Jiao Xie

Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections

The aim of this study was to determine an optimum voriconazole target concentration, to study the influence of CYP2C19 gene status on metabolism of voriconazole and to identify a dose-adjustment strategy for voriconazole according to CYP2C19 polymorphism in patients with invasive fungal infections. A total of 328 voriconazole trough plasma concentrations (C(min)) were collected and monitored from 144 patients. Information on efficacy and safety was obtained. Voriconazole therapy was effective in 81.9% of patients (118/144), and 12.5% (18/144) exhibited signs of hepatotoxicity. The relationships between voriconazole C(min) and clinical response and hepatotoxicity were explored using logistic regression, and a target clinical C(min) range of 1.5-4 mg/L was identified. Values of voriconazole C(min) and the ratio of C(min) to concentration of voriconazole-N-oxide (C(min)/C(N)) of poor metabolisers (PMs) were significantly higher than extensive metabolisers and intermediate metabolisers. Model-based simulations showed that PM patients could be safely and effectively treated with 200 mg twice daily orally or intravenously, and non-PM patients with 300 mg twice daily orally or 200mg twice daily intravenously. This study highlighted that voriconazole C(min) and C(min)/C(N) are strongly influenced by CYP2C19 polymorphism, and gene-adjusted dosing is important to achieve therapeutic levels that maximise therapeutic response and minimise hepatotoxicity.

Optimal tigecycline dosage regimen is urgently needed: results from a pharmacokinetic/pharmacodynamic analysis of tigecycline by Monte Carlo simulation

BACKGROUND The number of reported cases of resistance to tigecycline is increasing. The aim of this study was to evaluate the current standard tigecycline dosage regimen from a pharmacokinetic/pharmacodynamic (PK/PD) perspective. METHODS Pharmacokinetic parameters and microbiological data were analyzed by Monte Carlo simulation in an evaluation of effectiveness. RESULTS Tigecycline exhibits excellent in vitro antimicrobial activity, however the standard tigecycline dosing regimen fails to achieve the best outcome in vivo for the common drug-resistant strains, including Acinetobacter baumannii, Enterobacter spp, and Klebsiella pneumoniae. This may result in a lack of response to tigecycline therapy or to a further increase in the resistance rate. CONCLUSIONS In the absence of new drugs on the horizon, rather than using a single fixed dosing regimen, tigecycline dosing needs to be optimized in order to achieve the desired successful clinical response and to prevent an escalation in drug resistance.

Establishment of Paclitaxel-resistant Breast Cancer Cell Line and Nude Mice Models, and Underlying Multidrug Resistance Mechanisms in Vitro and in Vivo

BACKGROUND Breast cancer is a common malignant tumor which affects health of women and multidrug resistance (MDR) is one of the main factors leading to failure of chemotherapy. This study was conducted to establish paclitaxel-resistant breast cancer cell line and nude mice models to explore underlying mechanisms of MDR. METHODS The breast cancer drug-sensitive cell line MCF-7 (MCF-7/S) was exposed in stepwise escalating paclitaxel (TAX) to induce a resistant cell line MCF-7/TAX. Cell sensitivity to drugs and growth curves were measured by MTT assay. Changes of cell morphology and ultrastructure were examined by optical and electron microscopy. The cell cycle distribution was determined by flow cytometry. Furthermore, expression of proteins related to breast cancer occurrence and MDR was tested by immunocytochemistry. In Vivo, nude mice were injected with MCF-7/S and MCF-7/TAX cells and weights and tumor sizes were observed after paclitaxel treatment. In addition, proteins involved breast cancer and MDR were detected by immunohistochemistry. RESULTS Compared to MCF-7/S, MCF-7/TAX cells had a higher resistance to paclitaxel, cross-resistance and prolonged doubling time. Moreover, MCF-7/TAX showed obvious alterations of ultrastructure. Estrogen receptor (ER) expression was low in drug resistant cells and tumors while expression of human epidermal growth factor receptor 2 (HER2) and Ki-67 was up-regulated. P-glycoprotein (P-gp), lung resistance-related protein (LRP) and glutathione-S-transferase-π (GST-π) involved in the MDR phenotype of resistant cells and tumors were all overexpressed. CONCLUSION The underlying MDR mechanism of breast cancer may involve increased expression of P-gp, LRP and GST-π.

Developments in the pharmacokinetic/pharmacodynamic index of linezolid: a step toward dose optimization using Monte Carlo simulation in critically ill patients

OBJECTIVES This study evaluated the efficacy of the pharmacokinetic/pharmacodynamic (PK/PD) index for increasing the success rate of linezolid treatment based on Monte Carlo simulation, and compared differences between the calculated PK/PD breakpoints and those defined by committee for critically ill patients with linezolid treatment. METHODS A Monte Carlo simulation involving 10000 subjects was used to analyze the pharmacokinetic parameters and microbiological data of linezolid for an effectiveness evaluation at the corresponding AUC24/MIC values (area under the serum concentration-time curve over 24h/minimum inhibitory concentration). RESULTS As the PK/PD index of linezolid increased from 80 to 120, the corresponding probability of target attainment (PTA) decreased from 99.91% to 18.97%, with a MIC of 2mg/l. Furthermore, the cumulative fraction of response (CFR) reached <90% for several pathogens at an AUC24/MIC of 100-120, revealing a relatively lower efficacy with recommended linezolid dosing. CONCLUSIONS These findings reveal that the target AUC24/MIC value of 80-120 requires further classification for more accurate assessment of the linezolid dose regimen. At a MIC of ≥2mg/l, the clinical outcome varies greatly for different AUC24/MIC values when applying the same dose of linezolid. In such cases, we suggest optimized adjustment of the linezolid dosage regimen.

Pharmacokinetic/pharmacodynamic adequacy of echinocandins against Candida spp. in intensive care unit patients and general patient populations

This study evaluated whether contemporary echinocandin regimens achieved pharmacokinetic/pharmacodynamic targets in ICU patients and general patient populations (GPPs) and assessed caspofungin (CAS) regimens in hepatic impairment (HI) patients. A Monte Carlo simulation was performed using previously published data. Recommended dosing regimens of echinocandins in ICU patients, GPPs and healthy volunteers were evaluated: 70mg loading dose then 50mg maintenance dose (70/50mg) for CAS; 100mg q24h for micafungin (MCF); and 200/100mg for anidulafungin (ANF). Moreover, CAS 70mg and 100mg q24h in GPPs, and CAS 70/50mg and 70/35mg in mild and moderate HI patients, respectively, were evaluated. Cumulative fraction of response (CFR) was calculated for each dosing regimen. For Candida albicans, CFRs for the recommended doses of CAS, MCF and ANF were 95.8%, 13.5% and 50.5% in ICU patients and 96.3%, 42.4% and 61.6% in GPPs, respectively; for Candida glabrata, CFRs were 99.4%, 90.6% and 44.6% in ICU patients and 99.5%, 97.1% and 59.8% in GPPs. For Candida parapsilosis, CFRs of echinocandins for standard regimens were <70%; only CAS 100mg q24h achieved the target CFR. CAS 70/50mg and 70/35mg in mild and moderate HI patients were appropriate. Considerable interindividual variability was observed. For C. albicans and C. glabrata, CAS is good choice both for ICU and other patient populations, but for C. parapsilosis an increased dose should be considered. For MCF and ANF, administering higher doses with longer dosing intervals achieves better target attainment and should be investigated in clinical trials.

Pharmacokinetic and Pharmacodynamic Properties of Oral Voriconazole in Patients with Invasive Fungal Infections.

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).

Quantitative analysis and pharmacokinetics study of tigecycline in human serum using a validated sensitive liquid chromatography with tandem mass spectrometry method.

Tigecycline, a novel intravenously administered glycylcycline antibiotic, currently plays a key role in the management of complicated multiorganism infections. However, current liquid chromatography with tandem mass spectrometry methods briefly describe parameters and the only reported internal standard was sometimes difficult to obtain. In our study, an updated liquid chromatography with tandem mass spectrometry method for the quantitative analysis of tigecycline in human serum was developed. Sample preparation involved precipitation with 20% trichloroacetic acid. Chromatographic separation of tigecycline and tetracycline (internal standard) was achieved on a Hypersil GOLD C18 column using gradient elution. The selected reaction monitoring transitions were performed at m/z 586.1→513.2 for tigecycline and m/z 445.1→410.2 for tetracycline. The assay was linear over the concentration range of 5-2000 ng/mL. The intra- and interday precisions at three concentration levels (10, 100, and 1600 ng/mL) were <15% and their accuracies were within the range of 95.1-106.1%. The mean recovery ranged from 94.3 to 105.6% and the matrix effect from 92.1 to 97.6%. Tigecycline was stable under all tested conditions. This validated method was successfully applied to a pharmacokinetic study in critically ill patients. The data demonstrated that our method allows quantification of tigecycline in serum in a quick and reliable manner for widespread application.

Optimization of voriconazole dosage regimen to improve the efficacy in patients with invasive fungal disease by pharmacokinetic/pharmacodynamic analysis.

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.

The Adenosine Deaminase Gene Polymorphism Is Associated with Chronic Heart Failure Risk in Chinese

Adenosine (Ado) is an important cardioprotective agent. Since endogenous Ado levels are affected by the enzyme Ado deaminase (ADA), polymorphisms within the ADA gene may exert some effect on chronic heart failure (CHF). This study applied a case-control investigation to 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls in which nine single-nucleotide polymorphisms (SNPs) of ADA were genotyped and association analyses were performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. Overall, rs452159 polymorphism in ADA gene was significantly associated with susceptibility to CHF under the dominant model (p = 0.013, OR = 1.537, 95% CI = 1.10–2.16), after adjustment for age, sex, and traditional cardiovascular risk factors. No difference in genotype distribution and allele frequency for the rs452159 according to the functional New York Heart Association class was found. Furthermore, the values of left ventricular ejection fraction, left-ventricle end-diastolic diameter or left-ventricle end-systolic diameter did not differ significantly among the different rs452159 genotype CHF patients. Although further studies with larger cohorts and other ethnicities are required to validate the conclusions, the findings of this study potentially provide novel insight into the pathogenesis of CHF.

Pharmacokinetic/pharmacodynamic evaluation of linezolid for the treatment of staphylococcal infections in critically ill patients

Several studies have demonstrated that the ideal therapeutic effect of linezolid cannot be achieved in critically ill patients with the recommended standard dosing regimen of 600 mg every 12 h (q12h). Moreover, the optimal strategy for successful treatment is still lacking. This study analysed factors influencing the efficacy of linezolid treatment and determined the target for successful treatment by logistic regression in 27 critically ill patients with staphylococcal infection who received linezolid 600 mg q12h. The results showed that only the 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) ratio was significantly associated with staphylococcal eradication. Reaching 80% bacterial eradication required an AUC24/MIC of 120.5, defining the therapeutic target. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>99.9%) for the standard dosing regimen at MIC ≤ 1 mg/L, the PTA was almost 0 at MIC = 2 mg/L, thus the dosing regimen required adjustment. In addition, if the dosing regimen was adjusted to 600 mg every 8 h or 600 mg every 6 h, the major staphylococci (except for MRSA and MSSA) exhibited a cumulative fraction of response of >80%, showing a higher treatment success. These findings indicate that a strategy of high linezolid dosage may be needed to increase the probability of successful treatment at MIC > 1 mg/L. The role of therapeutic drug monitoring should be encouraged for optimising linezolid exposure in critically ill patients.