < 0.05) but was not observed in disease progression and PFS (P > 0.05). Age (< 65 years old), no smoking history, and efficacy evaluation after 4-dose treatment were associated with PFS (P < 0.05), but no significance was observed in other clinical characteristics. Total bilirubin and albumin had an influence on trough concentration, and monocytes and albumin were independent risk factors for PFS (P < 0.05). Our results suggest that the trough concentration level of camrelizumab might be a risk factor for the occurrence of irAEs in advanced lung cancer, and using the immunotherapy as early as possible may bring better clinical outcomes.

The efficacy of direct oral anticoagulants in patients on concomitant treatment with levetiracetam

Guidelines do not support the combination of direct oral anticoagulants (DOACs) and the antiepileptic drug levetiracetam, due to potential relevant P-glycoprotein (P-gp) mediated interaction that might result in decreased DOACs concentrations and increased thromboembolic risk. However, there is no systematic data on the safety of this combination. The aim of this study was to find patients concurrently treated with levetiracetam and DOAC, assess their plasma concentrations of DOAC, and the incidence of thromboembolic events. From our registry of patients on anticoagulation drugs we identified 21 patients concomitantly treated with levetiracetam and DOAC, 19 patients with atrial fibrillation and two patients with venous thromboembolism. Eight patients received dabigatran, 9 apixaban and 4 rivaroxaban. For each subject blood samples were collected for determination of trough DOAC and trough levetiracetam concentrations. The average age was 75 ± 9 years, 84% were males, HAS-BLED score was 1.8 ± 0.8, and in patients with atrial fibrillation CHA2DS2-VASc score was 4.6 ± 2.0. The average trough concentration level of levetiracetam was 31.0 ± 34.5 mg/L. Median trough concentrations of DOACs were for dabigatran 72 (range 25–386) ng/mL, for rivaroxaban 47 (range 19–75) ng/mL, and for apixaban 139 (range 36–302) ng/mL. During the observation period of 1388 ± 994 days none of the patients suffered a thromboembolic event. Our results did not demonstrate a reduction in DOACs plasma levels during levetiracetam treatment, suggesting that levetiracetam could not be an important P-gp inducer in humans. DOAC in combination with levetiracetam remained effective therapy to protect against thromboembolic events.

Antibody-guided proteases enable selective and catalytic degradation of challenging therapeutic targets

The exquisite specificity, natural biological functions, and favorable development properties of antibodies make them highly effective agents as drugs. Monoclonal antibodies are particularly strong as inhibitors of systemically accessible targets where trough-level concentrations can sustain full target occupancy. Yet beyond this pharmacologic wheelhouse, antibodies perform suboptimally for targets of high abundance and those not easily accessible from circulation. Fundamentally, this restraint on broader application is due largely to the stoichiometric nature of their activity-one drug molecule is generally able to inhibit a maximum of two target molecules at a time. Enzymes in contrast are able to catalytically turnover multiple substrates, making them a natural sub-stoichiometric solution for targets of high abundance or in poorly accessible sites of action. However, enzymes have their own limitations as drugs, including, in particular, the polypharmacology and broad specificity often seen with native enzymes. In this study, we introduce antibody-guided proteolytic enzymes to enable selective sub-stoichiometric turnover of therapeutic targets. We demonstrate that antibody-mediated substrate targeting can enhance enzyme activity and specificity, with proof of concept for two challenging target proteins, amyloid-β and immunoglobulin G. This work advances a new biotherapeutic platform that combines the favorable properties of antibodies and proteolytic enzymes to more effectively suppress high-bar therapeutic targets.

Interventions for increasing immunosuppressant medication adherence in solid organ transplant recipients.

Interventions for increasing immunosuppressant medication adherence in solid organ transplant recipients.

Novel tool for vancomycin dosing could provide multiple benefits

Pharmacists at Detroit Medical Center (DMC) led a research study that could help patients achieve targeted trough concentrations of vancomycin while at the same time reducing a pharmacist's workload. The research team wanted to validate a novel vancomycin dosing table for adult patients on continuous renal replacement therapy (CRRT). CRRT is commonly used to provide renal support in hemodynamically unstable, critically ill patients with renal failure. Their study found that for CRRT patients who were scheduled on vancomycin using the dosing tool, 58% were in the targeted range of achieving trough level concentrations of 15 to 20 mcg/mL, whereas only 37% of the patients who were dosed by levels were in that targeted range. When levels within 1 standard deviation of the target range were included, the trough levels for patients on scheduled vancomycin within target range increased to 89%. “The patients who were scheduled on vancomycin achieved the target level of 15 to 20 mcg/mL of vancomycin more than the patients who were dosed by levels,” said Merna Azuz, PharmD, who helped lead the research at Harper-Hutzel Hospital, which is part of DMC. “This was a very important conclusion since patients who were scheduled did not have to get as many levels drawn and they didn’t have to have as many notes entered by a pharmacist.” Consequently, the tool was saving pharmacists time because every level that is drawn has to be entered into the record. Azuz said they also found that CRRT patients should be given a loading dose of 25 mg/kg and not 20 mg/kg, as was the case previously. “Patients who are critically ill do have a higher volume of distribution, so giving a loading dose of 20 mg/kg was not achieving adequate levels,” she said. “In our new dosing table, we recommend patients be given a loading dose of 25 mg/kg.” Guidelines for dosing vancomycin prior to the study in this particular patient population suggest using a loading dose for patients of approximately 20 mg/kg, which targets a peak concentration of 25 to 30 mcg/mL. After that initial dose, the protocol at DMC is to base subsequent dosing on vancomycin serum monitoring every 12 to 48 hours. Different institutions have different protocols and different modalities. “This research was meant to provide guidance for pharmacists for dosing vancomycin in critically ill patients that are on CRRT,” said Azuz. Limited literature is available to guide clinicians on dosing antimicrobials during CRRT. Patients on CRRT experience life threatening infections with high mortality rates and require optimal dosing of antimicrobials. “This vancomycin table that we came up with actually looked at patient parameters, including patients’ weight, and it looked at the continuous fluid replacement rate that was being used for the patient,” Azuz said. “What we found out was that patients who had a higher replacement fluid rate were clearing the vancomycin more quickly than patients who had a lower replacement fluid rate. Based on that ultra-filtration rate, we came up with the vancomycin dose as well as the frequency at which the doses should be given.” The research provides valuable information for clinicians and more guidance on dosing patients on vancomycin therapy, said Azuz. “However, it is very important to note that this vancomycin dosing guide is solely a guide, it should not be mandatory, and it should not supersede the pharmacist's clinical judgement,” she said. The research is a testament to how pharmacists can be involved in potential policy changes at their respective institutions. Azuz was a resident at DMC from 2019 to 2020 and helped complete the second phase of the research project. Results have been presented to various committees at DMC with the ultimate goal of implementing the tool into hospital policy. Azuz is currently a clinical pharmacist at Ascension St. John Hospital in Detroit. The research was also presented at last year's American College of Clinical Pharmacy's virtual annual meeting.

Discontinuation of Tyrosine Kinase Inhibitor in Children with Chronic Myeloid Leukemia (JPLSG STKI-14 study)

Kada: Bayer Yakuhin: Other: personal fees for a member of independent data monitoring committee of clinical trials, outside of the submitted work.. Imai:Juno Therapeutics: Patents & Royalties.

High sensitivity versus low level of vancomycin needs to be concern for another alternative anti- Staphylococcus aureus as the first- line antibiotic.

Background and aim: Vancomycin has been the first-line therapy for MRSA infection disease for many years. According to standard guidelines, the therapeutic vancomycin trough concentration should be above 10 mg/L and optimally between 15-20 mg/L. The aim of this study was to evaluate vancomycin trough level concentration in patients infected with MRSA.Methods: This cross- sectional study included a sample of 170 patients admitted to the ICU of Loghman hospital. We used a standard questionnaire, then applied appropriate statistical tests. All collected data had been analyzed and interpreted by IBM SPSS Statistics 19.0.Results: Among this study population, 71.8% was male. Just 20.8% of the patients can reach the therapeutic level trough even after changing the dose. It should be noted that a significant percentage of toxicity was observed after increasing the dose. Conclusions: Even though high sensitivity against vancomycin disc has been seen in antibiogram tests, sufficient efficiency has not been distinguished, in the sense that, just a few patients by low trough level concentration, reached to therapeutic level after the dose change. Based on some sources, because of the side effects and limited safe range of vancomycin, we should consider a new approach to the alternative antibiotics. (www.actabiomedica.it)

Therapeutic drug monitoring of vancomycin by AUCτ-MIC ratio in patients with chronic kidney disease.

In this study which was conducted in Alzahra University Hospital (Isfahan, I.R. Iran), the therapeutic drug monitoring of vancomycin focused on determining area under the concentration-time curve at dosing interval (τ) at steady state/minimum inhibitory concentration (AUCτ/MIC) was carried out in chronic kidney disease (CKD) patients. The study population was selected from patients with the history of CKD (stages 3 or 4) treated by intravenous vancomycin. To determine vancomycin AUCτ, blood samples were taken at four different occasions (trough-1, peak, random, trough-2) between the fourth and fifth doses of vancomycin. Drug concentration was determined by fluorescence polarization technique, and the E-TEST technique was used to determine the MIC. Nineteen patients were included. For 8 (42%), 7 (37%), and 4 (21%) patients, trough concentration levels were found to be less than 10 mg/L, 10-20 mg/L, and more than 20 mg/L, respectively. The mean value of AUCτ for studied patients was 470.7 ± 228.3 mg.h/L and the mean MIC values was 1.04 ± 0.43 mg/L. Ten patients (53%) and 9 patients (47%) had the AUCτ/MIC ratios above 400 and below 400, respectively, with the average of 519.4 ± 391.3 h. Vancomycin dosing based on patient glomerular filtration rate (GFR), as a traditional method, is not accurate enough to gain the most desired vancomycin concentration in patients with decreased or changing kidney function. Measuring drug concentration and observing its therapeutic effects accordingly is inevitable in susceptible populations receiving vital drugs such as vancomycin.

Optimizing everolimus exposure when combined with calcineurin inhibitors in solid organ transplantation.

The mammalian target of rapamycin (mTOR) inhibitor everolimus is a narrow therapeutic index drug for which optimal exposure levels are essential. The consistent pharmacokinetic profile of everolimus allows trough concentration (C0) measurement to be an appropriate and reliable index for therapeutic drug monitoring (TDM). Exposure-response analyses of data from early fixed-dose trials demonstrated that rates of biopsy-proven acute rejection (BPAR) are significantly higher if everolimus C0 declines below 3 ng/mL, an observation confirmed in subsequent concentration-controlled trials. Evidence for the most favorable upper limit is less clear but with reduced-exposure calcineurin inhibitor (CNI) therapy, an upper limit of 8 ng/mL appears to balance efficacy and safety outcomes. The recommended C0 range is 3-8 ng/mL in kidney, liver and heart transplantation patients, based on LC-MS/MS monitoring in whole blood. Randomized clinical trials based on this target range have demonstrated rates of BPAR comparable to a regimen of mycophenolic acid with standard-exposure CNI. Everolimus exhibits moderate intrapatient pharmacokinetic variability, and it can be challenging to maintain stable concentrations within target range in some individuals. Many factors can influence everolimus exposure for a given dose, including hepatic function, activity of the drug efflux pump P-glycoprotein, the rate of everolimus metabolism, drug-drug interactions (predominantly with CYP3A4 and P-glycoprotein inhibitors, including cyclosporine), intake of fatty food, and patient adherence to the prescribed regimen. Trough concentration levels should be monitored 4-5days after the first dose and after any change in everolimus dose, with additional monitoring in response to any change in concomitant medication or other clinical circumstances which could alter everolimus exposure. Although LC-MS/MS is the gold standard for everolimus monitoring, various immunoassays are widely used due to their relative simplicity and lower cost, and results can show considerable discrepancies with reference methods due to issues such as interassay variability and cross-reactivity. Method standardization will be important in the future to improve the consistency and reproducibility of results between centers. In conclusion, based on an extensive program of clinical trials, the optimal exposure range for everolimus in combination with reduced-exposure CNI therapy has been established and can be achieved in most transplant recipients through careful, planned TDM.

A Pilot Randomized Controlled Trial to Promote Immunosuppressant Adherence in Adult Kidney Transplant Recipients

Background: Nonadherence to immunosuppressant medication is a prevalent practice among kidney transplant recipients and has been associated with increased risk for graft failure and economic burden. The aim of this pilot study was to test whether a culturally sensitive cognitive-behavioral adherence promotion program could significantly improve medication adherence to tacrolimus prescription as measured by telephone pill counts among kidney transplant recipients. Methods: Thirty-three adult transplant recipients were less than 98% adherent to tacrolimus prescription based on 3 telephone pill counts and were randomized either to the 2-session cognitive-behavioral adherence promotion program or to standard care. The curriculum was developed from an iterative process with transplant recipients into a 2-session group program that provided psychoeducation, addressed barriers to adherence, fostered motivation to improve adherence behavior, and discussed cultural messages on adherence behavior. Results: The intervention group displayed significantly higher levels of adherence when compared to the control group (t = 2.2, p = 0.04) and. similarly, when the amount of change was compared between the groups, the intervention group showed more change than the control condition (F (22,1) = 12.005, p = 0.003). Tacrolimus trough concentration levels were used as a secondary measure of adherence and, while there were no significant between-group differences for mean trough concentration levels, the variability in the trough levels did significantly decrease over time indicating more consistent pill-taking behavior in the intervention group. Conclusions: There is preliminary support for the pilot program as a successful intervention in helping patients with their immunosuppressant medication.

Lupus-anticoagulant testing at NOAC trough levels.

Non-vitamin K antagonist oral anticoagulants (NOAC), including rivaroxaban, apixaban or dabigatran, regularly show relevant effects on coagulation tests, making the interpretation of results difficult. The aim of this study was to evaluate possible interferences of NOACs in trough level concentrations in lupus anticoagulant (LA) testing. Citrate plasma specimens of 30 healthy volunteers were spiked with rivaroxaban, apixaban or dabigatran in four plasma concentration levels at or below trough NOAC levels. The NOAC concentration was measured using dedicated surrogate concentration tests and a stepwise diagnostic procedure for LA-testing was applied using screening, mixing and confirmatory testing. Results were compared to NOAC-free specimens. Starting with a plasma concentration of 12.5 ng/ml, dabigatran-spiked specimens showed significant prolongations in the lupus anticoagulant-sensitive activated partial thromboplastin time (aPTT-LA) as well as in the Dilute Russell viper venom time (dRVVT), leading to 43.3 % false positives in confirmatory testing in the dRVVT. In contrast, rivaroxaban, beginning with 7.5 ng/ml, exclusively affected dRVVT-based tests. In confirmatory tests, 30.0 % of rivaroxaban-spiked specimens showed false positive results. Starting with 18.75 ng/ml apixaban, a significant prolongation of the dRVVT and up to 20.7 % false positives in confirmatory tests were found. In contrast to other NOACs tested, apixaban did not present with a dose-dependent increase of the dRVVT ratio. In conclusion, the rate of false positive results in LA-testing is unacceptably high at expected trough levels of NOACs. Even at plasma concentrations below the LLOQ of commercially available surrogate tests, LA testing is best avoided in patients with NOAC therapy.

Prophylactic Use of Voriconazole for Invasive Fungal Infection in Children and Adolescents with Acute Myeloid Leukemia

BackgroundInvasive fungal infection (IFI) is a critical complication in the management of hematologic and malignant diseases. Patients with acute myeloid leukemia (AML) have been shown to be at high risk of IFI. Prophylactic therapy using antifungal agents is important for these patients because the timely and accurate diagnosis of IFI during the course of chemotherapy remains difficult. This study compared voriconazole (VRCZ) at a dose of 5 mg/kg/day versus 10 mg/kg/day for the prevention of IFI.MethodsBetween October 2005 and June 2011, 17 children and adolescents (9 boys and 8 girls, ages ranged from 0 to 20 years, with a median age of 7 years) undergoing chemotherapy for AML were prophylactically administered 5 mg/kg/day oral VRCZ starting at the beginning of chemotherapy. On the other hand, 22 patients (10 boys and 12 girls, ages ranged from 0 to 19 years, with a median age of 10 years) undergoing chemotherapy for AML were prophylactically administered 10 mg/kg/day oral VRCZ between July 2011 and December 2014. For prompt intervention against fungal infection, patients' blood samples were assayed for serum C-reactive protein by ELISA at least twice a week. When fever continued despite the administration of broad-spectrum antibiotics and/or a high level of C-reactive protein persisted, computed tomography (CT) of the chest and abdomen was performed and thoroughly inspected. In these patients, the detection of serum b-D glucan and Aspergillus galactomannan antigen was also carried out. IFI was defined and classified according to the standardized definitions from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Disease Mycosis study group (EORTC/MSG) consensus group. We compared the incidence of proven, probable or possible IFI during treatment between the 5 mg/kg/day and 10 mg/kg/day groups. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days after the initiation of chemotherapy.ResultsDespite the prophylactic use of VRCZ, 8 patients developed IFI (proven 1, probable 3, possible 4). Of these 8 patients, 4 belonged to the 5 mg/kg/day group and 4 to the 10 mg/kg/day group. FFS rates at 180 days after the initiation of chemotherapy were similar between the 5 mg/kg/day and 10 mg/kg/day groups (70.9% vs. 73.8%, P =0.582). The trough concentration levels of VRCZ in the 10 mg/kg/day group ranged from <0.09 to 2.17 mg/ml, with a median concentration of 0.27 mg/ml, and patients within the targeted trough concentration level (1 to 4 mg/ml) constituted only 18.8% of all evaluable patients, whereas the trough concentration levels of VRCZ of all patients in the 5 mg/kg/day group were below the limit of sensitivity (<0.09 mg/ml). In both groups, there were no cases forced to discontinue VRCZ due to adverse effects. No patients exhibited visual disturbances as an adverse effect of VRCZ.ConclusionSix-month FFS did not differ in children and adolescents with AML given prophylactic VRCZ at a dose of 5 mg/kg/day or 10 mg/kg/day. It is known to be more difficult to raise the concentration of VRCZ to the targeted concentration in children than in adults. Lower concentration levels of VRCZ might have served as a cause of the poor improvement in IFI prophylaxis despite an increased dosage. IFI prophylaxis using therapeutic drug monitoring of VRCZ might be able to improve FFS in patients with AML. DisclosuresNo relevant conflicts of interest to declare.

A study to explore the correlation of ABCB1, ABCG2, OCT1 genetic polymorphisms and trough level concentration with imatinib mesylate-induced thrombocytopenia in chronic myeloid leukemia patients

Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and pharmacogenetic screening is warranted for better management of imatinib therapy. The present study was framed to explore the influence of common drug transporter gene polymorphisms of ABCB1, ABCG2, OCT1 and trough level concentration on commonly occurring adverse events in CML patients treated with imatinib mesylate. A total number of 111 patients in chronic phase (Philadelphia chromosome +ve) were included in the study. The plasma drug concentration of imatinib was estimated using LC-MS/MS method. The mean ± SD trough level concentration of imatinib mesylate was found to be 1430.7 ± 438.7 ng/ml. The trough level concentration at steady state (Cmin.ss) was significantly higher in patients with grade 2-4 thrombocytopenia compared with patients without the adverse event (P value 0.033). The drug level of imatinib in plasma correlates with the severity of thrombocytopenia, which adds to the utility of TDM in the management of CML patients.

A study to explore the correlation of trough level concentration and ABCB1, OCT1, ABCG2 genetic polymorphisms with imatinib mesylate induced thrombocytopenia in chronic myeloid leukemia patients.

e13564 Background: Imatinib mesylate is presently the first line treatment for chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and pharmacogenetic screening is warranted for bette...

Postoperative Transplant Immunosuppression in the Critical Care Unit

Postoperative Transplant Immunosuppression in the Critical Care Unit

Pharmacokinetics for Once-Daily Modified Release Formulation Tacrolimus Hydrate in Unrelated Hematopoietic Stem Cell Transplantation.

Abstract 3048 Background:In solid organ transplantation, lifelong immunosuppression is required to preserve graft function, and medication nonadherence is a major risk factor for graft failure. Tacrolimus (Tac) was first developed as an oral twice-daily formulation (Tac BID) and has been widely used in hematopoietic stem cell and solid transplantation, but long-term adherence remains a concern. In renal transplant patients, morning dosing is associated with significantly higher adherence than evening dosing. In response to this potential adherence problem, a once-daily modified release formulation (Tac QD) has been developed with a morning dosing regimen that maximizes the potential for adherence. However, several investigators have recently reported a sustained decrease in Tac exposure in kidney transplant recipients after conversion from Tac BID to Tac QD. In this study, we measured Tac exposure after switching from Tac intravenous infusion (Tac iv) to Tac QD and analyzed the pharmacokinetics (PK) of Tac QD to investigate the correlation between area-under-curve (AUC) and trough in patients who received allogeneic hematopoietic stem cell transplantation (HSCT). This is the first report of the PK study of Tac QD in patients who received allogeneic HSCT. Methods:Patients who were 15–65 years of age and received HSCT from unrelated donors were eligible. They received Tac iv 0.03mg/kg by continuous infusion beginning one day before transplantation, and administration was converted to Tac QD at a 1:4 ratio when the patients engrafted and could tolerate oral medication. Doses were modified to maintain whole-blood trough concentration of 8–12 ng/ml. To analyze PK of Tac QD, plasma samples were obtained at baseline and at 0, 1, 2, 3, 6, 12, and 24 hours after the once-daily administration. Plasma concentration of Tac was determined by an ELISA method. Results:A total of 10 patients with hematological malignancies (AML 6, ALL 1, MDS 2, NHL 1) were enrolled in the PK study. Median age was 45 (23–65) years. Five patients received myeloablative preparative regimens, and 5 patients received reduced intensity regimens, and stem cell sources were bone marrow (BM) from HLA-matched unrelated donor (n=4), BM from HLA DRB1 mismatched unrelated donor (n=4), or cord blood (n=2). After conversion from Tac iv to Tac QD, six out of 10 patients (60%) showed a sustained decrease in Tac exposure and required an increase in their Tac QD daily dose. One patient experienced a quick decrease of more than 78% in trough level of Tac QD, and he developed grade II acute GVHD after the conversion. No other patients developed grade II-IV acute GVHD. None of the patients had to discontinue the agent because of adverse effects, and none developed treatment-related mortality within 100 days after HSCT. In PK analysis, median area-under-curve (AUC) was 246 ng·h/ml. There was a strong correlation between AUC and trough level (Figure 1). Obtaining over 240 ng•h/ml of AUC required 7.5 ng/ml of whole-blood trough levels of tacrolimus. Conclusions:Despite initial reports showing the bioequivalence of Tac QD with Tac BID, we found that 60% of patients experienced a sustained decrease in Tac exposure. Therefore, the conversion from Tac iv to Tac QD should be performed under close medical supervision. Our study demonstrated that AUC and trough concentration level curves showed a strong correlation in patients who underwent allogeneic HSCT. The whole-blood trough should be maintained above 7.5ng/ml to provide an adequate level of AUC. If the trough level of Tac QD can be maintained above 7.5 ng/ml, Tac QD can be as effective as Tac iv and stable administration can be maintained for the patients with reduced stress because of the easier administration schedule. Our findings indicate that the use of Tac QD instead of Tac BID for GVHD prophylaxis is beneficial for patients undergoing allogeneic HSCT without moderate toxicities. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation

The aim of this study was to determine the efficacy, safety, and immunosuppressant adherence in 125 stable liver transplant (LT) patients converted from twice-daily tacrolimus (TAC BID) to once-daily TAC (TAC OD). Tacrolimus trough levels, laboratory parameters, metabolic disorders, selected patient reported outcomes, and adverse events were assessed. Mean TAC trough level concentration was 6.1 ± 2.3 ng/ml at study entry, decreased to 5.5 ± 2.1 ng/ml (P = 0.016) and 5.5 ± 2.2 ng/ml (P = 0.019) after 1 and 2 weeks, respectively, and tended to equal the baseline value during further follow-up. At week 1, TAC concentrations were lower in 62.4% of patients and higher in 36.0% when compared with baseline. Renal and cardiovascular risk factors remained stable and no rejection episodes occurred over 12 months. Adverse events were consistent with the safety profile known from previous studies with TAC BID. Nonadherence measured by the "Basel Assessment of Adherence Scale to Immunosuppressives" was evident in 66.4% at study entry and decreased to 30.9% postconversion (P < 0.0001). Prevalence of nonadherence at baseline was significantly higher in patients converted >2 years after LT and in those ≤60 years of age. Conversion to TAC OD is safe, enhances immunosuppressant adherence and should be accompanied by a close TAC level monitoring during the initial period.