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A vancomycin steady‐state trough concentration (Cmin) of 15‐20 mg/L is recommended for achieving a ratio of the 24‐hour area under the curve to the minimum inhibitory concentration (AUC0‐24/MIC) of ≥400 in adults. Since few paediatric data are available, our objectives were to (a) measure the pharmacokinetic indices of vancomycin and (b) determine the correlation between Cmin and AUC0‐24/MIC in paediatric patients. Population‐based pharmacokinetic modelling was performed for paediatric patients to estimate the individual parameters. The relationship between Cmin and the calculated AUC0‐24/MIC was explored using linear regression and a probabilistic framework. A sensitivity analysis was also conducted using Monte Carlo simulations. Body‐weight significantly influenced the pharmacokinetics of vancomycin. Based on real data and simulations, Cmin ranges of 5.0‐5.9 and 9.0‐12.9 mg/L were associated with AUC0‐24/MIC ≥400 for MIC values of ≤0.5 and ≤1 mg/L, respectively. Vancomycin regimens of 10 and 15 mg/kg every 6 hours achieved a Cmin of 5.0‐5.9 mg/L and AUC0‐24/MIC ≥400 in >90% of the children when MIC was ≤0.5 mg/L. At a MIC of ≤1 mg/L, vancomycin at 15 mg/kg every 6 hours achieved Cmin of 9.0‐12.9 mg/L and AUC0‐24/MIC ≥400 in 2.0‐ and 1.6‐fold as many children compared to a dose of 10 mg/kg every 6 hours, respectively. Vancomycin Cmin values of 5.0‐12.9 mg/L were strongly predictive of achieving AUC0‐24/MIC ≥400, and rational dosing regimens of 10‐15 mg/kg q6h were required in paediatric patients, depending on the pathogen. [ABSTRACT FROM AUTHOR]

Invasive fungal disease ( IFD) is a significant cause of morbidity and mortality in hospitalized patients. To maximize the efficacy of voriconazole treatment, the study established the relationship between voriconazole pharmacokinetic/pharmacodynamic ( PK/ PD) and probability of response and optimized voriconazole dosage regimen in patients with IFD based on Monte Carlo simulation. Forty-four patients proven with IFD were involved in this study. Among them, the overall cure rate was 75% (33/44) and there was a significant difference between Cmin/ MIC values in patients with lack of response ( n = 11) and those with successful response ( n = 33) (mean value: 1.91 vs. 11.33; P < 0.05). Logistic regression model showed a high correlation between voriconazole Cmin/ MIC ratio and clinical response ( P = 0.044, OR = 1.349). According to Monte Carlo simulation results under different voriconazole dosing regimens, we could draw a conclusion that 200 mg voriconazole administered intravenously or orally twice daily for Candida infections and 300 mg administered orally or with 200 mg administered intravenously twice daily for Aspergillus infections were rational, which could achieve a value of the cumulative fraction of response >90%. This study built the relationship between voriconazole PK/ PD and clinical response and obtained the reasonable empirical dosage regimen, which can be used to customize individual dosage regimen and improve the efficacy of voriconazole treatment. [ABSTRACT FROM AUTHOR]

Study Objectives To assess the pharmacokinetic and pharmacodynamic ( PK/ PD) properties of voriconazole and to investigate the relationship between PK/ PD parameters and the efficacy of a fixed-dose oral regimen in the treatment of invasive fungal infections ( IFIs). Design Prospective and observational PK/ PD study. Setting A university-affiliated medical center. Patients Fifteen hospitalized patients with proven IFIs who were treated with oral voriconazole for at least 2 weeks. Methods We investigated the PK/ PD properties of voriconazole using a noncompartmental analysis in 15 patients. Results Marked interpatient variation in voriconazole pharmacokinetic properties was noted including peak plasma concentrations (median 2.31 mg/L, range 1.06-4.01 mg/L), 12-hour area under the plasma concentration-time curve ( AUCτ) (median 21.18 hr mg/L, range 7.71-42.07 hr mg/L), ratio of the unbound drug AUC over 24 hours ( fAUC24) divided by the minimum inhibitory concentration ( fAUC24: MIC; median 62.61, range 6.48-415.30), and the free trough plasma concentration (Cmin) divided by the MIC ( fCmin: MIC; median 1.81, range 0.46-15.52). There was a good correlation between voriconazole Cmin and AUCτ ( R2 = 0.805). Voriconazole therapy was effective in 66.7% of patients (10/15). No significant difference was observed with regard to successful clinical response between the patients with a fAUC24: MIC and fCmin: MIC values higher than 25 and higher than 1 (10/12 vs 10/13, respectively; χ2 = 1.61, p=0.688). Conclusion There is substantial interpatient variability in the PK/ PD properties of voriconazole. fAUC24: MIC values higher than 25 and fCmin: MIC values higher than 1 may predict clinical response in patients with IFIs. Designing an optimal dosage regimen based on individual PK/ PD properties will improve the efficacy in patients with IFIs. [ABSTRACT FROM AUTHOR]