Predictors of Voriconazole Trough Concentrations in Patients with Child–Pugh Class C Cirrhosis: A Prospective Study

This prospective observational study aimed to clinically describe voriconazole administrations and trough concentrations in patients with Child–Pugh class C and to investigate the variability of trough concentration. A total of 144 voriconazole trough concentrations from 43 Child–Pugh class C patients were analyzed. The majority of patients (62.8%) received adjustments. The repeated measured trough concentration was higher than the first and final ones generally (median, 4.33 vs. 2.99, 3.90 mg/L). Eight patients with ideal initial concentrations later got supratherapeutic with no adjusted daily dose, implying accumulation. There was a significant difference in concentrations among the six groups by daily dose (p = 0.006). The bivariate correlation analysis showed that sex, CYP2C19 genotyping, daily dose, prothrombin time activity, international normalized ratio, platelet, and Model for end-stage liver disease score were significant factors for concentration. Subsequently, the first four factors mentioned above entered into a stepwise multiple linear regression model (variance inflation factor <5), implying that CYP2C19 testing makes sense for precision medicine of Child–Pugh class C cirrhosis patients. The equation fits well and explains the 34.8% variety of concentrations (R2 = 0.348). In conclusion, it needs more cautious administration clinically due to no recommendation for Child–Pugh class C patients in the medication label. The adjustment of the administration regimen should be mainly based on the results of repeated therapeutic drug monitoring.

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Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01647-17 ◽

2018 ◽

Vol 62 (4) ◽

pp. e01647-17 ◽

Cited By ~ 10

Author(s):

Sheng-Hsuan Tseng ◽

Chuan Poh Lim ◽

Qi Chen ◽

Cheng Cai Tang ◽

Sing Teang Kong ◽

...

Keyword(s):

Steady State ◽

Trough Concentration ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

Vancomycin Trough ◽

Trough Concentrations ◽

The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

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Inflammation Is Associated with Voriconazole Trough Concentrations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03820-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7098-7101 ◽

Cited By ~ 44

Author(s):

Marjolijn J. P. van Wanrooy ◽

Lambert F. R. Span ◽

Michael G. G. Rodgers ◽

Edwin R. van den Heuvel ◽

Donald R. A. Uges ◽

...

Keyword(s):

Trough Concentration ◽

Retrospective Chart Review ◽

Therapeutic Window ◽

Therapeutic Drug ◽

C Reactive Protein ◽

Large Variability ◽

Reactive Protein ◽

Inflammatory Status ◽

Inflammatory Stimuli ◽

Trough Concentrations

ABSTRACTVoriconazole concentrations display a large variability, which cannot completely be explained by known factors. Inflammation may be a contributing factor, as inflammatory stimuli can change the activities and expression levels of cytochrome P450 isoenzymes. We explored the correlation between inflammation, reflected by C-reactive protein (CRP) concentrations, and voriconazole trough concentrations. A retrospective chart review of patients with at least one steady-state voriconazole trough concentration and a CRP concentration measured on the same day was performed. A total of 128 patients were included. A significantly (P< 0.001) higher voriconazole trough concentration was observed in patients with severe inflammation (6.2 mg/liter; interquartile range [IQR], 3.4 to 8.7 mg/liter;n= 20) than in patients with moderate inflammation (3.4 mg/liter; IQR, 1.6 to 5.4 mg/liter;n= 60) and in patients with no to mild inflammation (1.6 mg/liter; IQR, 0.8 to 3.0 mg/liter;n= 48). The patients in all three groups received similar voriconazole doses based on mg/kg body weight (P= 0.368). Linear regression analyses, both unadjusted and adjusted for covariates of gender, age, dose, route of administration, liver enzymes, and interacting coadministered medications, showed a significant association between voriconazole and CRP concentration (P< 0.001). For every 1-mg/liter increase in the CRP concentration, the voriconazole trough concentration increased by 0.015 mg/liter (unadjusted 95% confidence interval [CI], 0.011 to 0.020 mg/liter; adjusted 95% CI, 0.011 to 0.019 mg/liter). Inflammation, reflected by the C-reactive protein concentration, is associated with voriconazole trough concentrations. Further research is necessary to assess if taking the inflammatory status of a patient into account is helpful in therapeutic drug monitoring of voriconazole to maintain concentrations in the therapeutic window, thereby possibly preventing suboptimal treatment or adverse events.

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Optimal Trough Concentration of Teicoplanin in Febrile Neutropenic Patients with Hematological Malignancy

Chemotherapy ◽

10.1159/000481725 ◽

2017 ◽

Vol 63 (1) ◽

pp. 29-34 ◽

Cited By ~ 5

Author(s):

Yuhki Sato ◽

Kazufumi Hiramatsu ◽

Yosuke Suzuki ◽

Ryota Tanaka ◽

Tetsuya Kaneko ◽

...

Keyword(s):

Trough Concentration ◽

Operating Characteristic ◽

Methicillin Resistant Staphylococcus Aureus ◽

Hematological Malignancy ◽

Therapeutic Drug ◽

Receiver Operating Characteristic Curves ◽

Significant Difference ◽

Observational Cohort ◽

Severe Infections ◽

Neutropenic Patients

Background: Teicoplanin is a glycopeptide antibiotic currently used for the treatment of methicillin-resistant Staphylococcus aureus. The need for therapeutic drug monitoring of teicoplanin has been increasingly highlighted as important. It is generally accepted that whereas a plasma trough concentration (Cmin) of ≥10 mg/L is appropriate for the majority of infections, it should exceed 20 mg/L for severe infections. The target Cmin of teicoplanin in patients with febrile neutropenia (FN) has not been reported. The aim of this study was to estimate the target Cmin for the treatment of FN in patients with hematological malignancy. Methods: In this retrospective, single-center, observational cohort study, the records of 52 hospitalized patients with hematological malignancy who were treated with teicoplanin for FN due to bacteriologically documented or presumptive gram-positive infections were analyzed. Results: A significant difference in the first Cmin of teicoplanin was observed between the response and nonresponse groups in patients with bacteremia. The areas under the receiver operating characteristic curves were 0.80 for clinical efficacy. The cut-off value of teicoplanin Cmin on days 4-6 was 15.2 mg/L (sensitivity 80.0%, specificity 75.0%). Conclusions: The authors propose a target teicoplanin Cmin of ≥15.2 mg/L for FN in patients with hematological malignancy.

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Use of Therapeutic Drug Monitoring to Characterize Cefepime-Induced Neurotoxicity

10.1101/2020.08.13.250456 ◽

2020 ◽

Author(s):

Veena Venugopalan ◽

Cara Nys ◽

Natalie Hurst ◽

Yiqing Chen ◽

Maria Bruzzone ◽

...

Keyword(s):

Renal Function ◽

Therapeutic Drug Monitoring ◽

Trough Concentration ◽

Drug Monitoring ◽

Hospitalized Patients ◽

Therapeutic Drug ◽

Eeg Abnormalities ◽

Increased Risk ◽

Trough Concentrations ◽

The Relationship

AbstractBackgroundThe incidence of cefepime-induced neurotoxicity (CIN) in hospitalized patients is highly variable. Although greater cefepime exposures incite neurotoxicity, data evaluating trough thresholds associated with CIN remains limited. The objectives of this study were to evaluate the incidence of CIN, assess the relationship between cefepime trough concentrations and CIN, investigate clinical factors associated with CIN, and describe electroencephalogram (EEG) abnormalities in CIN.MethodsThis was a retrospective study of adult patients who had received ≥ 5 days of cefepime with ≥ 1 trough concentration > 25 mg/L. Potential CIN cases were identified utilizing neurological symptoms, neurologist assessments, EEG findings and improvement of neurotoxicity after cefepime discontinuation.ResultsOne-hundred and forty-two patients were included. The incidence of CIN was 13% (18/142). The mean cefepime trough concentration in CIN patients was significantly greater than the non-neurotoxicity group (74.2 mg/L ± 41.1 vs. 46.6 mg/L ± 23, p=0.015). Lower renal function (creatinine clearance < 30 ml/min), greater time to therapeutic drug monitoring (TDM) (≥72 hours), and each 1 mg/mL rise in cefepime trough were independently associated with increased risk of CIN. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CIN.ConclusionCefepime should be used cautiously in hospitalized patients due to the risk of neurotoxicity. Patients with greater renal function and those who had early cefepime TDM (≤ 72 hours) had lower risk of CIN.

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Phenobarbital Pharmacokinetics in Infants Using Saliva as a Biologic Fluid

Journal of Pharmacy Technology ◽

10.1177/875512259401000605 ◽

1994 ◽

Vol 10 (6) ◽

pp. 250-254

Author(s):

Stella Gutierrez ◽

Marta Vázquez ◽

Amanda Amodio ◽

Gustavo Giachetto ◽

Diana Moller ◽

...

Keyword(s):

Medical Center ◽

Randomized Study ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Loading Dose ◽

Seizure Disorders ◽

Elimination Half ◽

Significant Difference ◽

Daily Dose ◽

Trough Concentrations

Objective: To determine the pharmacokinetic parameters of phenobarbital in infants, using saliva as a biologic fluid, and to correlate the parameters obtained from saliva data with those obtained from plasma data. Design: A prospective, randomized study. Setting: Hospitalized patients at the Medical Center Pereira Rossell, a pediatric hospital in Montevideo, Uruguay. Patients: Sixteen infants with seizure disorders were included in the study. None of them was treated with other medications. Interventions: A direct intravenous loading dose of phenobarbital 10 mg/kg was administered, followed by a maintenance dosage of 5 mg/kg/d (once- or twice-daily dosing) given 12 hours after the loading dose. Main Outcome Measures: Saliva and plasma samples were obtained 6 and 12 hours after the loading dose and 3 days after the initiation of the maintenance dose (trough sample): the samples were analyzed by HPLC and the elimination half-life (t1/2), the volume of distribution (Vd), and the percentage of unbound drug in plasma (UDP) were calculated. Results: The t1/2 obtained from plasma and saliva data was 30 hours; the Vd was 0.73 L/kg from plasma data and 2.4 L/kg from saliva data; and the UDP was 75 percent. Trough concentrations showed no significant difference between treatments. Conclusions: Saliva is a useful biologic fluid to determine phenobarbital pharmacokinetic parameters, mainly in pediatric patients. Moreover, a single daily dose of phenobarbital is sufficient to obtain therapeutic concentrations.

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Therapeutic carbamazepine (CBZ) and valproic acid (VPA) monitoring in children using saliva as a biologic fluid

Journal of Epilepsy and Clinical Neurophysiology ◽

10.1590/s1676-26492008000200003 ◽

2008 ◽

Vol 14 (2) ◽

pp. 55-58 ◽

Cited By ~ 7

Author(s):

C. Maldonado ◽

Pietro Fagiolino ◽

M. Vázquez ◽

A. Rey ◽

I. Olano ◽

...

Keyword(s):

Valproic Acid ◽

Citric Acid ◽

Therapeutic Drug Monitoring ◽

Combined Therapy ◽

Therapeutic Drug ◽

Efflux Transporter ◽

Drug Levels ◽

Significant Difference ◽

Daily Dose ◽

Epileptic Children

OBJECTIVE: The aim of the study was to analyze retrospectively carbamazepine (CBZ) and valproic acid (VPA) salivary data collected from epileptic children during a 3-year period. METHODS: Saliva samples stimulated by citric acid were assayed by FPIA method. One hundred and three patients (aged 1-14 years) were in CBZ or VPA monotherapy or in CBZ-VPA combined therapy. RESULTS: VPA salivary levels were linearly related with daily dose, but a non-linear relationship was found for CBZ, in patients under monotherapy. VPA did not alter saliva CBZ concentration. Conversely, CBZ reduced VPA salivary levels. Non-responsive children displayed higher VPA concentrations. CBZ levels in uncontrolled patients showed non-significant difference in relation with controlled subjects even though their daily doses were higher. CONCLUSION: Citric acid stimulated saliva is reliable enough to perform therapeutic drug monitoring. Saliva drug levels in non-responsive patients would be explained according to the generalized efflux transporter overexpression hypothesis.

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Optimized Administration of Voriconazole and Therapeutic Drug Monitoring in Children and Adolescents: A Single-Centre Retrospective Experience from China

10.21203/rs.3.rs-222933/v1 ◽

2021 ◽

Author(s):

Yi-Chang Zhao ◽

Yang Zou ◽

Dan Tang ◽

Chen-Lin Xiao ◽

Yi-Wen Xiao ◽

...

Keyword(s):

Trough Concentration ◽

Therapeutic Drug ◽

Demographic Information ◽

Therapeutic Level ◽

Multiple Dosing ◽

Concentration Data ◽

Factors Affecting ◽

Dosage Regime ◽

Trough Concentrations ◽

Anti Fungal

Abstract Background Voriconazole (VRC) is a triazole anti-fungal agent and a first-line treatment for invasive fungal infection (IFI) generally. The purpose of our study was performed to explore the factors affecting voriconazole trough concentration (Ctrough) and to show VRC dose adjustment experience in children. Methods The demographic information, concentration data, CYP2C19 genotypes and clinical outcomes of eligible children from January 1th, 2016 to December 31th, 2018 were collected. Factors affecting the voriconazole trough concentration were statistically analyzed. Results A total of 145 trough concentrations in 94 patients were included in this study, 54.5% of which achieved the target concentrations; however, 35.9% and 9.6% of which were sub-therapeutic and super-therapeutic post-multiple dosing. For children ≤ 2, 2–6, 6–12, and 12–18 years, the median VRC maintenance doses of 5.7, 6.7, 5.0 and 3.3 mg/kg twice daily respectively had been required in order to achieve therapeutic level (P < 0.001). Co-administration of proton pump inhibitors affected VRC target trough concentration significantly (P = 0.001). Conclusion Younger pediatric patients might need a higher dosage regime to achieve therapeutic trough concentration. In order to ensure the effectiveness and safety of voriconazole in children, early and repeat monitoring of voriconazole is a powerful tool.

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Therapeutic Drug Monitoring and Impact Indicator of Vancomycin Pharmacokinetics in Abdominal Cancer Patients complicated with Severe Infectious Disease

10.21203/rs.2.9533/v1 ◽

2019 ◽

Author(s):

Xiaowu Zhang ◽

Yang Lyu ◽

Donghao Wang

Keyword(s):

Infectious Disease ◽

Mechanical Ventilation ◽

Cancer Patients ◽

Trough Concentration ◽

Therapeutic Drug ◽

Target Concentration ◽

Impact Indicator ◽

Vancomycin Trough ◽

Delayed Group ◽

Trough Concentrations

Abstract Abstract Objective: This study was designed to investigate effectiveness of therapeutic drug monitoring (TDM) and impact indicator of vancomycin pharmacokinetics in abdominal cancer patients complicated with severe infectious disease. Methods: A total of 78 patients abdominal cancer patients complicated with severe infectious disease were included. Vancomycin serum trough concentrations were measured using the fluorescence polarization immunoassay (FPIA) method. The patients were divided into early and delayed groups based on whether they achieve the target concentration. And clinical factors were compared between two groups. Results: The average initial therapeutic dose of vancomycin was 15.18±3.29 mg/kg (q12h). Ultimately, we collected 78 patient‘s trough concentrations data. The research revealed that the abdominal cancer patients complicated with severe infectious disease had significantly lower initial vancomycin trough concentrations (median [IQR]: 6.90[5.28-11.20] mg/L) compared with the recommended standard goal vancomycin trough concentration (10-15 or 15-20 mg/L). Multiple regression analysis revealed that Cys-C was the most important variable for vancomycin target trough achievement. We divided patients into early and delayed groups based on whether the initial trough concentration achieved standard goal trough concentration. Although the clinical outcomes were similar between two groups, the duration of mechanical ventilation in Early group was considerably shorter compared with group Delayed group (χ2=4.532; p < 0.05; Fig 1E). Propensity score weighting further confirmed that the duration of mechanical ventilation (χ2=6.607; p < 0.05; Fig 1F) and vasoactive agent (χ2=6.106; p < 0.05; Fig 1D) was considerably shorter compared with group Delayed group. Conclusions: The steady-state initial vancomycin trough concentration was significantly reduced in abdominal cancer patients complicated with severe infectious disease. Higher initial dosage regimen is needed to ensure clinical effectiveness. The baseline Cys-C level measured prior to administration of vancomycin is suggested to be the most suitable parameter to predict whether vancomycin trough concentration is up to standard dosage. Early attainment of target concentration significantly improved hemodynamic stability and reduced duration of mechanical ventilation.

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Variability in Trough Total and Unbound Teicoplanin Concentrations and Achievement of Therapeutic Drug Monitoring Targets in Adult Patients with Hematological Malignancy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02466-16 ◽

2017 ◽

Vol 61 (6) ◽

Cited By ~ 10

Author(s):

Catherine J. Byrne ◽

Jason A. Roberts ◽

Brett McWhinney ◽

Jerome P. Fennell ◽

Philomena O'Byrne ◽

...

Keyword(s):

Renal Function ◽

Body Weight ◽

Therapeutic Drug Monitoring ◽

Creatinine Clearance ◽

Trough Concentration ◽

Drug Monitoring ◽

Hematological Malignancy ◽

Therapeutic Drug ◽

Factors Associated ◽

Trough Concentrations

ABSTRACT The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.)

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Association of adalimumab trough concentrations and treatment response in patients with Juvenile Idiopathic Arthritis

Rheumatology ◽

10.1093/rheumatology/keab354 ◽

2021 ◽

Author(s):

Martijn J H Doeleman ◽

Sytze de Roock ◽

Mohsin El Amrani ◽

Erik M van Maarseveen ◽

Nico M Wulffraat ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Disease Activity ◽

Treatment Response ◽

Therapeutic Drug ◽

Adequate Response ◽

Paediatric Patients ◽

Drug Concentrations ◽

Significant Difference ◽

Secondary Failure ◽

Trough Concentrations

Abstract Objective To assess the relationship of adalimumab trough concentrations and treatment response in paediatric patients with juvenile idiopathic arthritis (JIA). Methods Monocentric cohort study of JIA patients treated with adalimumab. Clinical data and samples were collected during routine follow-up. Adalimumab trough concentrations were quantified by a novel liquid chromatography-tandem mass spectrometry assay. Anti-adalimumab antibodies were measured in samples with trough concentrations ≤5mg/l. Disease activity was evaluated using the clinical Juvenile Arthritis Disease Activity Score with 71 joint-count (cJADAS71). Response to adalimumab was defined according to recent international treat-to-target guidelines. Results 35 adalimumab trough samples were available from 34 paediatric patients with JIA. Although there was no significant difference in adalimumab dose, trough concentrations were significantly lower in patients with secondary failure (median 1.0 mg/l; IQR 1.0–5.3) compared with patients with primary failure (median 13.97 mg/l; IQR 11.81–16.67) or an adequate response (median 14.94 mg/l; IQR 10.31–16.19) to adalimumab. Conclusion Adalimumab trough concentrations were significantly lower in JIA patients with secondary failure compared with patients with primary failure or an adequate response to adalimumab. Results suggest that trough concentration measurements could identify JIA patients who require increased adalimumab doses to achieve or maintain therapeutic drug concentrations.

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