Tacrolimus trough level and oxidative stress in Tunisian kidney transplanted patients.

BACKGROUND: The effect of tacrolimus (TAC) on oxidative stress after kidney transplantation (KT) is unclear. This study aimed to evaluate the influence of TAC trough levels of oxidative stress status in Tunisian KT patients during the post-transplantation period (PTP). METHODS: A prospective study including 90 KT patients was performed. TAC whole-blood concentrations were measured by the microparticle enzyme immunoassay method and adjusted according to the target range. Plasma levels of oxidants (malondialdehyde (MDA) and advanced oxidation protein products (AOPP)) and antioxidants (ascorbic acid, glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) were measured using spectrophotometry. The subjects were subdivided according to PTP into three groups: patients with early, intermediate, and late PT. According to the TAC level, they were subdivided into LL-TAC, NL-TAC, and HL-TAC groups. RESULTS: A decrease in MDA levels, SOD activity, and an increase in GSH levels and GPx activity were observed in patients with late PT compared to those with early and intermediate PT (p < 0.05). Patients with LL-TAC had lower MDA levels and higher GSH levels and GPx activity compared with the NL-TAC and HL-TAC groups (p < 0.05). CONCLUSION: Our results have shown that in KT patients, despite the recovery of kidney function, the TAC reduced but did not normalize oxidative stress levels in long-term therapy, and the TAC effect significantly depends on the concentration used.

Infliximab serum concentrations in luminal Crohn's disease and its relationship with disease activity: A multicentric cross-sectional study.

OBJECTIVES: In Latin America, experience with monitoring serum Infliximab (IFX) concentrations is scarce. Our study aimed to compare IFX serum concentrations between patients with active disease or in remission. PATIENTS AND METHODS: A cross-sectional study was performed in patients with luminal Crohn's disease (CD) during maintenance treatment with IFX. Patients were classified as in remission or disease activity according to clinical scores and endoscopic, radiological, and laboratory markers. A comparison of IFX trough levels between the two groups was performed. RESULTS: 80 CD patients were included [41 (51%) in remission and 39 (49%) with active disease]. In the analysis of general disease activity, the median serum levels of IFX in patients with remission and with active CD were 5.63 [0.03-14.40] vs. 3.84 [0.03-14.40] (p=0.287). Furthermore, there was no difference in serum IFX concentrations in endoscopic, radiological, and laboratory activities. Only in the clinical evaluation there was a significant difference in the median serum IFX levels between patients in remission and disease activity, 5.63 [0.03-14.40] vs. 2.14 [0.32-10.54] (p=0.042). CONCLUSIONS: IFX serum concentrations during maintenance treatment were similar in patients with luminal CD in remission and general, endoscopic, radiological, and laboratory disease activity. Patients with clinically active disease had lower IFX concentrations than patients in remission.

A Prospective Cohort Study Assessing the Relationship between Plasma Levels of Osimertinib and Treatment Efficacy and Safety.

Osimertinib is a standard treatment for patients with EGFR-mutated non-small cell lung carcinoma (NSCLC). We evaluated the relationship between plasma osimertinib concentrations and treatment outcome in patients with NSCLC for this cohort study. The plasma levels of osimertinib and its metabolite AZ5104 were measured a week after the start of treatment (P1). The primary endpoint was to evaluate the correlation between plasma concentration and adverse events (AEs). The correlation with treatment efficacy was one of the secondary endpoints. In patients with CNS metastases, the concentration in the cerebrospinal fluid was also measured. Forty-one patients were enrolled. The frequency of AEs was highest for rash, followed by anorexia and thrombocytopenia. Thirty-eight cases provided measurements for P1. The median plasma concentration of osimertinib was 227 ng/mL, and that of AZ5104 was 16.5 ng/mL. The mean CNS penetration rate of two cases was 3.8%. The P1 in the group with anorexia was significantly higher than that in the group without anorexia (385.0 ng/mL vs. 231.5 ng/mL, p = 0.009). Divided into quartiles by P1 trough level, Q2 + Q3 (164-338 ng/mL) had longer PFS, while Q1 and Q4 had shorter PFS. An appropriate plasma level of osimertinib may avoid some adverse events and induce long PFS. Further large-scale trials are warranted.

Efficacy of Combined Initial Treatment of Methotrexate with Infliximab in Pediatric Crohn's Disease: A Pilot Study.

BACKGROUND: The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn's disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more familiar with thiopurines. This study aimed to compare the efficacy and immunogenicity of MTX and azathioprine (AZA) as concurrent therapies for pediatric CD. METHODS: In this pilot study, 29 newly diagnosed pediatric patients with moderate-to-severe CD were randomized to receive either MTX (n = 15) (15 mg/body surface area (BSA) per week) or oral AZA (n = 14) (0.5 mg/kg per day) in combination with Infliximab (IFX). The primary outcomes were the proportion of patients in endoscopic, biochemical, and transmural remission after 14 and 54 weeks of IFX therapy. The trough levels (TLs) of IFX and anti-drug antibody (ADA) levels were also compared. RESULTS: Among the 29 patients, there were no significant differences in the biochemical (p = 1.0 at week 14, p = 0.45 at week 54), endoscopic (p = 0.968 at week 14, p = 0.05 at week 54), or transmural (p = 0.103 at week 54) remission rates between the two medications during the concurrent therapy. Additionally, the trends in the IFX trough and ADA levels over time during the treatments were similar for both medications, with no significant differences (p = 0.686, p = 0.389, respectively). CONCLUSION: The MTX showed comparable efficacy to the AZA in pediatric CD patients with moderate-to-severe disease. This effectively maintained adequate IFX levels and reduced ADA production. Therefore, although additional large-scale clinical trials are needed, this study demonstrated that either MTX or AZA can be selected as IMMs in the concurrent treatment of pediatric CD, depending on individual medical institutions' circumstances.

Therapeutic Drug Monitoring of Mycophenolic Acid Identifies Kidney Transplant Recipients Responsive to Two SARS-CoV-2 mRNA Vaccine Doses.

Immune-responsiveness to SARS-CoV-2 mRNA vaccination is reduced in kidney transplant recipients (KTRs). Previous reports point to a role of mycophenolic acid (MPA). Our observational cohort study included all KTRs at University Hospital Zurich receiving two SARS-CoV-2 mRNA vaccine doses more than 6 months post-transplantation, who were assessed by measuring anti-spike immunoglobulin G (IgG). We applied principles of therapeutic drug monitoring (TDM) to correlate MPA exposure and lymphocyte counts with SARS-CoV-2 IgG. MPA trough levels differ largely among KTRs with a median of 3.1 mg/L (range 0.7-9.5 mg/L). 34 of 84 KTRs (40%) developed positive SARS-CoV-2 IgG after two vaccine doses. KTRs who developed positive SARS-CoV-2 IgG showed significantly higher eGFR (p < 0.001), lower MPA trough levels (p < 0.001) and higher CD19+ lymphocytes (p < 0.001). MPA trough levels <2.5 mg/l and CD19+ lymphocytes >40/µl identify KTRs with seroconversion. Upon logistic regression, MPA trough levels <2.5 mg/L were associated with a 7-fold (CI 95%: 1.589-29.934) and ciclosporin use with a 6-fold (CI 95%: 1.148-30.853) increase in the odds of seroconversion. Our study indicates that immune-responsiveness to SARS-CoV-2 mRNA vaccines correlates with MPA exposure measured by MPA trough level but argues against a class effect of MPA. TDM-guided MPA dosing may be a strategy to increase seroconversion rate.

A Multi-Centre Non-Interventional Study to Assess the Tolerability and Effectiveness of Extended-Release Tacrolimus (LCPT) in De Novo Liver Transplant Patients.

BACKGROUND: Available tacrolimus formulations exhibit substantial inter- and intra-individual variability in absorption and metabolism. The present non-interventional cohort study aimed to assess the tolerability and effectiveness of the once-daily tacrolimus formulation, LCPT, in hepatic allograft recipients in real life. MATERIALS AND METHODS: This study was conducted in Austria and the Czech Republic between July 2016 and August 2019. Patients aged ≥ 18 years old received LCPT per the approved label and local clinical routine. All the participants provided informed consent. Patients newly treated with tacrolimus (de novo) directly after transplantation were observed for six months. The relevant clinical variables were tacrolimus trough level (TL), total daily dose (TDD), number of dose adjustments, kidney and liver function, and tolerability. RESULTS: Of the 70 analyzed patients, 72.9% were male and 85.7% were aged < 65 years old. The mean (SD) time to achieve tacrolimus target TL was 6.4 (4.6) days after 4.4 (4.0) dose adjustments; thereafter, TL remained stable throughout observation at approximately 8 ng/mL. The LCPT TDD at initiation was 8 mg and decreased by a median of 41.4% to 5 mg at 6 months. Liver function continuously improved, and kidney function remained stable. LCPT was well tolerated with 24 adverse events in eight patients (17 related to immunosuppression, mostly mild renal insufficiency, and hematological adverse events); two serious unrelated adverse events were reported (atrial flutter and liver dysfunction). CONCLUSIONS: TL was rapidly attained with few dose adaptations after LCPT initiation in de novo liver transplant patients. Liver function rapidly improved, whereas kidney function remained normal. LCPT was well-tolerated in this population.

Efficacious dosing regimens for anti-TNF therapies in inflammatory bowel disease: where do we stand?

INTRODUCTION: During the last decades, biologics have revolutionized the treatment of Crohn's disease and ulcerative colitis. Even though the inflammatory bowel disease (IBD) armamentarium is rapidly expanding with novel biologics, anti-tumor necrosis factor (TNF) antibodies remain the first-line biologic therapy in most areas of the world. However, anti-TNF therapy is not effective in all patients (primary non-response) and patients can lose effect over time (secondary loss of response). AREAS COVERED: This review provides an overview of the current induction and maintenance dosing regimens of the available anti-TNF antibodies and associated challenges in adult patients with IBD. We outline different strategies to overcome these difficulties, including combination therapy, therapeutic drug monitoring (TDM), and dose escalation. Finally, we discuss expected future progress in anti-TNF management. EXPERT OPINION: Anti-TNF agents will remain a cornerstone of IBD treatment in the coming decade. Progress will be made in biomarkers for the prediction of response and individualized dosing regimens. The advent of subcutaneous infliximab challenges the need for concomitant immunosuppression.

Therapeutic Drug Monitoring of Vedolizumab in Inflammatory Bowel Disease Patients during Maintenance Treatment-TUMMY Study.

There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure-response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim of our study was to determine whether there is an association between VDZ trough concentration and clinical and biochemical remission in the maintenance phase. A prospective, observational multicenter study has been performed on patients with IBD on VDZ in the maintenance treatment (≥14 weeks). Patient demographics, biomarkers, and VDZ serum trough concentrations were collected. Clinical disease activity was scored by the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and the Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Clinical remission was determined as HBI < 5 and SCCAI < 3. Biochemical remission was defined as fecal calprotectin <250 mg/kg and serum CRP <5 mg/L. A total of 159 patients (59 CD, 100 UC) were included. In none of the patient groups, a statistically significant correlation between trough VDZ concentration and clinical remission was observed. Patients in biochemical remission had higher VDZ trough concentrations (p = 0.019). In this population, higher trough VDZ concentrations were associated with biochemical remission but not with clinical remission.

The Bayesian-Based Area under the Curve of Vancomycin by Using a Single Trough Level: An Evaluation of Accuracy and Discordance at Tertiary Care Hospital in KSA.

The AUC0-24 is the most accurate way to track the vancomycin level while the Cmin is not an accurate surrogate. Most hospitals in Saudi Arabia are under-practicing the AUC-guided vancomycin dosing and monitoring. No previous work has been conducted to evaluate such practice in the whole kingdom. The current study objective is to calculate the AUC0-24 using the Bayesian dosing software (PrecisePK), identify the probability of patients who receive the optimum dose of vancomycin, and evaluate the accuracy and precision of the Bayesian platform. This retrospective study was conducted at King Abdulaziz medical city, Jeddah. All adult patients treated with vancomycin were included. Pediatric patients, critically ill patients requiring ICU admission, patients with acute renal failure or undergoing dialysis, and febrile neutropenic patients were excluded. The AUC0-24 was predicted using the PrecisePK platform based on the Bayesian principle. The two-compartmental model by Rodvold et al. in this platform and patients' dose data were utilized to calculate the AUC0-24 and trough level. Among 342 patients included in the present study, the mean of the estimated vancomycin AUC0-24 by the posterior model of PrecisePK was 573 ± 199.6 mg, and the model had a bias of 16.8%, whereas the precision was 2.85 mg/L. The target AUC0-24 (400 to 600 mg·h/L) and measured trough (10 to 20 mg/L) were documented in 127 (37.1%) and 185 (54%), respectively. Furthermore, the result demonstrated an increase in odds of AUC0-24 > 600 mg·h/L among trough level 15-20 mg/L group (OR = 13.2, p < 0.05) as compared with trough level 10-14.9 mg/L group. In conclusion, the discordance in the AUC0-24 ratio and measured trough concentration may jeopardize patient safety, and implantation of the Bayesian approach as a workable alternative to the traditional trough method should be considered.

Exposure to tacrolimus trough levels below 6 ng/ml during the first year is associated with inferior kidney graft survival.

BACKGROUND: Accumulating data indicate that sub-therapeutic levels of tacrolimus are associated with long-term kidney graft loss. However, elevated doses increase the risk of infection and drug toxicity, which also threaten graft and patient longevity. We sought to determine the minimal tacrolimus level required to maintain graft survival. METHODS: We conducted a single-center historical cohort study. The first-year post-transplant exposure time was calculated for each of the five tacrolimus trough level intervals. This measure was adjusted to the exposure time below a given interval level, allowing us to define the threshold for the optimal tacrolimus level as the upper limit of the interval. We then determined the association between the adjusted exposure time at each tacrolimus level interval and our primary outcome, death-censored graft loss. RESULTS: One thousand four hundred and seventeen patients with a median follow-up of 5.3 years were included in the final cohort. The tacrolimus level interval of 5-6 ng/ml was the highest interval, which demonstrated a statistically significant association between adjusted exposure time and increased risk of graft loss (HR 1.58, per log days, p = .002). Cumulative exposure time above 14 days with a tacrolimus level below 6 ng/ml was associated with an increased rate of graft loss in most studied subgroups, except for recipients with pre transplant diabetes. CONCLUSIONS: Maintaining tacrolimus levels above 6 ng/ml during the first-year post-transplant might improve kidney graft survival.

Effectiveness of Switching From Intravenous to Subcutaneous Infliximab in Patients With Inflammatory Bowel Diseases: the REMSWITCH Study.

BACKGROUND AND AIMS: We assessed the effectiveness of switching from intravenous to subcutaneous infliximab in patients with inflammatory bowel diseases (IBDs) treated with or without intensified intravenous regimen. METHODS: In this multicenter observational study, IBD patients in clinical remission (partial Mayo score ≤2 or Harvey-Bradshaw index ≤4) were switched to a unique dose of subcutaneous infliximab (120 mg every other week). Pharmacological and biological data were collected at baseline, visit 1 (4-8 weeks postswitch), visit 2 (8-16 weeks postswitch), and visit 3 (16-24 weeks postswitch). Relapse was defined as clinical relapse or fecal calprotectin increase ≥150 µg/g compared with baseline. RESULTS: Among 184 eligible patients, 72.3% (n = 133 of 184) agreed to switch to subcutaneous infliximab. At visit 3, a relapse occurred in 10.2% (n = 6 of 59), 7.3% (n = 3 of 38), 16.7% (n = 3 of 18), and 66.7% (n = 10 of 15) (P < .001) of patients receiving 5 mg/kg every 8 weeks, 10 mg/kg every 8 weeks, 10 mg/kg every 6 weeks, and 10 mg/kg every 4 weeks, respectively. Dose escalation to 240 mg every other week led to recapture clinical remission in 93.3% (n = 14 of 15). Infliximab serum levels increased after the switch (P < .0001) except for patients receiving 10 mg/kg every 4 weeks. In multivariable analysis, 10 mg/kg every 4 weeks regimen (odds ratio, 12.4; 95% confidence interval, 1.6-98.4; P = .017) and fecal calprotectin >250 µg/g at baseline (odds ratio, 5.4; 95% confidence interval, 1.1-27.6; P = .042) had a higher risk of relapse as well as reduced (41.7%) or stable (36.8%) infliximab serum levels between baseline and visit 1 compared with increased serum levels (12.7%) (P = .020 and P = .019, respectively). Patients' acceptability (10-point scale) was improved by the switch (6.9 ± 1.6 vs 8.6 ± 1.4; P < .0001). No severe adverse event was reported. CONCLUSIONS: Switching from intravenous to subcutaneous infliximab 120 mg every other week is safe and well accepted, leading to a low risk of relapse in IBD patients except for those receiving 10 mg/kg every 4 weeks requiring 240 mg every other week.

Impact of single-nucleotide polymorphisms on tacrolimus pharmacokinetics in liver transplant patients after switching to once-daily dosing.

BACKGROUND: The effects of multidrug resistance-1 (MDR1), ABCC2, and P450 oxidoreductase (POR)*28 gene polymorphisms on tacrolimus metabolism following a switch to once-daily dosing have not been elucidated. We investigated the effects of recipient and donor CYP3A5, MDR1, ABCC2, and POR*28 polymorphisms on tacrolimus pharmacokinetics following a switch to once-daily tacrolimus dosing. METHODS: Eighty-seven liver transplant recipients who were switched from twice- to once-daily tacrolimus dosing following living-donor liver transplantation and 81 matched donors were genotyped for CYP3A5, MDR1 (1236C>T, 2677G>T/A, and 3435C>T), ABCC2 (-24C>T, 1249G>A, and 3972C>T), and POR*28. Tacrolimus dose-adjusted trough levels (C0/dose) before and after the switch were determined and calculated based on past medical records. Recipients were divided into two groups, one group constituted of 38 patients with a C0/dose decrease of less than 30% following conversion (group 1) and the other constituted of 49 patients with a C0/dose decrease of ≥ 30% (group 2). RESULTS: CYP3A5 *1/*3 and *3/*3 were more frequent in recipients in group 1 (60.5% vs. 36.8%), while CYP3A5 *1/*1 was more frequent in group 2 (59.2% vs. 32.7%) (p = 0.016). The proportions of donor ABCC2 1249G>A genotypes AA and AG were higher in group 2 than in group 1 (20.4% vs. 5.3%; p = 0.042). CONCLUSION: Recipient CYP3A5 polymorphism and donor ABCC2 1249G>A polymorphism affected tacrolimus pharmacokinetics following the switch to once-daily dosing. Dose adjustment to maintain therapeutic tacrolimus levels following the switch to once-daily dosing should be considered based on polymorphisms in both the recipient and donor.

Early Infliximab Trough Levels Predict the Long-term Efficacy of Infliximab in a Randomized Controlled Trial in Patients with Active Crohn's Disease Comparing, between CT-P13 and Originator Infliximab.

Background/Aims: The clinical efficacy and safety of CT-P13 are comparable to originator infliximab for Crohn's disease in CT-P13 3.4 study (NCT02096861). We performed a multivariate logistic analysis to demonstrate the association between early infliximab trough levels and treatment outcomes of CT-P13 and originator infliximab. Methods: Early serum infliximab trough levels and anti-drug antibody (ADA) levels were compared between CT-P13 (n=100) and originator infliximab (n=98) groups. Receiver operating characteristic (ROC) analysis and multivariate logistic analysis were conducted to identify optimal cutoffs of serum infliximab trough levels and predictive factors for clinical outcomes. Results: The median infliximab trough levels were not different between CT-P13 and originator infliximab groups at week 6, week 14, and in median ADA levels at week 14, respectively. ROC analysis found an infliximab concentration threshold of 4.5 µg/mL at week 6 and 4.0 µg/mL at week 14 as the cutoff value with the highest accuracy for the prediction of clinical outcomes. Serum infliximab trough levels at weeks 6 and 14 predicted clinical remission at weeks 30 and 54, and endoscopic remission at week 54. The combinations of clinical remission or C-reactive protein normalization with an early infliximab trough level improved the prediction of long-term clinical or endoscopic remission. Conclusions: A threshold in serum infliximab trough level at week 6 and week 14 was highly predictive for long-term clinical outcomes. There were no statistical differences in serum infliximab trough levels and ADA levels between CT-P13 and originator infliximab.

Subcutaneous Infliximab [CT-P13], a True Biologic 2.0. Real Clinical Practice Multicentre Study.

BACKGROUND: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation. There are few data on the efficacy and safety in clinical practice of infliximab (CT-P13) in subcutaneous formulation (SC) for the treatment of patients with IBD. METHODS: Multicenter, prospective study of patients with IBD in clinical remission, who had their treatment changed from intravenous (IV) infliximab to SC. Two groups of patients were evaluated according to whether they were on IV infliximab treatment at standard or intensified doses before the switch. RESULTS: A total of 30 patients were on standard dosing and another 30 in intensified therapy. Treatment persistence in both groups at 6 months was greater than 95%. In both groups after the change, neither the biomarkers of inflammation nor the activity indices underwent significant changes at 3 and 6 months compared to the baseline value. Similarly, in both groups, infliximab trough levels showed a significant increase 3 and 6 months after the change to SC. No serious adverse events were registered. CONCLUSIONS: The CT-P13 SC brings a new anti-TNF era. Achieving much higher drug levels that are constant over time opens new paths to explore the management of patients with IBD: less immunogenicity, better perianal disease control and higher achievement of mucosal healing.

Practical approaches to improve vancomycin-related patient outcomes in pediatrics- an alternative strategy when AUC/MIC is not feasible.

BACKGROUND: Anecdotal experience and studies have shown that most pediatric patients fail to reach target therapeutic vancomycin trough levels (VTLs) and required higher total daily doses (TDD). This retrospective study aims to evaluate the frequency of hospitalized children who achieved target VTLs with a vancomycin (VNCO) dosing regimen of 40-60 mg/kg/d q6h and to assess the VNCO-TDD required to attain the target and their effects on clinical outcomes in pediatric patients. METHODS: After ethical approval, patients of 3 month-12 years were evaluated in this chart review study who received ≥ 3 intravenous-VNCO doses and appropriately drawn blood samples of VTLs between October 2019 to June 2020. Data were retrieved for demographic and clinical characteristics, culture reports, VNCO-regimen, subsequent steady-state VTLs, concomitant nephrotoxic medications, and serum creatinine. Clinical pharmacists made interventions in VNCO therapy and higher VNCO-TDD were used. Safety of higher vs standard daily doses and their clinical impact on duration of therapy, hospital stay, and survival were evaluated. RESULTS: A total of 89 (39.1%) patients achieved target VTLs (SD-group). The smallest proportion (18.2%) of 2-6 years patients achieved target VTLs and reported the lowest mean value of 10.1 ± 0.2 mg/L which was a significant difference (p < 0.05) from all subgroups. Subtherapeutic VTLs were observed in 139 (60.9%) cases (HD-group), who received higher VNCO-TDD of 72 ± 8.9 mg/kg/d q6h to achieve the targets. Duration of therapy in culture-proven septic patients was significantly (p = 0.025) longer in SD-group [18.4 ± 12.2 days] than HD-group [15.1 ± 8.9 days]. Nephrotoxicity and electrolyte imbalance were comparable in groups. Length of hospital stay was significantly (p = 0.011) longer [median 22 (range 8-55) days] in SD-group compared to HD-group [median 16 (range 8-37) days]. Number of patients survived in HD-group were significantly (p = 0.008) higher than SD-group [129 (92.8%) vs 75 (84.3%)]. CONCLUSION: Initial Vancomycin doses of 72 ± 8.9 mg/kg/day q6h are required to achieve therapeutic target in 3 months to 12 years patients. High doses are not associated with higher nephrotoxicity than reported with low doses. In addition, efficient pharmacist intervention for the use of higher VNCO-TDD may improve clinical outcomes in terms of duration of therapy, hospital stay, and survival.

Infliximab trough level combined with inflammatory biomarkers predict long-term endoscopic outcomes in Crohn's disease under infliximab therapy.

BACKGROUND: Infliximab trough level (ITL) severely affects therapeutic outcomes of Crohn's disease (CD) patients under infliximab (IFX). Recently, frontier research has focused on identifying ITL based on different therapeutic targets. Although previous studies have elaborated clinical value of ITL monitoring on short-term outcomes in CD patients during therapy, studies contraposing the predictive value of ITL on long-term endoscopic outcomes in CD patients are still scarce domestically and overseas. AIM: To explore the predictive value of ITL in combination with inflammatory biomarkers on long-term endoscopic outcomes in CD with clinical remission during IFX maintenance therapy. METHODS: CD patients with endoscopic remission under long-term IFX maintenance therapy in the First Affiliated Hospital of Zhejiang Chinese Medicine University from January 2012 to December 2020 were collected. ITL and inflammatory biomarkers were continuously monitored during the therapy. The Step I study was conducted from weeks 14 to 54 of IFX treatment. The Step II study was conducted from weeks 54 to 108 of IFX treatment. Endoscopic outcomes were defined as endoscopic activity (Crohn's disease endoscopic index of severity score > 2 points or Rutgeerts score > i1) and endoscopic remission (Crohn's disease endoscopic index of severity score ≤ 2 points or Rutgeerts ≤ i1). Endoscopic relapse free survival was defined as endoscopic remission at the beginning of the study stage and maintaining endoscopic remission during the study stage. RESULTS: At week 14, low ITL [odds ratio (OR) = 0.666, 95% confidence interval (CI): 0.514-0.862, P < 0.01] and high fecal calprotectin (FCP) level (OR = 1.002, 95%CI: 1.001-1.004, P < 0.01) increased the risk of endoscopic activity at week 54. At week 54, low ITL (OR = 0.466, 95%CI: 0.247-0.877, P < 0.01) and high C-reactive protein (CRP) level (OR = 1.590, 95%CI: 1.007-2.510, P < 0.01) increased the risk of endoscopic activity at week 108. At week 14, ITL ≤ 5.60 µg/mL [area under the curve (AUC) = 0.83, 95%CI: 0.73-0.90, P < 0.001] and FCP > 238 µg/g (AUC = 0.82, 95%CI: 0.72-0.89, P < 0.001) moderately predicted endoscopic activity at week 54. ITL ≤ 5.60 µg/mL in combination with FCP > 238 µg/g indicated 82.0% possibility of endoscopic activity. At week 54, ITL ≤ 2.10 µg/mL (AUC = 0.85, 95%CI: 0.72-0.93, P < 0.001) and CRP > 3.00 mg/L (AUC = 0.73, 95%CI: 0.60-0.84, P = 0.012) moderately predicted moderate endoscopic activity at week 108. ITL ≤ 2.10 µg/mL in combination with CRP > 3.00 mg/L indicated 100.0% possibility of endoscopic activity. From weeks 14 to 54 of IFX treatment, patients with ITL > 5.60 µg/mL had higher rate of endoscopic relapse free survival than those with ITL ≤ 5.60 µg/mL (95.83% vs 46.67%). From weeks 54 to 108 of IFX treatment, patients with ITL > 2.10 µg/mL had higher rate of endoscopic survival free relapsed rate than those with ITL ≤ 2.10 µg/mL (92.68% vs 30.77%). CONCLUSION: Combination of ITL, CRP, and FCP contribute to long-term endoscopic prognosis monitoring. During IFX maintenance treatment, low ITL, high CRP level, and high FCP level were independent risk factors of CD patients with clinical remission in adverse endoscopy outcomes within 1-year follow-up.

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients.

We investigated whether HLA class II eplet mismatch was related to dnDSA development and analyzed its combined impact with tacrolimus levels for kidney transplantation outcomes. A total of 347 kidney transplants were included. HLA Matchmaker was used for the single molecular eplet, total eplet, antibody (Ab)-verified eplet mismatch analyses, and Ab-verified single molecular analysis to identify HLA-DR/DQ molecular thresholds for the risk of dnDSA development. A time-weighted tacrolimus trough level (TAC-C0) of 5 ng/mL and a TAC-C0 time-weighted coefficient variability (TWCV) of 20% were applied to find the combined effects on dnDSA development. A high level of mismatch for single molecular eplet (DQ ≥ 10), total eplet (DQ ≥ 12), Ab-verified eplet (DQ ≥ 4), and Ab-verified single molecular eplet (DQ ≥ 4) significantly correlated with HLA class II dnDSA development. Class II dnDSA developed mostly in patients with low TAC-C0 and high eplet mismatch. In the multivariable analyses, low TAC-C0 and high eplet mismatch showed the highest hazard ratio for the development of dnDSA. No significant combined effect was observed in dnDSA development according to TWCV. In conclusion, the determination of HLA class II eplet mismatch may improve the risk stratification for dnDSA development, especially in conjunction with tacrolimus trough levels.

Pharmacokinetic profile of children with haemophilia A receiving low-dose FVIII prophylaxis in Indonesia: A single centre experience.

BACKGROUND: Pharmacokinetic (PK) studies of low-dose prophylaxis (LDP) of coagulation factor VIII (FVIII) in children with severe haemophilia A (SHA) are scarce. OBJECTIVE: This study aims to investigate the PK profile of children with SHA receiving LDP of FVIII. METHODS: Paediatric patients receiving FVIII infusions (10 IU/kg twice weekly) were included. PK profiles were estimated using the Web Accessible Population Pharmacokinetic Service for Haemophilia (WAPPS-Haemo). The primary outcomes were the terminal half-life (t1/2 ), concentration-time profile, and time to reach an FVIII level of < 1%. The secondary outcome was the suggested dosing interval of FVIII prophylaxis based on the individual PK profile. RESULTS: Twenty-five patients were recruited; their mean age was 12.3 ± 3.0 years. The t1/2 differed among patients receiving LDP of FVIII twice weekly, with a median of t1/2 was 14.8 h (IQR 12.6-16). The median time to reach an FVIII level of < 1% was 73.8 h (IQR 58.8-80.3). Most patients could maintain a trough level of FVIII > 1% longer than 48 h. At 72-96 h, patients needed a second dose of FVIII infusion because the FVIII level was < 1%. The suggested dosing interval of FVIII prophylaxis ranged from daily to every 96 h, depending on the individual PK profile. CONCLUSION: Our study identified inter-individual differences in the PK parameters using LDP of FVIII twice weekly. The inter-individual results in different dosing intervals advise the timing of LDP. Estimating individual PK parameters enables the identification of the optimal prophylaxis frequency to prevent bleedings.

Axitinib Trough Concentration and its Influence on the Efficacy and Toxicity of Second-line Renal Cell Carcinoma Treatment.

INTRODUCTION: There are known correlations between axitinib exposure and treatment response. The aim of the article was to study relationships between the axitinib steady-state trough concentration and the treatment efficacy and toxicity. PATIENTS AND METHODS: 35 patients (24 men and 11 women), treated or initiating treatment with axitinib, were included in the study over the period 2016-2019. Blood samples were collected following 2 weeks of treatment (in patients who initiated the therapy) and at the end of Cycles 1, 2, and 3 thereafter (in the entire study population). For concentration measurements, high-performance liquid chromatography - mass spectrometry (HPLC-MS) was applied. Treatment efficacy was assessed according to the RECIST 1.1 criteria. Therapy toxicity was evaluated according to the CTCAE criteria. RESULTS: A statistically significant relationship between the first measured axitinib trough concentration (Ctrough first) value and treatment response (P = .004) as well as the median progression-free survival (mPFS) (P = .003) was observed. The association between axitinib Ctrough first and the median overall survival (mOS) was not statistically significant (P = .142). A statistically significant relationship was observed between the mean trough concentration from 3-month observation (Ctrough 1-3m) and treatment response (P = .008) as well as mPFS (P = .001), without a significant relationship for mOS (P = .097). At least grade 3 adverse reactions were meaningfully associated with Ctrough first (P = .012) and Ctrough 1-3m (P = .003). CONCLUSION: There are significant relationships between axitinib Ctrough and treatment response, PFS, and grade ≥ 3 toxicity. The data collected may be used to determine indications for axitinib therapy monitoring based on Ctrough measurements.

Proactive versus Reactive Therapeutic Drug Monitoring: Why, When, and How?

BACKGROUND: Up to a third of inflammatory bowel disease) patients show primary nonresponse to antitumor necrosis factor (anti-TNF) biological therapy, and of those who respond, up to 40% develop secondary loss of response (LOR). Therapeutic drug monitoring (TDM) plays a crucial role in assessing patients with LOR to guide therapy by giving more of the drug or switching to a different biological agent. Although reactive TDM is suggested or recommended by the majority of gastroenterology associations, proactive TDM seems to be more controversial. SUMMARY: In this article, we discuss the updated guidelines on TDM and will also discuss the available data supporting proactive and reactive TDM in patients with Crohn's disease and those with ulcerative colitis using the different available biological agents. KEY MESSAGES: Therapeutic drug monitoring (TDM) is a valuable tool to aid in inflammatory bowel disease (IBD) therapy optimization. Reactive TDM is widely accepted in IBD patients with suspected loss of response, especially in those receiving antitumor necrosis factor (anti-TNF) agents. Proactive TDM is emerging as a reasonable approach to patients initiated on anti-TNF therapy, specifically infliximab and, to some extent, adalimumab, particularly for patients with severe ulcerative colitis and fistulizing Crohn's disease. Similarly, TDM may play a role in patients considering de-escalation from combination therapy. To date, proactive TDM is not widely applied to ustekinumab and vedolizumab and more data are required before this becomes part of clinical practice.