Average Trough Concentrations Research Articles

Therapeutic drug monitoring of linezolid and exploring optimal regimens and a toxicity-related nomogram in elderly patients: a multicentre, prospective, non-interventional study.

The concentrations of linezolid, its optimal regimen and the associated side effects in elderly patients remain unclear. In this multicentre, prospective study, elderly patients receiving linezolid at four tertiary hospitals in Beijing between May 2021 and December 2022 were included. Linezolid concentrations and haematological toxicity were monitored dynamically. Risk factors for linezolid overexposure and moderate-to-severe linezolid-induced thrombocytopenia (M/S LIT) were analysed, and a predictive model of M/S LIT was developed. A total of 860 linezolid concentrations were measured in 313 patients. The median trough concentrations of linezolid were 24.4 (15.3, 35.8) mg/L at 36-72 h and 26.1 (17.0, 38.1) mg/L at 5-10 days (P = 0.132). Severe linezolid exposure was independently associated with age, estimated glomerular filtration rate (eGFR) and the worst SOFA score (SOFA1), and we further recommended dose regimens for elderly patients based on these findings. The incidences of linezolid-induced thrombocytopenia(LIT) and M/S LIT were 73.5% and 47.6%, respectively. M/S LIT was independently correlated with treatment duration, average trough concentration (TDMa), baseline platelet count, eGFR and baseline SOFA score (SOFA0). The developed nomogram predicted M/S LIT with an area under the curve of 0.767 (95% CI 0.715-0.820), a sensitivity of 71.1% and a specificity of 73.2%. Linezolid trough concentrations increased dramatically in the elderly, by about 10 mg/L in patients aged 65-80 years, followed by a further increase of 10 mg/L for every 10 years of age. Therapeutic drug monitoring is recommended in elderly patients receiving linezolid. The developed nomogram may predict M/S LIT and guide dosage adjustments of linezolid. Clinical trial registration number: ChiCTR2100045707.

Exposure–efficacy relationship of vedolizumab subcutaneous and intravenous formulations in Crohn’s disease and ulcerative colitis

ABSTRACT Background and aims This posthoc analysis of the GEMINI and VISIBLE studies in ulcerative colitis (UC) and Crohn's Disease (CD) assessed exposure−efficacy of vedolizumab intravenous (IV) and subcutaneous (SC). Methods A previously described population pharmacokinetic model was used to predict average serum and trough concentrations at steady state (Cav,ss, Ctrough,ss) and simulate the transition from vedolizumab IV to SC. Efficacy was defined as clinical remission at week 52: complete Mayo score ≤ 2 points and no individual subscore > 1 point (UC), and CD activity index score ≤ 150 points (CD). Results Data were from 1968 patients (GEMINI 1 [n = 334], VISIBLE 1 [n = 216], GEMINI 2 [n = 1009], VISIBLE 2 [n = 409]) who received maintenance treatment with vedolizumab IV-Q8W, IV-Q4W, SC-Q2W, or placebo. Model-predicted Cav,ss for IV-Q8W and SC-Q2W was similar in UC and CD. Cav,ss was higher for IV-Q4W than IV-Q8W and SC-Q2W. Ctrough,ss values from IV and SC aligned well with pooled observed Ctrough by treatment group in UC and CD. Cav,ss was equivalent for SC and IV. For UC and CD, efficacy rates were greater in patients in the highest quartiles of vedolizumab exposure for both formulations. Conclusion Exposure−efficacy relationships for IV and SC vedolizumab administration were comparable, confirming that both are equally effective during maintenance treatment.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ZY-IL1 in Three Patients with Cryopyrin-Associated Periodic Syndromes.

We present the first results of the proof-of-concept phase 2a study of oral NLRP3 inflammasome inhibitor in subjects with cryopyrin-associated periodic syndromes (CAPS). Three adult subjects with a confirmed diagnosis of CAPS were enrolled and administered 50mg of ZYIL1 twice daily for 7 days. A total of 5 treatment-emergent adverse events (TEAEs) were reported in 2 subjects. All 5 TEAEs were mild in severity and considered unrelated to the study drug. At steady state, the average plasma concentration and trough concentration ranged from 2.5 to 4.2 and 1.4 to 2.5µg/mL, respectively. Inflammatory markers and disease activity (physician and patient global assessment score) decreased notably 12 hours post-last dose.

Does therapeutic drug monitoring (TDM) of trough concentrations suffice for optimizing preemptive therapy with ganciclovir of cytomegalovirus infections in non-renal solid organ transplant recipients?

The aim of this study is to explore the relationship between ganciclovir exposure and clinical efficacy and/or safety in non-renal solid organ transplant (SOT) recipients receiving preemptive therapy with ganciclovir/valganciclovir and undergoing therapeutic drug monitoring (TDM)-guided dosing optimization. Non-renal SOT recipients admitted to IRCCS Azienda Ospedaliero-Universitaria of Bologna receiving preemptive therapy with ganciclovir or valganciclovir for active cytomegalovirus (CMV) infection and who underwent at least one TDM were included. Desired ganciclovir Cmin range was set at 1-3mg/L, and average ganciclovir trough concentrations (Cmin ) were calculated for each patient. Reduced CMV viral load below the lower limit of quantification (LLQ) at 30 days and occurrence of myelotoxicity were selected as the primary outcome. Univariate analysis was performed by comparing patients with average Cmin below or above 1 or 3mg/L. Receiver operating characteristic (ROC) curve analysis was performed to identify the average ganciclovir Cmin cut-off predictive for clinical efficacy or toxicity. Twenty-nine out of 89 retrieved patients met the inclusion criteria, with a median (interquartile [IQR]) baseline CMV viral load of 27,163 copies/mL (IQR 13159.75-151340.25 copies/mL). Reduced CMV viral load below the LLQ at 30 days was found in 17 patients (58.6%). No difference was found in the primary outcome between patients showing average Cmin below or above 1mg/L (100.0%vs. 53.8%; p= .25) and/or 3mg/L (65.2%vs. 33.3%; p = .20). ROC analysis did not allow to identify an average Cmin cut-off predictive of clinical efficacy or toxicity. No clear relationship between ganciclovir Cmin and neither CMV eradication nor safety issues was identified.

The efficacy of direct oral anticoagulants in patients on concomitant treatment with levetiracetam

Guidelines do not support the combination of direct oral anticoagulants (DOACs) and the antiepileptic drug levetiracetam, due to potential relevant P-glycoprotein (P-gp) mediated interaction that might result in decreased DOACs concentrations and increased thromboembolic risk. However, there is no systematic data on the safety of this combination. The aim of this study was to find patients concurrently treated with levetiracetam and DOAC, assess their plasma concentrations of DOAC, and the incidence of thromboembolic events. From our registry of patients on anticoagulation drugs we identified 21 patients concomitantly treated with levetiracetam and DOAC, 19 patients with atrial fibrillation and two patients with venous thromboembolism. Eight patients received dabigatran, 9 apixaban and 4 rivaroxaban. For each subject blood samples were collected for determination of trough DOAC and trough levetiracetam concentrations. The average age was 75 ± 9 years, 84% were males, HAS-BLED score was 1.8 ± 0.8, and in patients with atrial fibrillation CHA2DS2-VASc score was 4.6 ± 2.0. The average trough concentration level of levetiracetam was 31.0 ± 34.5 mg/L. Median trough concentrations of DOACs were for dabigatran 72 (range 25–386) ng/mL, for rivaroxaban 47 (range 19–75) ng/mL, and for apixaban 139 (range 36–302) ng/mL. During the observation period of 1388 ± 994 days none of the patients suffered a thromboembolic event. Our results did not demonstrate a reduction in DOACs plasma levels during levetiracetam treatment, suggesting that levetiracetam could not be an important P-gp inducer in humans. DOAC in combination with levetiracetam remained effective therapy to protect against thromboembolic events.

Toward optimization of cyclosporine concentration target to prevent acute graft‐versus‐host disease following myeloablative allogeneic stem cell transplant

Despite the common use of cyclosporine (CsA) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic stem cell transplant, the optimal CsA trough target remains unknown. Here, we report on outcomes of adult patients following myeloablative conditioning to identify an optimal CsA trough target and characterize the most relevant timeframe post-transplant for CsA trough targeting to minimize aGVHD. We retrospectively reviewed 399 consecutive patients who underwent first peripheral blood allogeneic stem cell transplant for hematological malignancies between January 2009 and December 2018. In the unadjusted and adjusted analyses, the incidence of grades 2-4 aGVHD was significantly higher among patients with an average CsA trough concentration <250mcg/L compared to patients with an average CsA trough concentration ≥250mcg/L during days 15-28 post-transplant (31.5% versus 18.8%, P = 0.037), with an odds ratio (OR) of 1.97 (95% confidence interval 1.04-3.71). In contrast, no correlations between CsA trough concentration and relapse, non-relapse mortality and overall survival was found. In conclusion, early post-transplant CsA trough concentrations are an important factor in the prophylaxis against aGVHD. Our findings suggest that CsA trough concentrations should be maximized between days 15-28 post-myeloablative transplant.

Pharmacometabolomics-guided clozapine therapy in treatment resistant schizophrenia: Preliminary exploration of future too near.

To study the association of clozapine pharmacometabolomics and clozapine response in Asian patients with treatment-resistant schizophrenia (TRS). A cross-sectional study was performed on 50 consecutive TRS patients following up in psychiatry department of the tertiary care hospital. Demographic details, response assessment, were collected on the case record form. A blood sample was also collected for trough concentration assessment of drug and its metabolites. Clozapine (CLZ) the parent drug and its two major metabolites - Clozapine N oxide (CNO) and N-Desmethyl clozapine (N-DSMC) levels were assessed using a high-performance liquid chromatography method. Clozapine responders and nonresponders patients were classified based upon Andreasen criteria. The average trough concentration of CNO, N-DSMC, and CLZ were 123±76.04, 171.93±93.24, 229.27±124.25ng/ml, respectively. The two patient subgroups did not differ for CLZ, CNO, and N-DSMC concentrations statistically. However, clozapine nonresponse was associated with a higher CLZ/N-DSMC ratio (p=0.03) and clozapine dose (p=0.01). The receiver operator characteristic curve showed that the cut-off CLZ/N-DSMC ratio of 1.54 with a sensitivity of 85% and a positive predictive value of 84% for identifying nonresponders. CLZ/N-DSMC ratio and clozapine dose were identified as significant variables for future dose optimization algorithms. Pharmacometabolomics-guided clozapine therapy has the potential to revolutionize TRS management.

Exposure-Response (E-R) Analysis of Olverembatinib (HQP1351) in Chinese Patients with Chronic Myeloid Leukemia (CML)

Introduction Olverembatinib (HQP1351), a third-generation BCR-ABL1 inhibitor, has been rationally developed to treat patients with CML that is refractory to or intolerant of tyrosine kinase inhibitors (TKIs), including acquired drug-resistant mutations. HQP1351 is effective against a broad spectrum of BCR-ABL1 mutations, including T315I, which confers resistance against all first- and second-generation TKIs. A phase I dose escalation study (SJ-0002) was conducted in Chinese patients with TKI-resistant/refractory CML. A total of 101 patients with CML, including 87 with chronic-phase CML (CML-CP) and 14 with accelerated-phase CML (CML-AP) have been enrolled in 11 dose escalation/expansion cohorts ranging from 1 mg to 60 mg HQP1351 every other day (QOD). The maximum tolerated dose (MTD) has been established as 50 mg, and the recommended phase II dose (RP2D) as 40 mg, QOD. To support selection of RP2D, we performed population pharmacokinetic (PK), exposure-efficacy, and exposure-safety analyses based on data from clinical study SJ-0002. Methods The population PK analysis was performed on the plasma drug concentration data from 65 patients. Exposure-efficacy analysis was performed on the primary clinical endpoint: major cytogenetic response (MCyR) at 6 months in 89 patients with CML. These included 78 individuals with CML-CP and 11 with CML-AP. Using a cell-life-span model in 101 patients with CML, we also performed an exposure-safety analysis on the most frequent adverse event: reduction in platelet count. Results Population PK analysis demonstrated that HQP1351 PK was best described by a two-compartment model with first-order absorption and first-order elimination. Total bilirubin, aspartate aminotransferase, and albumin were found to be significant covariates affecting the PK of HQP1351. In the exposure-response analyses, average dose was selected as the exposure measurement over average concentration at steady state (Cavg,ss) and average trough concentration at steady state (Ctrough,ss) based on the model performance. Exposure-efficacy analysis showed a clear E-R relationship, with the increased probability of achieving MCyR at 6 months with increasing average HQP1351 dose (Figure 1). The highest MCyR rate with HQP1351 was achieved at the MTD (50 mg QOD). In the exposure-safety analysis, there was a significant dose response relationship between average HQP1351 dose and incidence rate of grade 3 or greater (G3⁺) platelet count reductions (Figure 2). Conclusions E-R analyses of HQP1351 in Chinese patients with CML demonstrated a clear positive relationship between average HQP1351 dose and both efficacy and the probability of G3⁺ platelet count reductions. The results of E-R modeling and simulation support the RP2D of 40 mg QOD because it achieved a high rate of MCyR with manageable risk of G3⁺ platelet count reductions. Disclosures Lu: Ascentage Pharma Group: Current Employment, Current equity holder in publicly-traded company. Wang:Ascentage Pharma Group: Current Employment. Xu:Ascentage Pharma Group: Current Employment. Men:Ascentage Pharma Group: Current Employment. Xie:Ascentage Pharma Group: Current Employment. Chen:Ascentage Pharma Group: Current Employment. Niu:Ascentage Pharma Group: Current Employment. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

Remission of hepatotoxicity in chronic pulmonary aspergillosis patients after lowering trough concentration of voriconazole.

BACKGROUNDChronic pulmonary aspergillosis (CPA) is a rare syndrome that is often accompanied by gradual lung tissue destruction. Voriconazole is usually employed as the first-line agent for CPA treatment. However, some patients can develop hepatotoxicity and often were forced to stop voriconazole treatment.AIMTo record the improving trend of liver function and the therapeutic effects in patients after lowering the trough concentration of voriconazole. METHODSThis study retrospectively analyzed 12 adult CPA patients who developed hepatotoxicity during the voriconazole treatment. In these patients, the oral dose was reduced to 3/4 or 1/2 of the standard dose (4 mg/kg, twice daily), and the lower limit of voriconazole trough concentration was maintained more than 0.5 µg/mL. The trend of remission of liver toxicity after drug reduction in 12 patients was recorded. During the same period, 25 patients who received standard doses served as the control group. Data from the two groups were collected and analyzed for different parameters such as demographic characteristics, underlying pulmonary disorders, laboratory tests, and therapeutic effect. The differences between the two groups were statistically compared.RESULTSHepatotoxicity occurred in 12 patients within 28-65 d after oral voriconazole treatment. Hepatotoxicity was mainly manifested by the significantly increased level of gamma-glutamyltransferase and a slight increase of alanine aminotransferase and aspartate aminotransferase. The oral dose of voriconazole was reduced to approximately 3 mg/kg in seven patients and approximately 2 mg/kg in five patients. The average trough concentrations for the 12 patients before and after voriconazole oral dose reduction were 3.17 ± 1.47 µg/mL (1.5-6.0 µg/mL) and 1.70 ± 0.78 µg/mL (0.6-3.3 µg/mL), respectively (P = 0.02). After lowering the trough concentrations, the hepatotoxicity was alleviated in all the patients. However, gamma-glutamyltransferase levels declined slowly. After 4 mo of treatment, 7 of the 12 patients were successfully treated in the low trough concentrations group (41.7%). Similarly, 8 of the 25 patients in the standard treatment dose group (32.0%) were effectively treated. There was no statistical difference between the groups (P = 0.72).CONCLUSIONReducing the lower limit of the voriconazole trough concentration to 0.5 µg/mL can alleviate the hepatotoxicity and maintained certain clinical efficacy in CPA patients; however, patients should be closely monitored.

Combined Effect of Inter- and Intrapatient Variability in Tacrolimus Exposure on Graft Impairment Within a 3-Year Period Following Kidney Transplantation: A Single-Center Experience.

Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this studywas to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6-12months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPVandC0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6-12months post-transplantation. The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.

Validation of the usefulness of artificial neural networks for risk prediction of adverse drug reactions used for individual patients in clinical practice.

Artificial neural networks are the main tools for data mining and were inspired by the human brain and nervous system. Studies have demonstrated their usefulness in medicine. However, no studies have used artificial neural networks for the prediction of adverse drug reactions. We aimed to validate the usefulness of artificial neural networks for the prediction of adverse drug reactions and focused on vancomycin -induced nephrotoxicity. For constructing an artificial neural network, a multilayer perceptron algorithm was employed. A 10-fold cross validation method was adopted for evaluating the resultant artificial neural network. In total, 1141 patients who received vancomycin at Hokkaido University Hospital from November 2011 to February 2019 were enrolled. Among these patients, 179 (15.7%) developed vancomycin -induced nephrotoxicity. The top three risk factors of vancomycin -induced nephrotoxicity which are relatively important in the artificial neural networks were average vancomycin trough concentration ≥ 13.0 mg/L and concomitant use of piperacillin–tazobactam and vasopressor drugs. The predictive accuracy of the artificial neural network was 86.3% and that of the multiple logistic regression model (conventional statistical method) was 85.1%. Moreover, area under the receiver operating characteristic curve (AUROC) of the artificial neural network was 0.83. In the 10-fold cross-validation, the accuracy obtained was 86.0% and AUROC was 0.82. The artificial neural network model predicting the vancomycin -induced nephrotoxicity showed good predictive performance. This appears to be the first report of the usefulness of artificial neural networks for an adverse drug reactions risk prediction model.

MP45-02 POPULATION PHARMACOKINETIC MODELING AND SIMULATION TO ASSESS THE IMPACT OF AN 8-WEEK MAINTENANCE DOSING REGIMEN FOR INTRAMUSCULAR TESTOSTERONE UNDECANOATE

INTRODUCTION AND OBJECTIVE: Intramuscular (IM) testosterone undecanoate (TU) is indicated for testosterone (T) replacement in adult males with a deficiency or absence of endogenous T. IM TU is currently approved to be administered at initiation and at 4 weeks (wks) followed by a maintenance dose every 10 wks (750 mg/dose). However, a more frequent maintenance regimen (every 8 wks) may improve the management of symptoms of low T at the end of each dosing interval. The objective of this work was to develop a population pharmacokinetic (popPK) model for IM TU and to perform PK simulations to assess the impact of an 8-wk maintenance regimen on T exposures. METHODS: A popPK model was developed to characterize the PK of serum total T using data from 130 hypogonadal men receiving the approved 10-wk maintenance regimen of IM TU in Study IP157-001 Part C. T profiles were then simulated for 8-wk and 10-wk maintenance regimens (10 doses/regimen) based on the population size and demographics of Study IP157-001 Part C. Using simulated T concentrations, the following parameters were calculated: average concentration (Cavg), maximum concentration (Cmax), and trough concentration (Ctrough). Responder rates of clinical interest were determined for each parameter. RESULTS: The PK of TU was well-described by a 1-compartment model with 1st-order absorption and elimination kinetics. The model included a rapid suppression and gradual recovery of endogenous T production during TU administration. Lower clearance (CL/F) and volume of distribution (V/F) were associated with lower body weight, more rapid IM absorption with lower body weight, and greater CL/F with lower sex hormone binding globulin levels. Simulated T PK profiles and responder rates for Dose 10 are presented in Figure 1. Improved responder rates for Cavg and Ctrough were predicted for the 8-wk regimen compared to the 10-wk regimen with no increase in Cmax excursions >2500 ng/dL. CONCLUSIONS: Simulations indicate that the absolute percent of Ctrough responders (Ctrough >300 ng/dL) increased by 9.4% (95% confidence interval: 8.5% – 10.3%) for the 8-wk regimen compared to the 10-wk regimen. Smaller impacts of the 8-wk regimen were calculated for Cavg and Cmax with no increase in Cmax excursions >2500 ng/dL for the 8-wk regimen.Source of Funding: Endo Pharmaceuticals Inc.

Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting.

Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir's pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug-drug interactions. A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h-1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.

A Prospective Multicenter Clinical Observational Study on Vancomycin Efficiency and Safety With Therapeutic Drug Monitoring.

Vancomycin is a first-line antibiotic used for the treatment of severe gram-positive bacterial infections. Clinical guidelines recommend that the vancomycin trough concentration be 10-15 mg/L for regular infections and 15-20 mg/L for severe infections. We investigated whether increasing the vancomycin concentration would result in better clinical outcomes with sustainable adverse effects (AEs) in the Chinese population. A prospective, open, multicenter clinical observational study was performed in patients with gram-positive bacterial infections from 13 teaching hospitals. Patients received vancomycin therapeutic drug monitoring. Clinical, microbiological, and laboratory data were collected. In total, 510 patients were enrolled, and 470 were evaluable, of whom 370 were adults and 100 were children; 35.53% had methicillin-resistant Staphylococcus aureus infections (vancomycin 50% minimum inhibitory concentration [MIC50] = 1, 90% minimum inhibitory concentration [MIC90] = 1), and 23.19% had Enterococcus species infections (vancomycin MIC50 = 1, MIC90 = 2). The average trough concentration was 10.54 ± 8.08 mg/L in adults and 6.74 ± 8.93 mg/L in children. The infection was eradicated in 86.22% of adults and 96% of children. Thirty-six vancomycin-related nephrotoxicity cases were reported in the enrolled population. No severe AEs or deaths were related to vancomycin therapy. Logistic regression analysis showed that trough concentration had no relationship with clinical outcomes (adults P = .75, children P = .68) but was correlated with adult nephrotoxicity (P < .0001). Vancomycin trough concentration had an applicable cut point at 13 mg/L. Our study shows that vancomycin trough concentration has no statistical correlation with clinical outcomes, and is an indicator of nephrotoxicity in the observed population. We found no evidence that increasing vancomycin trough concentration to 15-20 mg/L can benefit Chinese patients with complicated infections. ChiCTR-OPC-16007920.

Distribution characteristics of plasma concentration of vancomycin and clinical efficacy in pediatric patients with severe pneumonia and congenital heart disease

Objective To analyze the distribution characteristics of vancomycin blood concentration in children with severe pneumonia complicated with congenital heart disease(CHD) and children with simple severe pneumonia after using the same dose vancomycin, and observe the clinical efficacy at the same time. Methods Plasma concentrations in pediatric patients with severe pneumonia complicated with CHD(CHD group) who treated by vancomycin from November 2012 to September 2013 in Shengjing Hospital of China Medical University were collected.Plasma concentrations of children with simple severe pneumonia(control group) treated by vancomycin were also collected at the same period.The blood concentration values and therapeutic effects of the two groups were recorded into the database for statistical analysis.Peak, trough concentrations and efficacy were analyzed by receiver operating characteristic(ROC) curve. Results Twenty-five children with CHD were collected, the average peak concentration was (28.39±6.68)mg/L, the average trough concentration was (13.34±6.62)mg/L.Control group were also 25 cases, the average peak concentration was (16.23±2.50)mg/L and the average trough concentration was (2.77±1.01)mg/L.Both peak and trough concentrations of CHD children were significantly higher than those of the control group (tpeak=8.52, Ppeak<0.05; ttrough=7.89, Ptrough<0.05). In the ROC of peak, trough concentrations and efficacy, area under the curve were 0.74(95%CI 0.547-0.935, P=0.01) and 0.77(95%CI 0.605-0.935, P=0.004) respectively, and the difference was statistically significant. Conclusion Plasma concentrations of vancomycin in children with CHD are generally higher, it is necessery to monitor plasma concentration even under regular doses, to make the application of vancomycin more safe and effective in children with CHD.There is a correlation between plasma concentration of vancomycin and clinical efficacy in children, the higher the blood concentration, the more likely the clinical efficacy is to be effective. Key words: Severe pneumonia; Congenital heart disease; Vancomycin; Serum concentration; Peak concentration; Trough concentration

Evaluation of Intravenous Vancomycin Pharmacokinetic Parameters in Patients With Acute Brain Injury

Background: Vancomycin is a glycopeptide antibiotic that is primarily cleared by renal elimination. Patients with acute brain injury often exhibit augmented renal clearance which has been associated with subtherapeutic vancomycin concentrations. Objective: To determine whether population pharmacokinetics accurately predict vancomycin empiric dose frequency in patients with acute brain injury. Methods: This was a single-center, retrospective cohort study conducted following institutional review board approval at Virginia Commonwealth University Health System. Data were collected from patients 18 years of age or older admitted with acute brain injury. The primary outcome was the difference in the elimination rate constant of vancomycin between population predicted pharmacokinetics and patient-specific pharmacokinetics. Results: A total of 158 patients were included in the analysis. A test of the paired differences between the mean population predicted and patient-specific elimination rate constants showed that the mean population predicted elimination rate constant was larger by 0.0211 h−1 (95% confidence interval [CI]: −0.028 to −0.015). The difference between the mean population predicted and patient-specific half-lives showed that the mean population predicted half-life was shorter by 1.01 hours (95% CI: 0.7-1.3). Vancomycin was administered at a mean initial dose of 15.4 mg/kg (standard deviation [SD] = 2.2), with an average frequency of 12 hours (SD = 1.1). The average trough concentration at steady state was 9.9 µg/mL (SD = 4.9). Conclusions: The small clinical difference in population and patient-specific elimination rate constants demonstrates that population pharmacokinetics may be an accurate empiric dosing strategy for determining vancomycin dose frequency in patients with acute brain injury.

Clinical efficacy and safety of vancomycin compared with linezolid for the treatment of neonatal gram-positive bacterial sepsis

To evaluate the clinical efficacy and safety of vancomycin and linezolid for the treatment of gram-positive neonatal bacterial sepsis. The data of neonates diagnosed as gram-positive bacterial sepsis in neonatology department of Suzhou Municipal Hospital from June 2009 to December 2015 were retrospectively collected. These neonates were divided into vancomycin group and linezolid group. Propensity score matching (PSM) on baseline variables was used to balance the two groups by identifying a comparable group of neonates who received vancomycin and linezolid therapy. Clinical and microbiologic success rates were compared by chi-square test, and changes of laboratory parameters before and after treatment at the end of treatment were then directly compared by rank-sum test between the matched groups. In vancomycin group, correlation between trough concentration of vancomycin and clinical efficacy were evaluated. Totally 108 and 209 cases were respectively selected in vancomycin and linezolid groups; 108 cases with well-matched baseline characteristics were included in matched linezolid group. The clinical success rates of vancomycin vs. linezolid therapy were 86.1%(93/108) and 88.9%(96/108)(P=0.681), and the microbiologic success rates were 91.7%(99/108) and 93.5%(101/108)(P=0.795). The average trough concentration of vancomycin was (12±8) mg/L. The rate of reaching the high trough concentration standard was only 33.3%(36/108). In 50 (46.3%) cases the dose was adjusted according to the initial concentration data. Compared to less than 10 mg/L, the clinical efficacy of trough concentration in 10-20 mg/L was much higher(93.9%(46/49) vs. 78.6%(33/42), P=0.031). Total bilirubin and platelet count had significant difference between the two-matched groups (34.1(14.9, 91.0)μmol/L vs. 53.0(27.0, 121.6)μmol/L, P=0.034; 301.0(198.8, 416.0)×10(9)/L vs. 195.5(94.0, 283.2)×10(9)/L, P=0.000). The incidence of linezolid related thrombocytopenia was 13.4%(28 cases). The clinical effect of vancomycin and linezolid on gram-positive bacterial sepsis in neonates is comparable. The rate of trough concentration of vancomycin reaching the high trough concentration standard is low, and the clinical efficacy is related to trough concentration. Linezolid have an effect on bilirubin and platelet count, the risk of thrombocytopenia should be monitored closely during linezolid treatment.

Rethinking Dosing Regimen Selection of Piperaquine for Malaria Chemoprevention: A Simulation Study.

BackgroundThe combination of short-acting dihydroartemisinin and long-acting piperaquine (DP) is among the first-line therapies for the treatment of uncomplicated Plasmodium falciparum malaria. Population pharmacokinetic models of piperaquine (PQ) based on data from acute treatment of young children can be used to predict exposure profiles of piperaquine under different DP chemoprevention regimens. The purpose of our study was to make such predictions in young children.MethodsBased on a prior population pharmacokinetic model of PQ in young Ugandan children, we simulated capillary plasma concentration-time profiles (including their variability) of candidate chemoprevention regimens for a reference population of 1–2 year olds weighing at least 11 kg. Candidate regimens that were tested included monthly administration of standard therapeutic doses, bimonthly dosing, and weekly dosing (with and without a loading dose).ResultsOnce daily doses of 320 mg for three days (960 mg total) at the beginning of each month are predicted to achieve an average steady-state trough capillary piperaquine concentration of 35 ng/mL, with 60% achieving a level of 30 ng/mL or higher. In contrast, weekly dosing of 320 mg (i.e., 33% higher amount per month) is predicted to approximately double the average steady-state trough concentration, increase the percent of children predicted to achieve 30 ng/mL or higher (94%), while at the same time lowering peak concentrations. Exposure at steady-state, reached at approximately 3 months of multiple dosing, is expected to be approximately 2-fold higher than exposure following initial dosing, due to accumulation. A loading dose improves early exposure, thereby reducing the risk of breakthrough infections at the initiation of chemoprevention.ConclusionsOnce weekly chemoprevention of DP predicts favourable exposures with respect to both trough and peak concentrations. These predictions need to be verified, as well as safety evaluated, in field-based clinical studies of young children. Simulations based on prior knowledge provide a systematic information-driven approach to evaluate candidate DP chemopreventive regimens for future trial designs.

Alternate-day dosing of itraconazole in healthy adult cats.

The current available formulations of itraconazole are not ideal for dosing in cats. The capsular preparation often does not allow for accurate dosing, the oral solution is difficult to administer and poorly tolerated, and the bioavailability of compounded formulations has been shown to be poor in other species. The aim of this study was to evaluate every other day dosing of 100 mg itraconazole capsule in healthy adult cats. Ten healthy adult cats received a 100 mg capsule of itraconazole orally every 48 h for 8 weeks. Peak and trough serum concentrations of itraconazole were measured weekly using high-performance liquid chromatography (HPLC). Physical examination, complete blood count (CBC), and chemistry profiles were performed weekly. The dosage regimen achieved average therapeutic trough concentrations (>0.5 μg/mL) within 3 weeks. The protocol yielded no adverse effects in 8 of the 10 study cats, with affected cats recovering fully with discontinuation of the drug and supportive care. At 8 weeks, an average peak concentration of 1.79 ± 0.952 μg/mL (95% CI: 0.996-2.588) and an average trough concentration of 0.761 ± 0.540 μg/mL (95% CI: 0.314-1.216) were achieved. Overall, a 100 mg every other day oral dosage regimen for itraconazole in cats yielded serum concentrations with minimal fluctuation and with careful monitoring may be considered for treatment of cats with systemic fungal disease.

Therapeutic monitoring of intravenous vancomycin in a pediatric critical care unit

In critically ill pediatric patients vancomycin distribution and elimination is altered underscoring the need for pharmacokinetic monitoring; however the therapeutic trough ranges have not been validated for children. To describe the pharmacokinetics of intravenous vancomycin in critically ill pediatric patients using plasmatic vancomycin monitoring. Retrospective, descriptive study performed in a paediatric critical care unit. Vancomycin serum levels (Cmin and Cpeak), t ½ and Vd were determined in 1 month to 12 year old patients receiving ≥ 40 mg per-kg-per day. Plasmatic levels were measured at therapy onset and during follow up, evaluating the proportion of trough level determinations within therapeutic range, the average trough concentration, and the Cpeak achieved. A total of 65 plasmatic vancomycin monitorings were analysed in 45 patients. The average values for Ctrough, Cpeak, t1/2 and Vd were 10.4 μg/mL, 22.7 μg/mL, 3,1 h and 0.7 L/kg, respectively. An average dose of 47,1 mg/kg/day achieved initial Ctrough levels < 10 mg/mL in 60% of patients (n = 27), between 10 and 14,9 μg/mL in 22,2% (n = 10), between 15 to 20 μg/mL in 4% (n: 2), and > 20 μg/mL in 13,3% (n: 6). Vancomycin doses of 40 mg/kg/day are insufficient for critically ill paediatric patients without renal failure. A higher starting dose and monitoring of plasma levels must be considered in this population.