The Serum Concentration of Vancomycin as a Diagnostic Predictor of Nephrotoxic Acute Kidney Injury in Critically Ill Patients

The impact of serum concentrations of vancomycin is a controversial topic. Results: 182 critically ill patients were evaluated using vancomycin and 63 patients were included in the study. AKI occurred in 44.4% of patients on the sixth day of vancomycin use. Vancomycin higher than 17.53 mg/L between the second and the fourth days of use was a predictor of AKI, preceding AKI diagnosis for at least two days, with an area under the curve of 0.806 (IC 95% 0.624–0.987, p = 0.011). Altogether, 46.03% of patients died, and in the Cox analysis, the associated factors were age, estimated GFR, CPR, and vancomycin between the second and the fourth days. Discussion: The current 2020 guidelines recommend using Bayesian-derived AUC monitoring rather than trough concentrations. However, due to the higher number of laboratory analyses and the need for an application to calculate the AUC, many centers still use therapeutic trough levels between 15 and 20 mg/L. Conclusion: The results of this study suggest that a narrower range of serum concentration of vancomycin was a predictor of AKI in critically ill septic patients, preceding the diagnosis of AKI by at least 48 h, and it can be a useful monitoring tool when AUC cannot be used.

Tocilizumab Trough Levels Variability in Kidney-Transplant Candidates Undergoing Desensitization

The presence of anti-HLA antibodies is an increasing challenge in kidney transplantation. Tocilizumab (TCZ), a monoclonal antibody targeting the interleukin-6 receptor (IL-6R), has been proposed to complement conventional desensitization therapy. We aimed to describe TCZ plasma trough concentrations and their variability and to investigate the link between TCZ concentration and the evolution of anti-HLA antibodies. Sensitized kidney-transplant candidates treated monthly with TCZ (8 mg/kg) for desensitization were retrospectively included. TCZ concentrations were determined by liquid chromatography-tandem mass spectrometry. Seventy-four TCZ concentrations from 10 patients were analyzed. The TCZ trough concentration ranged from <1.0 to 52.5 mg·L−1, with a median of 25.6 mg·L−1 [25th–75th percentiles: 13.2–35.3 mg·L−1). The inter- and intra-individual coefficients of variation were 55.0% and 33.0%, respectively. The TCZ trough concentration was not related to IL-6 (rho = −0.46, p = 0.792), soluble IL-6R (rho = −0.81, p = 0.65) concentrations or reduction of anti-HLA antibodies (mixed-effects model adjusting, effect of TCZ trough concentration: rho = −0.004, p = 0.26). The individual median TCZ concentration tended to be associated with the number of antibodies, with an initial MFI > 3000 that dropped to <3000 after TCZ treatment (rho = 0.397, p = 0.083). TCZ trough concentrations in kidney-transplant candidates treated for desensitization were highly variable. Further studies on larger cohorts are needed to study the possible link between TCZ concentrations and the reduction of anti-HLA antibodies.

Natalizumab concentrations during pregnancy in three patients with multiple sclerosis

In women with very active multiple sclerosis (MS), natalizumab can be continued during pregnancy to prevent rebound disease activity. Our aim was to evaluate changes in serum natalizumab trough concentrations during pregnancy. Blood samples of 3 patients were collected before, during, and after pregnancy. Natalizumab trough concentrations gradually decreased during pregnancy. The patient with the lowest trough concentrations during the third trimester was treated with extended interval dosing (EID). After delivery, natalizumab concentrations increased to similar levels as before pregnancy. All patients remained clinically and radiologically stable. MS neurologists should be aware of decreasing natalizumab concentrations during pregnancy, especially in patients with low initial trough concentrations and patients with EID.

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.

The relationship of vancomycin 24-hour AUC and trough concentration

Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Prior to the 2020 release of a joint consensus guideline on monitoring of vancomycin therapy for serious methicillin-resistant Staphylococcus aureus (MRSA) infections, clinicians had escalated vancomycin doses for 2 decades while targeting trough concentrations of 15 to 20 µg/mL, leading to an increased frequency of nephrotoxicity. For MRSA infections, the 2020 guideline recommends adjusting doses to achieve a 24-hour area under the concentration-time curve (AUC) of 400 to 600 µg · h/mL; however, monitoring of trough concentrations has been entrenched for 3 decades. Calculating dose regimens based on AUC will require obtaining an increased number of vancomycin serum concentrations and, possibly, advanced software. The aim of this investigation was to determine the relationship between AUC and trough concentration and the influence of dosing regimen on goal achievement. Methods The relationship between trough concentration and AUC was explored through derivation of an equation based on a 1-compartment model and simulations. Results 24-hour AUC is related to dosing interval divided by half-life in a nonlinear fashion. The target trough concentration can be individualized to achieve a desired AUC range, and limiting use of large doses (&gt;15-20 mg/kg) can protect against excessive 24-hour AUC with trough-only monitoring. Conclusion After initially determining pharmacokinetic parameters, subsequent monitoring of AUC can be accomplished using trough concentrations only. Trough concentration may be used as a surrogate for AUC, although the acceptable target trough concentration will vary depending on dosing interval and elimination rate constant. This work included development of an AUC-trough equation to establish a patient-specific target for steady-state trough concentration.

Evaluation of Posaconazole Dosing in Children and Young Adults: A Single-Center Review

OBJECTIVE Initial posaconazole dosing regimens in children often do not achieve target concentrations, and data continue to support the need for higher initial dosing regimens. The objective of this study is to contribute to the current data regarding suboptimal posaconazole dosing in pediatric patients by retrospectively observing dosing strategies and subsequent drug concentrations. METHODS This study was conducted at a single institution in 27 patients aged 1 to 21 years. Patients who were initiated on any formulation of posaconazole for prophylaxis or treatment while admitted to the hospital were included. The primary outcome was to determine the percentage of pediatric patients who achieved the targeted trough concentration using their initial posaconazole dosing regimen. Secondary outcomes included percentage of patients who experienced a breakthrough invasive fungal infection (IFI), percentage of patients with elevated liver function tests (LFTs), and discontinuation for any reason. RESULTS There were 15 patients (55.5%) who reached desired trough serum concentration after the initial dosing regimen. The number of dose modifications to achieve the desired trough ranged from 1 to 3. Most patients received delayed-release tablets (n = 17), and the average doses for reaching prophylactic and treatment trough concentrations were 6.1 mg/kg/day and 11 mg/kg/day, respectively. There were 2 patients (7.4%) who experienced breakthrough IFI. Overall, 5 patients developed elevated LFTs and 7 patients discontinued treatment early. CONCLUSIONS The results describe a single population of pediatric patients, of whom 55% were able to achieve target trough concentrations of posaconazole with the initial dosing strategy used.

Association between CYP3A4, CYP3A5, and ABCB1 Genotype, Tacrolimus Concentrations, and Outcomes Among Allogeneic Hematopoietic Stem Cell Transplantation Patients

Background Successful treatment with tacrolimus (TAC) to prevent graft versus host disease (GVHD) and minimize TAC-related toxicities among allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients is contingent upon achieving and maintaining plasma trough concentrations within a narrow therapeutic range. Despite standardized weight-based dosing, inter-individual variability is observed in TAC trough concentrations which may in part be attributable to pharmacogenetic variants influencing the pharmacokinetic disposition of TAC. The primary objective was to investigate the association between CYP3A4, CYP3A5, or ABCB1 genotype and the proportion of patients that attained an initial TAC trough concentration in the therapeutic range following initiation of intravenous (IV) TAC and conversion to oral (PO) TAC administration. Additional associations with clinical outcomes were also explored. Methods We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHSCT and were prescribed a TAC-based regimen for GVHD prophylaxis between January 1, 2014 and February 28, 2020 at the Moffitt Cancer Center. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Patients received TAC in combination with either sirolimus (SIRO), methotrexate (MTX), or other immunosuppressant regimen. Ideal body weight was used to dose TAC unless it was less than the patient's actual body weight. When given with SIRO, TAC targeted trough concentrations were 3 to 7 ng/ml. In patents receiving TAC plus either MTX or other regimens, the target therapeutic range was 10 to 15 ng/ml. Biobanked pre-transplant blood samples were used for CYP3A4/5 and ABCB1 genotyping. Based on the frequency of phenotypes observed, analyses were performed comparing CYP3A5 normal/intermediate (NM/IM) metabolizers to CYP3A5 poor metabolizers (PM), CYP3A4 rapid metabolizers (RM) to CYP3A4 NM/IM/PM, and ABCB1 normal function (NF) to ABCB1 intermediate/low function (IF/LF). Results Median age at time of alloHSCT was 57 years (range: 20.4-76.7); 60% were men and 83% were white. CYP3A4/5 and ABCB1 phenotypes observed in the study population are presented in Table 1. No significant associations were identified between CYP3A4, CYP3A5, or ABCB1 phenotype groups and the proportion of patients attaining initial therapeutic trough concentrations after the start of IV TAC. In transitioning from IV to PO TAC, 66 of 86 patients had evaluable data. Compared to CYP3A5 PM, CYP3A5 NM/IM were significantly less likely to attain an initial target trough concentration in the therapeutic range following PO TAC administration (40% CYP3A5 NM/IM vs 76.5% CYP3A5 PM, p=0.02). A significantly lower proportion of CYP3A4 RM attained initial target trough concentrations in the therapeutic range following the switch to PO TAC compared to CYP3A4 NM/IM/PM (43% CYP3A4 RM vs 75% CYP3A4 NM/IM/PM, p=0.049). No associations were identified with PO TAC trough concentrations and ABCB1 phenotype groups. The cumulative incidences of grades 2-4 acute GVHD (aGVHD)at day 100 among CYP3A5 NM/IM vs CYP3A5 PM were 47% and 28%, respectively (p=0.07), and for CYP3A4 RM vs CYP3A4 NM/IM/PM were 46% and 30%, respectively (p=0.16). No significant differences were seen in the incidences of chronic GVHD (cGVHD) nor in non-relapse mortality. Relapse rates at 2 years were not significantly higher among patients that were CYP3A5 NM/IM and CYP3A4 RM compared to CYP3A5 PM and CYP3A4 NM/IM/PM, respectively. Overall survival (OS) for CYP3A5 NM/IM was 52% and for PM was 78% (p=0.01). When comparing CYP3A4 groups, OS for RM was 55% and for NM/IM/PM was 76% (p=0.07) (Table 2). Conclusion The findings of the present study revealed that CYP3A4/5 genotype may play an important role in dosing of PO TAC in alloHSCT recipients, whereas ABCB1 did not significantly influence either route of TAC administration. CYP3A4/5 genotypes may also influence long term survival after transplant. Larger prospective studies are needed to confirm the impact of these genes on GVHD, relapse and survival. Figure 1 Figure 1. Disclosures Perkins: AcroTech Pharma: Research Funding. Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Bejanyan: Magenta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medexus: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Well Corp (Spouse disclosure): Current equity holder in publicly-traded company; Avrobio (Spouse disclosure): Current equity holder in publicly-traded company; Crispr Therapeutics (Spouse disclosure): Current equity holder in publicly-traded company; Humanigen (Spouse disclosure): Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon (Spouse disclosure): Consultancy; Merck (Spouse disclosure): Current equity holder in publicly-traded company; Organon (Spouse disclosure): Current equity holder in publicly-traded company; Teladoc Health (Spouse disclosure): Current equity holder in publicly-traded company; Thermo Fisher (Spouse disclosure): Current equity holder in publicly-traded company; Unitedhealth Group (Spouse disclosure): Current equity holder in publicly-traded company. Pidala: Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Regeneron: Consultancy; Incyte: Consultancy; Pharmacyclics: Other: Clinical trial support, Research Funding; BMS: Other: Clinical trial support, Research Funding; Novartis: Other: Clinical trail support; Takeda: Other: Clinical trail support; Jannssen: Other: Clinical trial support; Johnson and Johnson: Other; AbbVie: Other; BMS: Other.

Omalizumab serum levels predict treatment outcomes in patients with chronic spontaneous urticaria: A three months prospective study

Aim: To examine the association between serum levels and effectiveness of omalizumab in patients with chronic spontaneous urticaria (CSU), and explore patient-specific factors associated with omalizumab pharmacokinetics. Methods: Patients with CSU, who were refractory to high-dose antihistamines and who initiated treatment with omalizumab (300 mg every four weeks) were eligible for the study. Treatment was evaluated every 4 week during 12 weeks of treatment with urticaria activity score in the past week (UAS7) as primary outcome and urticaria control test (UCT), Chronic Urticaria Quality of Life Questionnaire (CU QoL) and dermatology life quality index (DLQI) as secondary outcomes. Serum drug level of omalizumab was measured before (trough level) and at day seven (peak level) after each injection. Results: A total of 23 patients were included. After 12 weeks of treatment with omalizumab, an improvement of 16.8 UAS7 points (95% CI 10.8-22.8), p<0.001 was seen. The omalizumab trough and peak levels were 7.0-33.1 µg/mL and 11.4-54.0 µg/mL and reached a plateau (steady state) after 8-12 weeks of treatment. Among the patient-specific factors measured at baseline (age, sex, body mass index (BMI), angioedema, basophil histamine release (HR) test, blood basophils and eosinophils, and serum total IgE), BMI was the only significant predictor of omalizumab peak concentrations during the study (difference -2.75, p<0.05), whereas omalizumab trough concentrations were significantly associated with UAS7 scores (difference -0.82, p<0.001). The same was observed for UCT, DLQI, and CU QoL. Conclusion: In patients with CSU initiating treatment with omalizumab, a higher BMI predicts lower peak concentrations of omalizumab during treatment, whereas lower trough concentrations of omalizumab are associated with a poorer response on UAS7 and other patient reported outcomes.