Higher Trough Concentrations Research Articles

Safety, tolerability and pharmacokinetics of subcutaneous meropenem as an alternative to intravenous administration.

Subcutaneous delivery of antibiotics is a practical alternative to IV administration. Meropenem is commonly used to treat infections caused by resistant Gram-negative organisms. This was a prospective, crossover self-controlled study in 11 stable inpatients established on meropenem. Participants received a single dose of subcutaneous meropenem, in 50 mL normal saline via gravity feed. Venous blood sampling was performed at baseline, 0.5, 1, 2, 4 and 8 h following the subcutaneous and IV doses. Antibiotic concentrations were measured using UPLC-MS/MS. Pharmacokinetic data were analysed using a non-linear mixed-effects modelling approach. Pain scores and infusion site reactions (oedema/erythema) were assessed. Subcutaneous meropenem was well tolerated. The bioavailability of subcutaneous administration was 81.5% (95% CI 71.6%-93.2%). Increasing BMI was associated with slower absorption from subcutaneous tissue. Compared with IV, subcutaneous administration resulted in lower peak and higher trough concentrations. Despite the lower bioavailability observed, the PTA for free drug concentrations greater than the MIC for more than 40% of the time between doses was higher for subcutaneous than IV administration at MIC values between 0.03 and 8 mg/L. Simulated subcutaneous doses of 1.5 g twice daily, or 3 g continuous 24 h infusion had improved PTA relative to standard IV dosing of 1 g three times daily. Subcutaneous meropenem appears to be well tolerated and has a favourable pharmacokinetic profile. Either 1.5 g twice daily or 3 g as a 24 h subcutaneous infusion could be considered for future evaluation.

A lower initial dose of bosutinib for patients with chronic myeloid leukemia patients resistant and/or intolerant to prior therapy: a single-arm, multicenter, phase 2 trial (BOGI trial)

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.

Exploring the Knowledge, Attitude, and Practice of Sudanese Medical Doctors Towards Tacrolimus, at Ahmed Gasim Hospital, Kidney Transplant Center Unit, Khartoum, Sudan (2022 – 2023)

Tacrolimus is one of the most commonly prescribed immunosuppressive drugs that varies between individuals depending on different ethnic groups, the presence of different CYP3A5 genetic variants, and the duration of time since the transplantation, which makes targeting optimal tacrolimus concentration levels more challenging. This study aimed to explore the knowledge, attitude, and practice of Sudanese medical doctors towards Tacrolimus. An observational, cross-sectional study was conducted on the Sudanese medical doctors in the nephrology clinic at Ahmed Gasim Hospital, Kidney Transplant Center Unit, Khartoum, Sudan, who were in direct contact with kidney transplant patients under tacrolimus treatment. Data were collected using a questionnaire modified to record the pharmacogenomic impact. The data were analyzed using a statistical package for social sciences (SPSS). Total of 15 medical doctors, Female 8 (53.3%) and male 7 (46.7%) with mean ± SD age of 31.60 ± (3.906). All of them were currently practicing in governmental hospitals (n=15; 83.3%), private hospitals (n=2; 11.1%), and private clinics (n=1; 6.7%). There were 67% of the medical doctors had high knowledge about the genetic profile of the patient's impact on the tacrolimus trough concentrations, while 66.7% of the medical doctors had low attitude levels toward tacrolimus. The observations among the different Sudanese ethnic groups tacrolimus trough concentrations were found to be variable, as Arabs and Fulani were observed to have low trough concentrations (n=6; 40%), while Nuba and Beja were observed to have high trough concentrations (n=5; 33.3%), instead of fur observed to had fluctuations (n=2; 13.3%). A significant correlation between practice toward tacrolimus with the location of practice, doctor specialty, and years of experience was found (P value ≤ 0.05). The medical doctors exerted a high level of knowledge about the impact of the genetic profile (metabolic alleles) in the dosing and dose adjustment of tacrolimus.

High intra-patient variability of tacrolimus within post-operative 1month predicted worse 1-year outcomes in pediatric liver transplant recipients.

The pharmacokinetics of tacrolimus (TAC) show high intra-patient variability (IPV), which is associated with poor long-term outcomes following adult liver transplantation(LT). However, this relationship remains to be confirmed in pediatric liver transplant (PLT) recipients. The present study aimed to investigate the association between TAC IPV and grafts or patient outcomes after pediatric liver transplantion. This retrospective study included 848 PLT recipients (including infants) between January, 2016, and June, 2021. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of trough concentrations in whole blood within 1month after transplantation. Patients were categorized into two groups, low IPV (CV < 45%) and high IPV (CV ≥ 45%), based on the third quartile of the CV distribution. A total of 848 patients were included in our study. The low CV group included 614 patients, with a mean TAC trough concentration of 8.59 ± 1.65ng/ml and a median CV of 32.37%. In contrast, the high CV group included 214 patients, the mean TAC trough concentration and median CV were 8.81 ± 2.00ng/ml and 54.88%, respectively. The median hospital duration was significantly higher in the high CV group (22days vs. 20days, P = 0.01). Univariate analysis was performed to evaluate the significant differences in 1-year recipient survival (P = 0.041) and 1-year graft survival (P = 0.005) between the high- and low-CV groups. Moreover, high CV (HR 2.316, 95%CI 1.026-5.231, P = 0.043) and persistent EBV viremia (HR 13.165, 95%CI 3.090-56.081, P < 0.001) were identified as independent risk factors for 1- year mortality after PLT. PLT recipients with high TAC trough concentration of CV in the first month were associated with poor 1-year outcomes. This CV calculation provides a valuable strategy to monitor TAC exposure.

Linezolid-Induced Thrombocytopenia in Patients with Renal Impairment: A Case Series, Review and Dose Advice.

Oral linezolid is often used as alternative therapy for intravenous vancomycin. According to the current guidelines, no dose adjustment has to be made in case of renal impairment. Nevertheless, in our hospital we have seen several patients with renal impairment who developed linezolid-induced thrombocytopenia when linezolid was taken in the standard dose. In this case series and review we want to emphasize the necessity of reviewing the Dutch and international guidelines. We describe five cases with renal impairment that developed linezolid-induced thrombocytopenia in our hospital. A PubMed literature review was conducted to identify other cases and find the optimal dosing regimen for these patients. Our cases join a long list of cases and available literature about linezolid-induced thrombocytopenia in patients with renal impairment. Less linezolid-induced thrombocytopenia was found, both in our cases and in the literature, after dose reduction of 50%. High linezolid trough concentrations were associated with a higher risk of linezolid-induced thrombocytopenia. Besides renal impairment, other risk factors for developing linezolid-induced thrombocytopenia were also identified, such as low body weight, high daily dose/kg, higher age, longer duration of therapy, low baseline count, malignity, low-dose aspirin and interacting co-medication. Re-evaluation of the current dose advice is necessary. We advocate for a standard dose reduction to 50% after 2days of standard dosing for all patients with an estimated glomerular filtration of <60mL/min/1.73m2. Besides this, therapeutic drug monitoring and thrombocytes monitoring may be executed weekly when patients have renal impairment or other risk factors for developing linezolid-induced thrombocytopenia.

Alterations in the Gut Microbiome in Liver Recipients with Post-Transplant Diabetes Mellitus

Post-transplant diabetes mellitus (PTDM) increases the risk of graft failure and death in liver transplant (LT) recipients. Experimental studies have indicated that enteric dysbiosis mediated by immunosuppressive tacrolimus (TAC) could contribute to glucose disorders, but no data on human recipients with PTDM have been reported. Here, by combining high-throughput shotgun metagenomics sequencing and metabolomics profiling, we characterized the intestinal microbiome (IM) in LT recipient cohort with or without PTDM and deciphered the potential relationship among IM, TAC dosage, and diabetes. By comparing with both non-PTDM and classical type 2 diabetes mellitus (T2DM), we identified microbial signatures of PTDM, which was characterized by the enriched Proteobacteria and decreased Bacteroidetes. Additionally, the altered microbes, as well as the microbial metabolomics, correlated with the dosage of TAC. Specifically, the levels of beneficial microbes associated with PTDM were lowered in recipients with the high TAC trough concentrations (> 5 ng∙mL–1) than those with low ones (< 5 ng∙mL–1), which was accompanied by reduced faecal metabolites involved in the biosynthesis of α-linolenic acid and arachidonic acid-lowering factors of developing T2DM. Moreover, these microbial signatures linked with the extent of glucose disorders in LT recipients. In summary, the faecal microbiome and metabolome differed between PTDM and non-PTDM patients, which were linked with TAC dosage. This study was the first to explore taxonomic alterations and bacterial gene functions to better understand the contribution of the IM to PTDM.

Voriconazole plasma concentrations and dosing in paediatric patients below 24 months of age.

Voriconazole (VCZ) is an important first-line option for management of invasive fungal diseases and approved in paediatric patients ≥24 months at distinct dosing schedules that consider different developmental stages. Information on dosing and exposures in children <24 months of age is scarce. Here we report our experience in children <24 months who received VCZ due to the lack of alternative treatment options. This retrospective analysis includes 50 distinct treatment episodes in 17 immunocompromised children aged between 3 and <24 months, who received VCZ between 2004 and 2022 as prophylaxis (14 patients; 47 episodes) or as empirical treatment (3 patients; 3 episodes) by mouth (46 episodes) or intravenously (4 episodes) based on contraindications, intolerance or lack of alternative options. Trough concentrations were measured as clinically indicated, and tolerability was assessed based on hepatic function parameters and discontinuations due to adverse events (AEs). VCZ was administered for a median duration of 10 days (range: 1-138). Intravenous doses ranged from 4.9 to 7.0 mg/kg (median: 6.5) twice daily, and oral doses from 3.8 to 29 mg/kg (median: 9.5) twice daily, respectively. The median trough concentration was 0.63 mg/L (range: 0.01-16.2; 38 samples). Only 34.2% of samples were in the recommended target range of 1-6 mg/L; 57.9% had lower and 7.9% higher trough concentrations. Hepatic function parameters analysed at baseline, during treatment and at end of treatment did not show significant changes during VCZ treatment. There was no correlation between dose and exposure or hepatic function parameters. In three episodes, VCZ was discontinued due to an AE (6%; three patients). In conclusion, this retrospective analysis reveals no signal for increased toxicity in paediatric patients <24 months of age. Empirical dosing resulted in mostly subtherapeutic exposures which emphasises the need for more systematic study of the pharmacokinetics of VCZ in this age group.

Vancomycin Hydrochloride as a Risk Factor for Acute Kidney Injury: A Retrospective Study

Introduction: The incidence of acute kidney injury (AKI) caused by vancomycin hydrochloride (VCM) was reported to be 5–43%. VCM-induced AKI was reported to be more likely to occur 4–17 days after initiating VCM treatment; however, it may occur earlier. The aim of this study was therefore to investigate risk factors for the development of AKI within two (AKI_2days) and seven (AKI_7days) days of VCM administration. Methods: This was a single-center, retrospective study including patients who underwent VCM therapy between April 1, 2013, and December 31, 2019. AKI was evaluated based on the Kidney Disease: Improving Global Outcomes criteria. Results: In total, 287 patients were enrolled. The incidence of VCM-induced AKI within 7 days was 10.8% (31/286 cases), and the incidence of AKI within 2 days was 5.9% (15/252 cases). Serum VCM trough concentrations and tazobactam-piperacillin (TZP) were shown to be a risk factor for VCM-induced AKI. The serum VCM trough concentration was 12.67 μg/mL within the 48 h threshold (AKI_2days) and 19.03 μg/mL within the 7-day threshold (AKI_7days). Conclusion: Our study demonstrated that high serum VCM trough concentrations and the combination of VCM and TZP were independent risk factors for VCM-induced AKI. Avoiding the concomitant use of TZP, or thorough monitoring of renal function with the concomitant use of TZP, may be helpful in reducing the occurrence of AKI. Furthermore, monitoring serum VCM trough concentrations within 2 days may effectively reduce the incidence of AKI.

Impact of direct oral anticoagulant concentration on clinical outcomes in Asian patients with atrial fibrillation.

A real-world association between direct oral anticoagulant (DOAC) concentration and clinical outcomes among Asian patients with atrial fibrillation (AF) is reported herein. Patients with AF aged ≥20 years who used DOAC for ≥3 days were enrolled. Trough and peak DOAC concentrations were measured and compared to the expected range reported in clinical trials. The Cox proportional hazard model was used to investigate the association between concentration and outcomes. From January 2016 to July 2022, a total of 859 patients were enrolled. Among them, 22.5%, 24.7%, 36.4%, and 16.4% were on dabigatran, rivaroxaban, apixaban, and edoxaban, respectively. Compared to clinical trials, the proportion of DOAC concentrations higher or lower than the expected range were 9.0% and 14.6% for trough, respectively, and 20.9% and 12.1% for peak, respectively. The average follow-up duration was 2.4±1.6 years. The incidence of stroke and systemic thromboembolism (SSE) was 1.31 per 100-person years, and low trough concentration predicted SSE (hazard ratio [HR]=2.78 [1.20, 6.46]). The incidence of major bleeding was 1.64 per 100-person years, and high trough was associated with major bleeding (HR=2.63 [1.09, 6.39]). The association between peak concentration and SSE or major bleeding was non-significant. Off label under dosing (odds ratio [OR]=2.69 [1.70, 4.26]), once daily DOAC dosing (OR=3.22 [2.07, 5.01]), and high creatinine clearance (OR=1.02 [1.01, 1.03]) caused low trough concentration. Contrarily, congestive heart failure was significantly associated with high trough concentration (OR=1.71 [1.01, 2.92]). In conclusion, trough DOAC concentration measurements should be considered among patients at risk of out-of-expected range DOAC concentrations.

Pediatric Nephrotoxicity: How Aware Are We?

Vancomycin and aminoglycosides are potentially nephrotoxic broad-spectrum antibiotics, which can be used both in the treatment of severe infections and in surgical prophylaxis, in pediatric patients. Prolonged antibiotic therapy and high trough concentrations are associated with toxicity. Additionally, several individual factors contribute to nephrotoxicity increasing the risk of acute kidney injury (AKI) and consequent chronic kidney disease in the future. We developed a retrospective and observational study in the Pediatrics Department of a tertiary hospital in Portugal, to analyze clinical practice regarding monitoring and surveillance of vancomycin and aminoglycosides. The results showed low rates of monitoring, which reinforces the importance of raising awareness about this issue, recognizing its importance, and adopting preventive measures that may mitigate the risk of toxicity and improve children’s renal prognosis in adult life.

Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis.

We evaluated the relationship between the pharmacokinetic parameters of linezolid (LZD) and development of adverse drug reactions (ADRs) in patients with pulmonary drug-resistant tuberculosis. A prospective cohort of adults with pulmonary multidrug-resistant tuberculosis with additional resistance to fluoroquinolone (MDR-TBFQ+) received treatment with bedaquiline, delamanid, clofazimine, and LZD. Blood samples were collected during weeks 8 and 16 at eight time points over 24 h. The pharmacokinetic parameters of LZD were measured using high-performance liquid chromatography and associated with ADRs. Of the 165 MDR-TBFQ+ patients on treatment, 78 patients developed LZD-associated anemia and 69 developed peripheral neuropathy. Twenty-three patients underwent intense pharmacokinetic testing. Plasma median trough concentration was 2.08 µg/mL and 3.41 µg/mL, (normal <2 µg/mL) and AUC0-24 was 184.5 µg/h/mL and 240.5 µg/h/mL at weeks 8 and 16, respectively, showing a linear relationship between duration of intake and plasma levels. Nineteen patients showed LZD-associated ADRs-nine at week 8, twelve at week 16, and two at both weeks 8 and 16. Thirteen of the nineteen had high plasma trough and peak concentrations of LZD. A strong association between LZD-associated ADRs and plasma LZD levels was noted. Trough concentration alone or combinations of trough with peak levels are potential targets for therapeutic drug monitoring.

Plasma protein binding of ceftriaxone in critically ill patients: can we predict unbound fractions?

Standard antibiotic dosing is not suitable for critically ill patients, due to altered pharmacokinetics (PK) in these patients. Knowledge of protein binding is important for optimizing antibiotic exposure because only the unbound fraction is pharmacologically active. If unbound fractions can be predicted, minimal sampling techniques and less costly methods can be routinely used. Data from the DOLPHIN trial, a prospective randomized clinical trial that included critically ill patients, were used. Total and unbound ceftriaxone concentrations were determined using a validated UPLC-MS/MS method. A non-linear saturable binding model was made using 75% of the trough concentrations and validated on the remaining data. Our model and previously published models were tested for their performance for subtherapeutic (<1 mg/L) and high (>10 mg/L) unbound concentrations. In total, 113 patients were sampled [Acute Physiology And Chronic Health Evaluation version 4 (APACHE IV) score 71 (IQR 55-87), albumin 28 g/L (IQR 24-32)]. This resulted in 439 samples (trough = 224, peak = 215). Unbound fractions were significantly different between samples taken at trough and peak times [10.9% (IQR 7.9-16.4) versus 19.7% (IQR 12.9-26.6), P < 0.0001], which was not explained by concentration differences. Our model and most literature models showed good sensitivity and low specificity to determine high and subtherapeutic ceftriaxone trough concentrations using only the total ceftriaxone and albumin concentrations. Ceftriaxone protein binding is not concentration related in critically ill patients. Existing models show good ability to predict high concentrations, but low specificity in predicting subtherapeutic concentrations.

Relationship Between Osimertinib Concentration and Clinical Response in Japanese Patients With Non-small Cell Lung Cancer.

Osimertinib is the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The present study aimed to determine the previously unclarified association of osimertinib plasma trough concentrations with efficacy, adverse events, and genetic polymorphisms in Japanese patients with NSCLC harboring EGFR mutations. In this prospective study, blood samples of 25 patients who received osimertinib were collected to measure plasma osimertinib concentrations and to genotypically characterize ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2 polymorphisms. Plasma osimertinib concentrations were analyzed using validated multiple reaction monitoring mode-based liquid chromatography-tandem mass spectrometry. Osimertinib concentration necessary to achieve optimal median progression-free survival (PFS) was determined using receiver operating characteristic curve analysis. PFS and overall survival were analyzed using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Plasma osimertinib concentrations between different patient groups were compared using the Mann-Whitney U-test. Patients were divided into high and low concentration groups based on a plasma osimertinib cut-off concentration of 211 ng/ml. Median PFS was longer in the high trough concentration group than that in the low trough concentration group (46.3 vs. 16.8 months, p=0.029). Plasma osimertinib concentrations adjusted for dose and body weight did not differ between the patients with and without variant polymorphisms. Monitoring plasma trough concentrations during maintenance might improve osimertinib treatment efficacy in patients with NSCLC harboring EGFR mutations.

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate.

We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA). This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed. In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20-23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66-14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs. The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA.

1130P Real-world data of osimertinib (osi) for the treatment of metastatic epidermal growth factor receptor (EGFR+) non-small cell lung cancer (NSCLC) patients (pts), with a focus on age, body mass index (BMI) and trough levels

For pts with metastatic NSCLC and a sensitizing EGFR mutation, osi is standard treatment, either in first line (1L) or beyond (2L+, if T790M+). Limited osi efficacy data is available in relation to plasma trough levels, as well as elderly or those with low or high BMI. Retrospective Dutch multicentre (two academic, one non-academic) study. Eligible: pts ≥18 years, with metastatic EGFR+ NSCLC regularly treated with osi. Start date of osi was used as index date, data was extracted from medical files. Primary endpoint: progression free survival (PFS). Secondary endpoint: overall survival (OS), objective response rate (ORR, RECIST v1.1) and disease control rate (DCR). Kaplan-Meier and multivariate Cox proportional hazard models were used to compare different subgroups for age, BMI and steady state plasma trough levels (Cmin,SS), measured <3 months (m) before disease progression (age [<70 / ≥70], BMI [<18.5 / 18.5 – 24.9 / 25.0 – 29.9 / >30] and plasma trough level [<149 / 149 – 259 / >259]). In total 294 pts were included: mean age 67 years (range = 29 – 87 years), mean BMI 25.3 (range = 17.6 – 67.1), 35% male, 90% Caucasian, 54% exon 19 deletion, 30% L858R, 17% other. Osi was given in 1L (n = 118, 40%), 2L (n = 134, 46%) or beyond (3L+, n=42, 14%). Median PFS was 14.6 m (95% CI = 10.2 – 20.0) (1L), 13.7 m (95% CI = 11.1 – 15.6) (2L) and 8.7 m (95% CI = 5.1 – 12.7) (3L+). ORR and DCR were similar in all lines (1L: 68% and 96%, 2L: 62% and 93% and 3L+: 69% and 91%). Pts ≥70 years at osi start achieved similar PFS and OS compared to pts <70 years (PFS: aHR = 0.93; 0.68 – 1.28; OS: aHR = 1.14; 0.77 – 1.68). Low BMI (<18.5) led to lower absolute effectiveness (PFS and OS), but not statistically significant, due to the low number of pts in the subgroup (n = 8). A high plasma trough concentration was associated with lower PFS (aHR = 1.92, 95% CI = 1.10 – 3.37). PFS and OS with 1L osi were lower compared to those found in the FLAURA trial, while in 2L survival was slightly longer in daily practice. Age was not associated with PFS, while a low BMI and a high Cmin,SS may be correlated with worse treatment outcomes on osi.

A Regression Model to Predict Linezolid Induced Thrombocytopenia in Neonatal Sepsis Patients: A Ten-Year Retrospective Cohort Study.

Background: Linezolid-induced thrombocytopenia (LIT) is the main factor limiting the clinical application of linezolid (LZD). The incidence and risk factors of LIT in neonatal patients were possibly different from other populations based on pathophysiological characteristics. The purpose of this study was to establish a regression model for predicting LIT in neonatal sepsis patients. Methods: We retrospectively included 518 patients and divided them into the LIT group and the non-LIT group. A logistic regression analysis was used to analyze the factors related to LIT, and a regression model was established. A receiver operating characteristic (ROC) curve was drawn to evaluate the model’s predictive value. We prospectively collected 39 patients’ data to validate the model and evaluate the effect of LZD pharmacokinetics on LIT. Results: Among the 518 patients, 103 patients (19.9%) developed LIT. The Kaplan–Meier plot revealed that the overall median time from the initiation of LZD treatment to the onset of LIT in preterm infants was much shorter when compared with term infants [10 (6, 12) vs. 13 (9.75, 16.5), p = 0.004]. Multiple logistic regression analysis indicated that the independent risk factors of LIT were lower weight at medication, younger gestational ages, late-onset sepsis, necrotizing enterocolitis, mechanical ventilation, longer durations of LZD treatment, and lower baseline of platelet level. We established the above seven-variable prediction regression model and calculated the predictive probability. The ROC curve showed that the predicted probability of combined body weight, gestational age, duration of LZD treatment, and baseline of platelet had better sensitivity (84.4%), specificity (74.2%), and maximum AUC (AUC = 0.873). LIT occurred in 9 out of 39 patients (23.1%), and the accuracies of positive and negative predictions of LIT were 88.9 and 76.7%, respectively. Compared with the non-LIT patients, the LIT patients had higher trough concentration [11.49 (6.86, 15.13) vs. 5.51 (2.80, 11.61) mg/L; p = 0.028] but lower apparent volume of distribution (Vd) [0.778 (0.687, 1.421) vs. 1.322 (1.099, 1.610) L; p = 0.010]. Conclusion: The incidence of LIT was high in neonatal sepsis patients, especially in preterm infants. LIT occurred earlier in preterm infants than in term infants. The regression model of seven variables had a high predictive value for predicting LIT. LIT was correlated with higher trough concentration and lower Vd.

The association of high Vancomycin trough concentration with acute kidney injury during combination therapy of Piperacillin/Tazobactam and Vancomycin

BackgroundCo-administration of Piperacillin/Tazobactam (PIPC/TAZ) and Vancomycin (VCM) as an antibiotic therapy for severe infectious diseases increases the risk of nephrotoxicity. We retrospectively investigated the utility of monitoring VCM trough concentration in early stage of developing acute kidney injury (AKI) on this combination therapy. MethodsWe enrolled all infectious disease patients who were managed with concurrent PIPC/TAZ and VCM. The record of dosage and the administration interval of each antibiotic and its clinical parameters, as well as the VCM trough concentrations, blood culture for bacteria, and serum creatinine values, were collected. VCM trough concentration was measured during the initial 48–72 h of VCM administration. Nephrotoxicity was evaluated as the degree of AKI. ResultsA total of 47 patients fulfilling the criteria were registered, and AKI developed in 10 patients. There was no statistical difference between the AKI and non-AKI groups with regard to age, height, weight, basal creatinine level, body surface area, body mass index, PIPC/TAZ dose, VCM dose, gender, artificial management, and death within around 30 days. The VCM trough level was increased significantly in the AKI group (mean [standard deviation {SD}]: 25.9 [7.8] μg/mL) compared to that in the non-AKI group (mean [SD]: 15.7 [6.9] μg/mL) (p = 0.003). During the clinical course, renal function returned to normal levels in three out of four AKI stage 2 patients, whereas only partial recovery was achieved in all AKI stage 3 patients. ConclusionsA high VCM trough concentration may have an influence on the occurrence of AKI during combination therapy of PIPC/TAZ and VCM. Careful monitoring of VCM trough concentration will be required to prevent AKI progression.

Impact of different renal function equations on direct oral anticoagulant concentrations

The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft–Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p < 0.001). CKD-EPI and MDRD estimates classified fewer patients as having GFR < 50 mL/min than CrCL in all 3 groups. Both CrCL and CKD-EPI were associated with higher-than-expected ranges of dabigatran or rivaroxaban concentrations. Nevertheless, none of the renal function equations was associated with higher-than-expected apixaban concentrations. For participants aged ≥ 75 years, CKD-EPI may be associated with higher-than-expected trough concentration of dabigatran. In conclusion, CrCL and CKD-EPI both can be used to identify patients with high trough concentrations of dabigatran or rivaroxaban. Among elderly patients who used dabigatran, CKD-EPI may be associated with increased drug concentration.

High anti-TNFα Concentrations Are Not Associated With More Adverse Events in Pediatric Inflammatory Bowel Disease.

Anti-tumor necrosis factor alpha (anti-TNFα) therapy is commonly used to treat refractory pediatric inflammatory bowel disease (IBD) and carry risks for adverse events. We aimed to assess the relationship between anti-TNFα trough concentrations and adverse events rate among pediatric patients with IBD. The medical records of pediatric patients with IBD who were treated with anti-TNFα agents from 2015 to 2020 and had sequential monitoring of trough concentration (TC) were reviewed retrospectively for the presence of adverse events. The study cohort included 135 eligible patients (59 [43.7%] girls, mean age at diagnosis 12.9 [±3] years, 111 [82.2%] Crohn disease) who had 1589 measurements of TCs (1037 [63%] infliximab). During a median follow-up period of 1.7 years (IQR 1.1-2.7), we recorded 156 adverse events in 50 patients (37%). Higher TCs were not associated with higher rate of anti-TNFα-related adverse events whereas these events (excluding increase in liver transaminases) were associated with younger age.

Abstract 1672: Overall survival in metastatic melanoma correlates with pembrolizumab exposure and T cell exhaustion markers

Abstract Background: There are few clinically validated predictive biomarkers for benefit to immune checkpoint blockade (ICB) in metastatic melanoma. Real world evidence has shown patients with higher exposure to ICB have improved best overall response (BOR) and longer survival [1]. Increased expression of T cell exhaustion markers and specific chemokine signatures have been associated with poor response to ICB in metastatic melanoma [2]. We sought to determine the relationship between pharmacokinetic (PK) and clinical outcomes of patients with metastatic melanoma treated with pembrolizumab. Translational correlative objectives included identifying expression of circulating T cell exhaustion markers and specific chemokine signatures in patients with progressive disease. Methods: Metastatic melanoma patients received weight based pembrolizumab and had serial peripheral blood draws. BRAF mutation positive patients were pre-treated with targeted therapy, otherwise pembrolizumab was first line. Plasma trough levels were assessed using the Abcam® pembrolizumab ELISA kit. BOR groups: complete response (CR), partial response (PR) and progressive disease (PD), were classified as per irRECIST. The T-cell exhaustion and chemokine markers were determined using Flow Cytometry on the BD Science Fortessa® X20. The cohort was stratified into high versus low pembrolizumab trough concentrations, split by the median. Kaplan-Meier survival analysis for progression free (PFS) and overall survival (OS) was performed based on these groups. Non-parametric correlation analysis was used to test for correlations between clinical characteristics, pembrolizumab trough concentrations and translational markers. Results: Twenty-eight patients were enrolled. Median follow up was 32.5 months. The pembrolizumab plasma trough levels were not significantly different between BOR categorical groups. Trough levels are a valid surrogate for drug exposure[3]. There were no significant correlations between pembrolizumab trough levels and expression of T-cell exhaustion and chemokine markers over time.The high pembrolizumab exposure group experienced significantly longer OS (median not reached versus 48 months, p=0.014), than the low exposure group. A similar positive exposure PFS relationship was found (median not reached versus 48 months, p=0.045). There was significantly higher frequency of co-expression of CXCR6 and TIM3 on CD4+ T cells for PD (mean 21.5% CI 14.9% - 26.06%) compared to CR (mean 12.2% CI 9.40% - 14.99%) (p=0.003) and PR (mean 9.9% CI 7.76% - 12.05%) (p=0.0001). There was also significantly higher frequency of co-expression of CXCR6 and TIM3 on CD8+ T cells for PD (mean 32.59% CI 25.76% - 39.43%) compared to PR (mean 21.9% CI 18.22% - 25.56%) (p=0.032).Conclusions: We describe a positive exposure PFS and exposure OS relationship for pembrolizumab in metastatic melanoma. The data indicate the co-expression of CXCR6 and T-cell exhaustion markers on circulating CD4+ and CD8+ T cells are potential biomarkers of disease progression on single-agent pembrolizumab.AcknowledgementsThis study was funded by a Hunter Medical Research Institute Project Grant (HMRI983).Hunter Cancer Biobank Serial Blood Collection Project Citation Format: Vishal Navani, Moira C. Graves, Giovana Celli Marchett, Hiren Mandaliya, Nikola A. Bowden, Andre Van Der Westhuizen. Overall survival in metastatic melanoma correlates with pembrolizumab exposure and T cell exhaustion markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1672.