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.

Factors Affecting Voriconazole Trough Concentration and Optimal Maintenance Voriconazole Dose in Chinese Children

Voriconazole is a triazole antifungal agent commonly used for the treatment and prevention of invasive aspergillosis (IA). However, the study of voriconazole's use in children is limited. The present study was performed to explore maintenance dose to optimize voriconazole dosage in children and the factors affecting voriconazole trough concentration. This is a non-interventional retrospective clinical study conducted from 1 January 2016 to 31 December 2020. The study finally included 94 children with 145 voriconazole trough concentrations. The probability of achieving a targeted concentration of 1.0–5.5 µg/mL with empiric dosing increased from 43 (45.3%) to 78 (53.8%) after the TDM-guided adjustment. To achieve targeted concentration, the overall target maintenance dose for the age group of less than 2, 2 to 6, 6 to 12, and 12 to 18 years old was approximately 5.71, 6.67, 5.08 and 3.31 mg·kg−1/12 h, respectively (p < 0.001). Final multivariate analysis found that weight (p = 0.019), dose before sampling (p < 0.001), direct bilirubin (p < 0.001), urea nitrogen (p = 0.038) and phenotypes of CYP2C19 were influencing factors of voriconazole trough concentration. These factors can explain 36.2% of the variability in voriconazole trough concentration. Conclusion: In pediatric patients, voriconazole maintenance doses under the target concentration tend to be lower than the drug label recommended, but this still needs to be further studied. Age, body weight, dose, direct bilirubin, urea nitrogen and phenotypes of CYP2C19 were found to be influencing factors of voriconazole concentration in Chinese children. The influence of these factors should be taken into consideration during voriconazole use.

A Large Sample Retrospective Study on the Distinction of Voriconazole Concentration in Asian Patients from Different Clinical Departments

Voriconazole (VRZ) is widely used to prevent and treat invasive fungal infections; however, there are a few studies examining the variability and influencing the factors of VRZ plasma concentrations across different clinical departments. This study aimed to evaluate distinction of VRZ concentrations in different clinical departments and provide a reference for its reasonable use. From 1 May 2014 to 31 December 2020, VRZ standard rates and factors affecting the VRZ trough concentration were analyzed, and a multiple linear regression model was constructed. The standard rates of VRZ in most departments were above 60%. A total of 676 patients with 1212 VRZ trough concentrations using a dosing regimen of 200 mg q12h from seven departments were enrolled in the correlation analysis. The concentration distribution varied significantly among different departments (p < 0.001). Fifteen factors, including department, CYP2C19 phenotype, and gender, correlated with VRZ concentration. A multiple linear regression model was established as follows: VRZ trough concentration = 5.195 + 0.049 × age + 0.007 × alanine aminotransferase + 0.010 × total bilirubin − 0.100 × albumin − 0.004 × gamma-glutamyl transferase. According to these indexes, we can predict possible changes in VRZ trough concentration and adjust its dosage precisely and individually.

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.

Variability of Tacrolimus Trough Concentration in Liver Transplant Patients: Which Role of Inflammation?

Tacrolimus presents high intra and inter-individual variability in its blood trough concentration (Cmin). Knowledge of the factors that are involved in tacrolimus Cmin variability is thus clinically important to prevent or limit it. Inflammation can affect the pharmacokinetic properties of drugs. We evaluated the contribution of acute inflammation in the pharmacokinetic variability of tacrolimus blood Cmin in a large cohort of liver transplant patients. Demographic, biological, and clinical data from 248 liver transplant patients treated with tacrolimus from January 2010 to December 2016 were retrospectively collected from medical records. In total, 1573 Cmin/dose and concomitant C-reactive protein (CRP) measurements were analysed. In multivariate analysis, the log Cmin/dose of tacrolimus was significantly and positively associated with the hematocrit, ALAT, and CRP concentrations. CRP concentrations were higher (p = 0.003) for patients with tacrolimus overexposure (i.e., tacrolimus Cmin > 15 µg/L) (median CRP (10th–90th percentiles): 27 mg/L (3–149 mg/L), n = 91) than they were for patients with a tacrolimus Cmin ≤ 15 µg/L (13 mg/mL (3–95 mg/L), n = 1482)). CRP in the fourth quartile (49 to 334 mg/L) was associated with a 2.6-fold increased risk of tacrolimus Cmin overexposure. Our study provides evidence that inflammation contributes to tacrolimus Cmin variability and suggests that inflammation should be considered for the correct interpretation of tacrolimus blood concentration.

The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report

Background Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker. Case presentation We report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC0–12 h was measured at 51 μg h/mL, which was within the therapeutic range (40–60 μg h/mL). Afterward, viral load decreased and became undetectable. Conclusions This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.

Valproic Acid After Neurosurgery Induces Elevated Risk of Liver Injury: A Prospective Nested Case-Control Study

Background Valproic acid (VPA) has been widely used to prevent epileptic seizures after neurosurgery in China. We have found that the incidence of liver injury (LI) in patients using VPA after neurosurgery is higher than that in other patients. Objective The objective of this study was to investigate the risk factors of LI in patients using VPA after neurosurgery. Methods A nested case-control study was conducted in patients using VPA after neurosurgery between September 2019 and March 2021. Cases of LI were matched to controls by age and body mass index (BMI). Conditional logistic regression was used to estimate matched odds ratios representing the odds of LI. A receiver operating characteristic curve was used to analyze the optimal cutoff condition. Results A total of 248 people (62 LI and 186 control) were enrolled. Among patients with vs without LI, the matched odds ratio for trough concentration of VPA was significant (matched odds ratio [OR], 1.09; 95% confidence interval [CI]: 1.01-1.19). The course of treatment (OR: 1.17, 95% CI: 1.02-1.33), Glasgow score (OR: 0.26, 95% CI: 0.10-0.67), gene polymorphisms of CYP2C19 (OR: 2.09, 95% CI: 1.03-146.93), and UGT1A6 (OR: 34.61, 95% CI: 1.19-1003.23) were all related to the outcome. The optimal cutoff of the course of treatment was 10 days, while the trough concentration of VPA was determined to be 66.16 mg/L. Conclusion Length of treatment, VPA trough concentration, and Glasgow score were associated with LI in patients after neurosurgery. A gene test may be necessary for people who are prescribed VPA for a long time.

Therapeutic Drug Monitoring of Voriconazole in AIDS Patients

Background The safety and efficacy of Voriconazole in Acquired Immune Deficiency Syndrome (AIDS) patients is difficult to guarantee. In this study, Therapeutic Drug Monitoring (TDM) of Voriconazole in AIDS patients was investigated with the aim to further verify the significance of voriconazole TDM in AIDS patients and to explore more strategies to improve individualized medication. Methods The data of AIDS patients who underwent voriconazole TDM in our hospital from May 2018 to August 2021 were collected. The basic information of patients, the results of voriconazole TDM, the individualized intervention, the affecting factors of voriconazole concentration were analyzed, as well as the relationship between voriconazole trough concentration and safety. Results A total of 46 tests of voriconazole TDM were performed in 28 AIDS patients. Only 57.14% patients reached the therapeutic range at first TDM, and 87.50% patients reached the therapeutic range after intervention based on first TDM. 21.43% patients develop voriconazole-related Adverse Drug Reactions (ADRs), and ADRs were mostly occurred when voriconazole concentration is above 5.0 µg/mL. Spearman correlation coefficient rs was calculated to be 0.729 for voriconazole trough concentration and the incidence of ADRs, exhibiting a significant, positive linear correlation (P=0. 017). 50% patients had polypharmacy and drug interactions are common. For example, rifampicin can significantly reduce the plasma concentration of voriconazole. Multiple linear regression analysis showed Hypoproteinemia was a significant factor affecting voriconazole trough concentration(P=0.006). Conclusion AIDS patients usually have a low attainment rate of voriconazole trough concentration after initiation of standard dosing regimen. The affecting factors seem multifactorial and complex, of which hypoproteinemia is of great significance. Meanwhile, we need to be alert to the effects of drug interactions. The incidence of voriconazole related ADRs is high, mostly occurring when voriconazole concentration is above 5.0 µg/mL. Therefore, TDM can provide meaningful guidance for dosage optimization of voriconazole, and the dosage adjustment method in Chinese Guideline is applicable for the population of AIDS patients.