Mean Trough Levels Research Articles

Population Pharmacokinetics of Vancomycin in Intensive Care Patients with the Time-Varying Status of Temporary Mechanical Circulatory Support or Continuous Renal Replacement Therapy.

This study characterized the population pharmacokinetics (PK) of vancomycin in patients treated with and without continuous renal replacement therapy (CRRT) or temporary mechanical circulatory support (tMCS), including extracorporeal membrane oxygenation or extracorporeal ventricular assist device. Critically ill adults with and without tMCS or CRRT prescribed vancomycin were enrolled for population PK modeling. MonteCarlo simulation provided dosing recommendations based on the probability of target attainment (PTA), achieving a 24-h area under curve (AUC24h) of 400-600mg*h/L. Twenty-five patients with 184 plasma samples were analyzed. The median age was 61.0years. The final model was a two-compartment PK model. CRRT, serum creatinine, and body weight were significant predictors of clearance. CRRT was a covariate on the central volume of distribution. tMCS significantly decreased the intercompartmental clearance. The simulated mean trough levels at the 48th hour were lower in the tMCS group (13.4 versus 14.2mg/dL in non-tMCS, p < 0.001) in a 70-kg subject with a creatinine of 1mg/dL and a daily dose of 20mg/kg, but the PTA was similar (61.8% versus 62.2%). A reduction of maintenance dose from 30 to 10mg/kg/day with loading dose from 25 to 15mg/kg is recommended while serum creatinine progresses from 0.5 to 4.0mg/dL. For CRRT, the optimal regimen consists of 20-25mg/kg loading and maintenance of 15mg/kg/day. The dosing strategy of vancomycin can be based on body weight or renal function, regardless of tMCS. Intercompartmental clearance decreases under tMCS, which can mislead a dosing adjustment based on trough level.

Population Pharmacokinetics of Adalimumab in Juvenile Idiopathic Arthritis Patients: A Retrospective Cohort Study Using Clinical Care Data.

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability. Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates. A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8±3.9years, with a median body weight of 49kg (interquartile range 29.4-59.8kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37L per day per 70kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4±5.5mg/L. The two dosing regimens of 20 and 40mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure. Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA.

Optimum tacrolimus trough levels for enhanced graft survival and safety in kidney transplantation: a retrospective multicenter real-world evidence study.

The current study aimed to determine the optimal tacrolimus trough levels for balancing graft survival and patient safety following kidney transplantation. We conducted a retrospective cohort study involving 11,868 kidney transplant recipients from five medical centers. The association between tacrolimus exposures (periodic mean trough level, coefficient of variability, time in therapeutic range) and composite allograft outcome (de novo donor specific antibody, biopsy-proven rejection, kidney dysfunction, and graft failure), as well as safety outcomes (severe infection, cardiovascular events, malignancy, and mortality) were assessed. Data were sourced from Clinical Data Warehouses and analyzed using advanced statistical methods, including Cox marginal structural models with inverse probability treatment weighting. Tacrolimus levels of 5.0-7.9ng/mL and 5.0-6.9ng/mL during the 2-12 month and 12-72 month post-transplantation periods, respectively, were associated with reduced risks of composite allograft outcomes. During the first post-transplant year, the adjusted hazard ratios (aHR) for composite allograft outcomes were: 0.69 (95% CI 0.55-0.85, P<0.001) for 5.0-5.9ng/mL; 0.81 (95% CI 0.67-0.98, P=0.033) for 6.0-6.9ng/mL; and 0.73 (95% CI 0.60-0.89, P=0.002) for 7.0-7.9ng/mL (compared to levels ≥8.0ng/mL). For the 6-year composite outcomes, aHRs were 0.68 (95% CI 0.53-0.87, P=0.002) for 5.0-5.9ng/mL and 0.65 (95% CI 0.50-0.85, P=0.001) for 6.0-6.9ng/mL. These optimal ranges showed reduced rates of severe infection (6y), malignancy (6y), and mortality (1y). This multicenter study provides robust evidence for optimal tacrolimus trough levels during the periods 2-12 and 12-72 months following kidney transplantation.

Tacrolimus Intrapatient Variability on Graft Outcomes inAdherent Renal Transplantation Patients: A Cross-SectionalStudy.

Tacrolimus is the mainstem of immunosuppressive therapy in kidney transplant patients. It has high intrapatient variability (Tac-IPV), which has been reported to affect graft function by predisposing patients to rejection or nephrotoxicity. We conducted this study with the aim of assessing the influence of Tac-IPV on 2-year graft function, biopsy-proven rejection, and infections in compliant renal recipients. In this single-center retrospective analytic cross-sectional study, 250 patients who underwent transplantation from March 21, 2018, to March 20, 2020 and had at least three outpatient tacrolimus trough levels on the same daily dose 6 to 12 months after transplantation were recruited. Tac-IPV was defined as a coefficient variation of > 15%. Graft function, biopsy-proven rejection, cytomegalovirus (CMV) and BK virus viremia, and calcineurin inhibitor (CNI) toxicity were evaluated. Of 202 transplant recipients, 128 were included with a mean age of 45.48 ± 13.14 years. The median Tac-IPV was 13.28% with 43.75% of patients with Tac-IPV > 15%. There were no significant differences in graft function, rejection, CNI toxicity, and CMV viremia among the groups during the 24-month study (P > .05). However, BK viremia was significantly higher among patients with Tac-IPV > 15% (13 vs. 2.9%, P = .042). The risk of antibody mediated rejection alone (22.7 vs. 2.9%) or any kind of rejection (22.7 vs. 11.8%) was significantly higher in patients with higher Tac-IPV, and in those who had mean trough levels below 7 ng/mL (P = .015, .032; respectively). Tac-IPV is low in adherent patients (with the median of 13.28%) and maintaining tacrolimus trough level above 7 ng/mL can overcome the adverse graft outcome of Tac-IPV in compliant kidney transplant recipients. DOI: 10.52547/ijkd.7815.

Abstract 7162: Killing a fly with a sledgehammer: standard flat-dosing administration of Atezolizumab leads to marked overexposure in real-world lung cancer patients

Abstract Atezolizumab is an anti-PDL1 approved for treating small cell lung cancer and non-small cell lung cancers. A threshold of 6 µg/ml in plasma has been associated with target engagement with Atezolizumab. The extent to which patients could be overexposed with the standard 1200 mg Q3W flat-dosing remains unknown, but several in silico studies have suggested that flat-dosing with immune checkpoint inhibitors could lead to plasma concentrations far above the necessary levels to be efficacious. Here, we monitored Atezolizumab peak and trough levels in 27 real-world patients with lung cancer as part of routine therapeutic drug monitoring. Individual pharmacokinetic parameters were calculated using a population approach and optimal dosing-intervals were simulated with respect to the target trough levels of Atezolizumab. No patient displayed plasma levels below 6 µg/ml. The results showed that the mean trough level after the first course was 78.3 ± 17 µg/ml, i.e., 13 times above the target concentration associated with target engagement. The overall response rate was 55.5%. Low-grade IRAEs was observed in 37% of patients. No severe immune-related toxicities was observed. On univariate analysis, no relationship was found between exposure metrics of Atezolizumab (i.e., Cmin, Cmax, AUC at the first cycle or during the forthcoming courses) and pharmacodynamic endpoints (i.e., efficacy, toxicity). First-line Atezolizumab treatment and treatment for NSCLC were both significantly associated with efficacy on univariate analysis (p=0.0067 and p=0.0497, respectively), but further multivariate analysis did not confirm this relationship (p=0.2465 and p=0.9981). Smoking status was moderately associated with toxicities on univariate analysis (p=0.03), but this effect was not confirmed on further multivariate analysis (p=0.99). None of the other covariates (i.e., age, sex, NLR, number of metastatic sites, associated chemotherapy) were associated with efficacy or toxicity. Further simulations suggested that the dosing interval could be extended from the standard 21 days (i.e., Q3W) to 49 up to 136 days (mean: 85.7 days, i.e., Q12W dosing), while ensuring plasma levels always above the 6 µg/ml target threshold. This observational, real-world study confirms for the first time in real-world patients that the standard 1200 mg Q3W fixed-dose regimen of Atezolizumab results in significant overexposure in plasma. Of note, this overexposure was not associated with increased side-effects. As plasma levels always exceed pharmacologically active concentrations, the inter-individual variability we observed in PK parameters did not impact efficacy and could not explain differences in response. Our data suggest that dosing intervals could be markedly extended with respect to the target threshold associated with efficacy, thus lowering drug-cost in the future. Citation Format: Sophie Marolleau, Alice Mogenet, Mourad Hamimed, Clara Boeri, Laurent Greillier, Joseph Ciccolini. Killing a fly with a sledgehammer: standard flat-dosing administration of Atezolizumab leads to marked overexposure in real-world lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7162.

Conversion from twice-daily everolimus to once-daily sirolimus in long-term stable liver transplant recipients

BackgroundAfter organ transplantation, strategies for simplifying the therapeutic regimen may improve adherence and prevent acute organ rejection and/or late graft loss. The present study aimed to evaluate the safety and efficacy of conversion from everolimus (EVR) twice daily to sirolimus (SIR) once daily in a large cohort of liver transplantation (LT) patients. MethodsWe included 108 LT patients with at least 12 months of post-transplant follow-up and no rejection episodes in the last year. Conversion was based on a 1:1 ratio (but eventually adapted to available formulations of SIR). ResultsThe median age at the time of conversion was 68.9 years (range: 26.1–83.6); 75.0% were men. The main indications for mTOR inhibitor use were renal failure (38.9%) and/or a history of malignancy (37.0%). Median conversion time after LT was 14.8 years (range: 2.3–31.5). The median dose of EVR and SIR (initially) was 1.50 mg/day (range: 0.5–4.5). The mean follow-up after conversion was 15.8±4.4 months. Median serum EVR/SIR trough levels before/after conversion were 3.85 ng/mL vs. 6.32 ng/mL (p < 0.05), i.e. a 1:1.64 ratio. At the end of follow-up after conversion, the median dose of SIR was 1.25 mg/day (range: 0.5–3.5), and the mean serum SIR trough level was 5.23 ng/mL; 9 patients (8.3%) had returned to EVR, because of side effects (mainly digestive), that resolved thereafter. No biopsy-proven acute rejection episode was observed. Finally, 87.1% of patients considered the conversion beneficial and the cost was reduced by 50.3%. ConclusionThe results of our study indicate that conversion from once-daily EVR to once-daily SIR in stable LT patients is safe, but needs dose adaptations and careful monitoring.

P885 Pharmacokinetics, pharmacodynamics, and immunogenicity of biosimilar infliximab in pediatric patients with inflammatory bowel disease

Abstract Background The pharmacokinetics and pharmacodynamics of biosimilar infliximab (IFX-BioS) in pediatric inflammatory bowel disease (IBD) are poorly understood. We examined some factors predicting IFX-BioS trough levels (TLs) in children. Methods Children with Crohn's disease (CD) and ulcerative colitis (UC) with an indication to start IFX-BioS in our center were prospectively included (January 2021-June 2022). TLs were measured with an in vitro lateral flow immunoassay (therapeutic range:3-7 microg/mL) at the 4th and 6th infusions and correlated with several covariates. Results A total of 110 TLs in 55 children (34 UC and 21 CD) were included. The mean TLs were 8.8±7.6 microg/mL and 9.8±6.7 microg/mL at the 4th and 6th infusions, respectively. The multivariate linear regression model at the 4th infusion found a positive correlation between TLs and age at diagnosis (B: 1.950, 95% CI: [0.019, 3.882], p=0.048) and IFX-BioS dose/kg (B: 1.962, 95% CI: [0.238, 3.687], p=0.029), and a negative correlation with clinical scores (B: -0.401, 95% CI: [-0.738, -0.064], p=0.023). At the 6th infusion, female gender (B: 6.887, 95 CI: [0.861, 12.913], p=0.029), hemoglobin (B: 1.853, 95% CI: [0.501, 3.204], p=0.011), and IFX-BioS dose/kg (B: 1.792, 95% CI: [0.979, 2.605], p&amp;lt;0.001) were found to be positively correlated to TLs. Clinical remission was achieved in 71% (4th infusion) and 67.2% (6th infusion) of patients. Logistic regression analysis revealed no significant association between combined clinical and biochemical remission and TLs at the 4th (OR: 0.010, 95% CI: [0.928; 11.099], p=0.819) or 6th (OR: 0.017, 95% CI: [0.924; 1.119], p=0.732) infusion, corrected for IFX-BioS dose/kg and interval between infusions. Conclusion We discovered some predictors IFX-BioS TLs in IBD children. Understanding the IFX-BioS pharmacokinetics and pharmacodynamics could allow physicians to identify which patients are at higher risk of poor outcomes and adjust treatment accordingly.

Clinical characteristics of new-onset diabetes after liver transplantation and outcomes.

We aimed to identify the characteristics of new-onset diabetes after liver transplantation (LT) (NODAT) and investigate its impacts on post-transplant outcomes. Adult LT patients between 2014 and 2020 who used tacrolimus as initial immunosuppression and survived 3 months at least were evaluated. Patients who developed NODAT within 3 months after LT were classified as NODAT group. Also, patients were further classified as history of diabetes before LT (PHDBT) and non-diabetes (ND) groups. Patient characteristics, post-LT outcomes, and cardiovascular and/or pulmonary complications were compared. A total of 83, 225, and 263 patients were classified into NODAT, PHDBT, and ND groups. The proportion of cholestatic liver disease and rejection within 90 days were higher in NODAT group. Mean serum tacrolimus concentration trough level in the first week after LT was 7.12, 6.12, and 6.12 ng/mL (p < 0.001). Duration of corticosteroids was significantly longer in NODAT compared to PHDBD or ND (416, 289, and 228 days, p < 0.001). Three-year graft and patient survival were significantly worse in NODAT than ND (80.5% vs. 95.0%, p < 0.001: 82.0% vs. 95.4%, p < 0.001) but similar to PHDBT. Adjusted risks of 3-year graft loss and patient death using Cox regression analysis were significantly higher in NODAT compared to ND (adjusted hazard ratio [aHR] 3.41, p = 0.004; aHR 3.61, p = 0.004). Incidence rates of cardiovascular or pulmonary complications after LT in NODAT were significantly higher than ND but similar to PHDBT. Higher initial tacrolimus concentration and early rejection might be risk factors for NODAT. NODAT was associated with worse post-transplant outcomes.

Graft-recipient-weight ratio and lowered immunosuppression is important for the success of adult liver retransplantation

This study analyzed the risk of liver retransplantation and factors related to better outcome. Adult liver transplantations performed during 1996–2021 were included. Comparison between first transplantation and retransplantation were performed. Among retransplantation cases, comparison between whole liver and partial liver graft was performed. Multivariable Cox analyses for analyzing risk factors for primary graft and overall patient survival were performed for the entire cohort as well as the subgroup of patients with retransplantation. A total 2237 transplantations from 2135 adults were included and 103 cases were retransplantation. A total of 44 cases (42.7%) were related to acute graft dysfunction while 59 cases (57.3%) were related to subacute or chronic graft dysfunction. Retransplantation was related poor primary graft (HR 3.439, CI 2.230–5.304, P < 0.001) and overall patient survival. (HR 2.905, CI 2.089–4.040, P < 0.001) Among retransplantations, mean serum FK506 trough level ≥ 9 ng/mL was related to poor primary graft (HR 3.692, CI 1.288–10.587, P = 0.015) and overall patient survival. (HR 2.935, CI 1.195–7.211, P = 0.019) Graft-recipient-weight ratio under 1.0% was related to poor overall patient survival in retransplantations. (HR 3.668, CI 1.150–11.698, P = 0.028). Retransplantation can be complicated with poor graft and patient survival compared to first transplantation, especially when the graft size is relatively small. Lowering the FK506 trough level during the first month can be beneficial for outcome.

Genetic polymorphisms of glucocorticoid receptor and their association with new-onset diabetes mellitus in kidney transplant recipients

IntroductionThe variability in developing New-onset Diabetes Mellitus After Transplantation (NODAT), together with previously well-established interindividual variation in glucocorticoid sensitivity, led us to hypothesize that polymorphisms in the NR3C1 gene encoding glucocorticoid receptor may alter glucose balance in kidney transplant recipients. This study aimed to evaluate the association of three functional polymorphisms, BclI, N363S, and ER22/23EK, on the NR3C1 gene with NODAT in kidney allograft recipients. MethodsFrom Jun 2020 to July 2022 in Shiraz, 52 patients with NODAT (case group) and 52 non-diabetic kidney transplant recipients (control group) were randomly screened and recruited in this case-control study. The PCR-RFLP technique determined the genotypes of BclI, N363S, and ER22/23EK polymorphisms. ResultsThe allelic frequencies of the mutant alleles of BclI, N363S, and ER22/23EK polymorphisms in all patients were 0.36, 0.03, and 0.009, respectively. BclI mutant genotypes (CG and GG) were significantly associated with an increased risk of NODAT (P = 0.016), while the two other polymorphisms disclosed no significant association with NODAT development. In the case group, no significant association was detected between the onset time of NODAT and studied polymorphisms, including BclI (P = 0.43), N363S (P = 0.30), and ER22/23EK. P value was not reported for the last polymorphism because all patients with NODAT had the wild-type genotype (GG/GG) and performing statistical analysis was not feasible. Among studied demographic/clinical/paraclinical variables, factors such as higher mean trough level of tacrolimus during the first month after transplantation and higher mean daily dose of prednisolone significantly linked with NODAT development. ConclusionOur data suggested that BclI polymorphism significantly affects NODAT development among Iranian kidney allograft recipients.

Pharmacokinetics, Safety, and Tolerability of Cariprazine in Pediatric Patients with Bipolar I Disorder or Schizophrenia.

<b><i>Objective:</i></b> Cariprazine is a dopamine D₃-preferring D₃/D₂ and serotonin 5-HT_1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This sequential-cohort, dose-escalation study was the first to evaluate the pharmacokinetic, safety, and tolerability profile of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), in pediatric patients with schizophrenia or bipolar I disorder. <b><i>Methods:</i></b> This phase I open-label study enrolled patients with schizophrenia (13-17 years of age) or bipolar I disorder (10-17 years of age). Patients met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia or bipolar I disorder and had Positive and Negative Syndrome Scale (PANSS) total scores ≥70 or Young Mania Rating Scale (YMRS) total scores ≥20. Patients were assigned to one of four treatment groups to receive 6 weeks of cariprazine treatment through slow titration to 1.5, 3, or 4.5 mg/d or fast titration to 4.5 mg/d. Pharmacokinetics, adverse events (AEs), and various safety parameters were analyzed. Efficacy was evaluated as an exploratory outcome. <b><i>Results:</i></b> A total of 50 participants were enrolled. Based on mean trough levels, steady state appeared to be reached within 1-2 weeks for cariprazine and DCAR and within 4-5 weeks for DDCAR. Systemic exposure of cariprazine, DCAR, and DDCAR generally increased approximately in proportion to the increases in dose from 1.5 to 4.5 mg/d. The most frequent treatment-related, treatment-emergent AEs included sedation, parkinsonism, tremor, dystonia, and blurred vision. Improvements from baseline on the PANSS and YMRS were observed throughout treatment. <b><i>Conclusion:</i></b> In this first investigation of cariprazine in a pediatric population with schizophrenia or bipolar disorder, pharmacokinetic parameters were consistent with those observed in adults. Cariprazine appeared to be safe and tolerable in children and adolescents.

Correlation Between Trough Level of Abiraterone and Prostate-Specific Antigen (PSA) Response in Metastatic Hormone-Sensitive Prostate Cancer.

BackgroundProstate cancer growth is primarily driven by testosterone and 5α-dihydrotestosterone. Abiraterone is an irreversible inhibitor of CYP17, and CYP17 inhibition is a required step in testosterone biosynthesis. Previous studies have shown that abiraterone trough levels are predictive of prostate-specific antigen (PSA) response in metastatic castrate-resistant prostate cancer (mCRPC). It has not been demonstrated if this association exists for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to explore the correlation and association between abiraterone trough levels and PSA levels in patients with mHSPC.Material/MethodsThis was a single-center, prospective, observational study of patients with mHSPC being treated with abiraterone acetate (AA) 1000 mg once daily. Abiraterone trough levels (22–26 h after drug administration) were drawn at 1, 3, and 7 months after treatment initiation.ResultsThirteen patients with mHSPC were enrolled, and complete pharmacokinetic data were available for 8 patients. The mean trough levels at 1 month, 3 months, and 7 months were 34.49 ng/mL (3.36–240.46), 13.82 ng/mL (2.91–29.96), and 15.7 ng/mL (3.58–26.86), respectively. The correlation between the 1-month abiraterone trough level and 1-month PSA level was 0.29 (P=0.38), between 3-month abiraterone trough and 3-month PSA was −0.61 (P=0.08), and between 7-month abiraterone trough and 7-month PSA was −0.31 (P=0.54).ConclusionsThis study demonstrated a trend toward a negative correlation between 3-month abiraterone trough levels and PSA levels, but the correlation was not statistically significant. A study with a larger prospective sample size is needed to validate these findings.

What Is the Impact of Mammalian Target of Rapamycin Inhibitors on Hepatocellular Carcinoma Recurrence After Liver Transplantation.

We read with great interest the article by Lee et al1 regarding the pooled data from 2 randomized trials evaluating the 24 mo safety and efficacy of mammalian target of rapamycin inhibitor (mTORi) everolimus with reduced tacrolimus (EVR with reduced tacrolimus, n = 387) versus standard tacrolimus (n = 385) regimen after liver transplantation (LT). Interestingly, the authors found that the recurrence of hepatocellular carcinoma (HCC) was numerically lower, although not statistically significant, in patients transplanted beyond Milan with EVR with reduced tacrolimus than in patients with standard tacrolimus (5.9% versus 23.1%; P = 0.215), whereas no difference was found in those within Milan criteria (2.9% versus 2.1%; P = 1.0). The authors mentioned that these findings were similar to our meta-analysis,2 but in fact, in our study,2 we had found that the rate of HCC recurrence was significantly lower in LT recipients under mTORi than in those under calcineurin inhibitors (CNIs; tacrolimus or cyclosporine), but only in those with pre-LT HCC within Milan criteria (mTORi: 3.8% versus CNIs: 9.2%; P = 0.03); comparatively, the rate of HCC recurrence was similar among patients transplanted for HCC outside Milan criteria (mTORi: 29.5% versus CNIs: 29.2%; P = 1.0). Indeed, our findings were confirmed in the SiLVER randomized trial,3 in which sirolimus (another mTORi) showed a benefit only in low-risk LT recipients (ie, those with HCC within Milan criteria pretransplant). Although Lee et al1 did not provide any explanation, these discordance results could not be attributed to different anti neoplastic properties between sirolimus and EVR. (In fact, in our meta-analysis, HCC recurrence was significantly more frequently observed in patients who received sirolimus than in those who received EVR [10.5% versus 4.1%; P = 0.02]). The absence of any clear benefit from EVR administration regarding HCC recurrence might be attributed to the relatively low rates of HCC recurrence in both groups under the mTORi and the mTORi-free regimens at 24 mo (3.3% and 6.3%, respectively).1 Interestingly, in the SiLVER study,3 the recurrence-free survival at 24 mo was 83% in the group under mTORi and 77% in the mTORi-free group, which was possibly related to the lower proportion of patients with HCC within Milan criteria, compared with the study by Lee et al1 (eg, in the group under mTORi: 65.1% versus 82.9%, respectively). Nevertheless, longer follow-up would be useful in the study by Lee et al1 to overcome this limitation, as in the SiLVER study,3 recurrence-free survival benefit was evident in the first 3 to 5 y, especially in low-risk patients. Finally, it would be useful to provide the trough levels of CNIs, particularly during the first month after LT,4 as well as the trough levels of mTORi in those with and without HCC recurrence, as we recently showed that the recipients with mean trough levels of EVR ≥6 ng/mL at 7 to 12 mo post-LT, compared with those with EVR <6 ng/mL, had decreased HCC recurrence rates (log-rank: 2.3; P = 0.007).5

MTOR Inhibitors Induce Erythropoietin Resistance in Renal Transplant Recipients.

AimTo elucidate the role of mTOR inhibitors on iron, hepcidin and erythropoietin-mediated regulation of hemopoiesis in stable renal transplant recipients (RTR).BackgroundImpaired hemopoiesis is common following renal transplantation managed using mTOR inhibitors. The mechanisms responsible are uncertain but include direct effects on iron, hepcidin or erythropoietin-mediated hemopoiesis.MethodsWe conducted a single center prospective case-control study of 26 adult RTR with stable allograft function. RTR received stable mTOR dosing (cases, 11/26 [42%]) or stable tacrolimus dosing (controls, 15/26 [58%]). Baseline demographics, full blood count, renal function, iron studies, hepcidin-25, Interleukin-6 (IL-6) and erythropoietin (EPO) levels were determined.ResultsThere were no differences in age, gender or allograft function. Mean daily sirolimus dose for cases was 1.72 mg, with mean trough level of 8.46 ng/mL. Mean daily tacrolimus dose for controls was 4.3 mg, with mean trough level of 5.8 ng/mL. There were no differences in mean hemoglobin (143 vs. 147 g/L; p = 0.59), MCV (88 vs. 90 fL; p = 0.35), serum ferritin (150 vs. 85.7 μg/L; p = 0.06), transferrin saturation (26 vs. 23.3%; p = 0.46), IL-6 (11 vs. 7.02 pg/ml; p = 0.14) or hepcidin-25 (3.62 vs. 3.26 nM; p = 0.76) between the groups. EPO levels were significantly higher in the group receiving mTOR therapy (16.8 vs. 8.49 IU/L; p = 0.028). On logistic regression analysis EPO level was the only variable that had a significant impact providing an odds ratio of 0.84 (95%CI 0.66–0.98). The area under the receiver operator characteristic curve (ROC) for the analysis was 0.77 (95%CI 0.54–0.94) with p = 0.04.Conclusion: Higher levels of EPO in the absence of deranged iron biochemistry or hepcidin-25 levels suggest that EPO resistance rather than impaired iron metabolism may contribute to the impaired hemopoiesis previously demonstrated in RTR on mTOR therapy.

P303 Biologic Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease: Are we aiming high?

Abstract Background Infliximab and Adalimumab are the only funded biologic therapies for inflammatory bowel disease (IBD) in New Zealand. We hypothesised that clinicians are aiming for higher drug trough levels to mitigate for the absence of alternative therapies. Methods Retrospective study of IBD patients at Lakes DHB from, 2016 to, 2021. Data collected using the IBD patient register and electronic patient records. Change in management included dose escalation, de-escalation and switching biologic. Analyses were performed using chi-square and student t-test. Target trough levels are Infliximab &amp;gt;5 mg/L and Adalimumab&amp;gt;7.5 mg/L. We defined high trough levels as greater than double the suggested target levels (Infliximab &amp;gt;10mg/L, Adalimumab&amp;gt;15mg/L). Results 197 patients in the IBD register., 79 (40.1%) receiving biologic therapy (Infliximab, 31 [39.2%], Adalimumab, 48 [60.8%]).Therapeutic drug monitoring (TDM) performed in, 61 (77.2%) biologic patients with a total of, 129 TDM results available. Mean trough levels: Infliximab, 7.7 (sd, 9.2) mg/L, Adalimumab, 5.7 (sd5.8) mg/L. Conclusion High trough levels were seen more with Infliximab use, reflecting its increased use as a, 2nd line agent and a final option to optimise medical management prior to considering surgery. Fewer changes to management were seen with high trough levels indicating improved clinical outcomes and acceptability of high levels within our practice.

P441 Clinical efficacy, drug sustainability and results from therapeutic drug monitoring in Crohn’s disease patients treated with ustekinumab – 1-year follow-up of a prospective, nationwide, multicenter cohort from Hungary

Abstract Background Although efficacy and safety of ustekinumab (UST) in the treatment of inflammatory bowel disease have been demonstrated through randomized trials, data from real-life prospective cohorts are still of great interest. Our aim was to evaluate the clinical efficacy, drug sustainability, frequency of dose intensification, and results from therapeutic drug monitoring in UST treated Crohn’s disease (CD) patients using a prospective, nationwide, multicenter cohort from Hungary. Methods Patients were consecutively enrolled in this cohort between 2019 January and 2020 May from 5 academic centers and 5 county hospitals. Data from patient demographics, disease phenotype, treatment history (surgical history, prior and present medical therapies), clinical disease activity (using the Crohn’s Disease Activity Index (CDAI), Harvey Bradshaw Index (HBI)), biomarkers (C-reactive protein – CRP), and therapeutic drug monitoring were captured. Evaluations were performed at week8 (post-induction), w16-20, w32-36, and w52-56 follow-up visits. Results N=142 CD patients were included with a median follow-up time of 60 weeks (IQR:47.5–79.5w) [57.4% female; age 38.4±13.0 years]. Based on the Montreal classification, complicated disease behavior (B2orB3) was 48.2%, whereas ileocolonic disease location(L3) 55.7%. Perianal manifestation was present in 46.8% of the patients. Previous anti-TNF exposition was 97.2%, while previous vedolizumab failure was 25.5%. 66.2%/ 66.9% of the patients had moderate-to-sever clinical disease activity at baseline (CDAI&amp;gt;220/HBI&amp;gt;7). Clinical response and remission rates were 78.1% and 57.7% using CDAI, and 82.5% and 51.8% based on HBI scores after induction treatment (w8). One year clinical remission rates were 58% / 57.3% (CDAI/HBI) Composite clinical and biomarker remission (CDAI&amp;lt;150 and CRP&amp;lt;10mg/L) rates were 35.4%; 33.3%; 38.6% and 36.6% at w8/w16-20/w32-36 and w52-56. Parallel corticosteroid use was 34%/26.3%/16.5%/21%/16.9% at baseline and w8/w16-20/w32-36/w52-56. Drug sustainability was high with 81.9% (SD: 3.4) of patients remaining on treatment at one year.(Figure1) Probability of dose intensification was high and introduced early in the treatment, 42.2% (SD: 4.2) at ~w32 and 51.9% (SD: 4.4%) at 1y.(Figure2) Patients with complex disease phenotype (B2/B3) had higher probability for dose intensification (log-rank: p=0.042). Mean serum trough levels of UST were 4,28±3,35/ 1,35±1,42/ 0,82±0,65 and 1,13±0,74µg/mL measured at w8/w16-20/w32-36 and w52-56. ADAs were exceeding 1AU/mL in only 2 patients. Conclusion Ustekinumab showed good drug sustainability and clinical efficacy in a population with severe disease phenotype and high rates of previous anti-TNF failure, however frequent and early dose intensification was required.

Impact of infliximab therapeutic drug level monitoring on outcomes of patients with inflammatory bowel disease: A real-world experience from a Middle Eastern cohort

Background and study aimTherapeutic drug monitoring (TDM) through measurement of infliximab (IFX) trough levels and antibodies to infliximab (ATI) is performed to guide IFX intensification strategies and improve its efficacy. We conducted this study to explore the relationship between clinical and endoscopic/radiological remission and IFX and ATI levels in patients with inflammatory bowel disease (IBD) treated with IFX and to evaluate the appropriateness of treatment decision post TDM. Patients and methodsThis was a cross-sectional study of a cohort of adult patients with IBD. Serum IFX trough concentrations and ATI were measured. ResultsA total of 129 patients [104] with ulcerative colitis (UC) and 25 with Crohn’s disease (CD)] were included in this study, of whom 61.2% were men. The mean disease duration was 6.7 years, and 72% of patients with UC had extensive colitis. The mean serum IFX trough level was 4.1 µg/mL; the IFX trough levels were subtherapeutic in 75 patients (58%), therapeutic in 37 patients (29%), and supratherapeutic in 17 patients (13%). Positivity to ATI was found in 16 patients (12.4%). Only 43 patients (33.3%) underwent an appropriate change in therapy after TDM, patients with penetrating CD disease had low IFX levels and higher C-reactive protein levels at 12 months before TDM. ConclusionsPatients with IBD with therapeutic IFX levels tend to have increased endoscopic/radiological remission rates. However, an appropriate change in management based on TDM was absent in the majority of patients, potentially reflecting the need to have a dashboard to support and guide clinicians in decision-making.

Impact of a computerised clinical decision support system on vancomycin loading and the risk of nephrotoxicity

BackgroundA vancomycin loading dose is recommended for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. However, clinicians often do not adhere to these recommendations, mainly due to nephrotoxicity risk, unfamiliarity with the guideline, or complexity of calculating an individual dose. Therefore, we introduced a computerised clinical decision support system (CDSS) for vancomycin loading (hereafter Vancomycin CDSS) to promote the use of vancomycin loading dose. MethodsWe describe a quasi-experimental study spanning 6 months before and 18 months after the deployment of a Vancomycin CDSS. The Vancomycin CDSS was integrated into the hospital’s electronic medical record system in the form of a vancomycin order set. Our primary endpoint was the incidence of nephrotoxicity; the secondary endpoint was mean initial vancomycin trough levels. We also conducted a survey to evaluate the reasons why clinicians opted not to utilise a vancomycin loading dose. ResultsAfter implementation of Vancomycin CDSS, 363 out of 746 patients (49 %) who were first administered vancomycin received a loading dose. We did not find significant differences in nephrotoxicity between the pre- and post-intervention groups, nor between the loading- and non-loading groups. In the pre-intervention group, the mean initial vancomycin trough level was 7.10 mg/L, which was significantly lower than that in the post-intervention group of 11.11 mg/L. In the vancomycin loading group, the mean initial trough level was 11.95 mg/L, compared to 7.55 mg/L in the non-loading group. The main reason stated for not prescribing a vancomycin loading dose was concern about nephrotoxicity. ConclusionIntroduction of the Vancomycin CDSS did not increase nephrotoxicity and increased the mean initial dose and trough level of vancomycin.

Vancomycin pharmacokinetic parameters in patients undergoing hematopoietic stem cell transplantation.

Current guidelines on vancomycin dosing lack specific recommendations about its dosing in hematopoietic stem cell transplant (HSCT) patients, the objective of the current study was to compare vancomycin pharmacokinetic variables in this population with those of general population. A prospective study was designed and the calculated parameters of vancomycin pharmacokinetic were compared with individualized parameters. Two trough levels before 4th and 5th doses and a peak level after the 4th dose, were taken. All patients received a dose of 15 mg/kg of vancomycin two or three times a day. Pharmacokinetic parameters were calculated using a one compartmental model. The association between different variables and of acute kidney injury (AKI) development and achievement of target levels were also evaluated. A significant difference was observed between population Volume of distribution (Vd) and individualized Vd (mean 57.33 L vs 162.86 L, p value 0.019) and trough and peak levels (p values 0.0001 and 0.001; for mean trough and peak levels respectively). The achievement of the recommended trough levels and area under the concentration time curve per minimum inhibitory concentration (AUC24/MIC) was very low (5/71 and 24/71 patients respectively). No significant differences were observed between population and individualized clearance and rate of elimination of vancomycin (p values of 0.092 and 0.55 respectively). Concomitant receipt of cyclosporine was significantly related with development of AKI (p value 0.046). The dosing methods which use population-based pharmacokinetic variables does not result in desired therapeutic levels in HSCT patients, mainly because of larger vancomycin volume of distribution.

Pharmacokinetics of Tobramycin Administered at the Beginning of Intermittent Hemodialysis Session (ESRD Study).

Background and Objectives:There is a renewed interest in the successful use of aminoglycosides due to increasing resistance in gram-negative infections. Few studies to date have examined the pharmacokinetics (PK) of intradialytic infusions of tobramycin. This study sought to characterize the pharmacokinetic profile of intradialytically administered tobramycin in infected patients receiving chronic intermittent hemodialysis and to determine whether it is possible to achieve favorable PK targets.Design, Setting, Participants, and Measurements:In this prospective pharmacokinetic study, a single dose (5 mg/kg) of tobramycin was administered intradialytically to 11 noncritically ill patients undergoing chronic intermittent hemodialysis. Blood samples were collected at selected time to determine tobramycin serum concentrations. The PK analysis was performed using Phoenix™ NLME. The efficacy exposure outcome for nonsevere gram-negative infections sensitive to tobramycin with a minimum inhibitory concentration ≤1 were maximum concentration (Cmax ≥ 10 mg/L) and area under the curve (AUC24 h > 30 mg⋅h/L). For toxicity, the goal was to identify plasma trough concentrations <2 mg/L.Results:Tobramycin disposition was best described by a one-compartment model using a total clearance composed of the systemic clearance and a transitory hemodialysis clearance. Tobramycin mean (SD) Cmax, trough levels, and AUC24h were 13.1 (1.3) mg/L, 1.32 (0.47) mg/L, and 61 (23) mg⋅h/L, respectively. Monte Carlo simulation run with 1000 virtual patients showed that a 5 mg/kg dose of tobramycin administered intradialytically can outperformed the usual low-dose postdialysis dosing (80% meeting all targets versus <1%, respectively).Conclusions:A single high dose of tobramycin can achieve favorable PK outcome when administered using intradialytic infusions in hemodialysis patients. This practical dosing regimen may represent an effective and safer alternative to the usual dosing in the treatment of nonsevere gram-negative infections.