Plasma and intraprostatic concentrations of ertapenem following preoperative single dose administration: a single-centre prospective experience and clinical implications-the ERTAPRO study.

The incidence of urinary tract infections caused by extended-spectrum ß-lactamase (ESBL)-producing pathogens is increasing. These infections are associated with a long hospital stay in patients undergoing urological procedures. We aimed to demonstrate that significant intraprostatic diffusion of ertapenem is achieved after a single preoperative administration. A referred sample of 19 patients requiring surgery for benign prostatic hyperplasia was prospectively included. Patients received a 1 g intravenous (i.v.) dose of ertapenem 1 h (n = 10, group A) or 12 h (n = 9, group B) before blood and prostatic samples were collected. Plasma and intraprostatic concentrations of ertapenem were measured using LC-MS/MS. Intraprostatic concentrations were considered satisfactory when higher than the MIC90 value of urinary-targeted pathogens perioperatively and for 40% of the dosing interval. The Wilcoxon test and a pharmacokinetic predictive model were used. Median plasma concentrations of ertapenem were 144.3 mg/L (95% CI 126.5-157.9) in group A and 30.7 mg/L (95% CI 22.9-36.4) in group B (P < 0.001); median intraprostatic concentrations were 16.6 mg/L (95% CI 13.3-31.4 mg/L) and 4.2 mg/L (95% CI 3.1-4.9 mg/L), respectively (P < 0.001), which were above the MIC90 values of bacteria, including ESBL-producers, during surgery and for 40% of the dosing interval. The plasma-to-prostate concentration ratio was not significantly different between groups (P = 0.97). Single-dose i.v. ertapenem reached satisfactory intraprostatic concentrations, suggesting that it could be a relevant prophylactic strategy for carriers of ESBL-producing bacteria undergoing prostatic procedures, which needs to be confirmed by further prospective trials.

Physicochemical and microbiological stability of azathioprine in InOrpha suspending agent studied under various conditions.

Azathioprine is an antineoplastic antimetabolite drug currently used as an immunosuppressive agent after organ transplantation and for several dysimmunitary diseases. The usual daily dose ranges from 1 to 5 mg/kg orally. Azathioprine is marketed in France under the trade name Imurel in tablet form for oral administration that contains either 25 mg or 50 mg of the active ingredient. This Galenic formulation is not suitable for pediatric use and often requires a grinding operation or a dose fractionation to facilitate administration. In addition to a potential risk of imprecision in the administered dose, tablet grinding might unnecessarily expose nurses and families to a toxic compound. To overcome this problem, the objective of this study was to develop and evaluate the physicochemical and microbiological stabilities of azathioprine in a sugar-free, alcohol-free, and paraben-free InOrpha suspending agent. The studied samples were formulated into a 10-mg/mL suspension and stored in 24 plastic bottles of 60 mL at two different temperature conditions (between 2 degrees C to 8 degrees C and room temperature). Two series of 12 samples were tested for physicochemical stability using high-performance liquid chromatography as well as for a microbiological status for 35 days (daily opening of the bottles from day 0 of compounding) and for 56 days, upon daily flask opening (first opening at day 28 from compounding and daily opening for 28 consecutive days). The high-performance liquid chromatography method developed is linear, accurate, precise, and robust. In addition, a forced degradation study validated the selectivity and the specificity requirements of the method validated as stability indicating. At room temperature storage, high-performance liquid chromatography analysis showed that tested samples had concentrations ranging from 90% to 110% of the initial concentration throughout the course of the study. Microbiological status remained stable during the 56 days of investigation. Based on the data collected, the study led to the development of a new Galenic formulation of azathioprine that is suitable for pediatric use and can be safely stored at room temperature for 28 days (before and after opening for a maximum of 56 consecutive days).

Routine application of Raman spectroscopy in the quality control of hospital compounded ganciclovir.

This study compares the performance of a reference method of HPLC to Raman spectroscopy (RS) for the analytical quality control (AQC) of therapeutic objects. We assessed a model consisting of a widely used antiviral drug, i.e., ganciclovir, which was compounded in a medical device and then transferred in a vacuum glass vial prior to analyses. As the aim of the alternative RS method is to replace the destructive, time-consuming HPLC method, requiring sample preparation, it needs to be demonstrated that RS performs at least as good as the HPLC method. Therefore, the two methods were validated by calculating the accuracy profile and provided excellent results for the analytical validation key criteria, i.e., trueness, precision and accuracy, ranging from 0.8 to 10mg/mL. The Spearman and Kendall correlation tests (p-value<1.10-15) and the statistical studies performed on the graphs confirm a strong correlation in the results between RS and the standard HPLC under the experimental conditions. These results confirmed the potential of this option for future applications, owing to its analytical and practical quality and its contributions to the safety of the medication circuit. This method also greatly contributes to the protection of caregivers and their working environment.

The contribution of Raman spectroscopy to the analytical quality control of cytotoxic drugs in a hospital environment: eliminating the exposure risks for staff members and their work environment.

The purpose of the study was to perform a comparative analysis of the technical performance, respective costs and environmental effect of two invasive analytical methods (HPLC and UV/visible-FTIR) as compared to a new non-invasive analytical technique (Raman spectroscopy). Three pharmacotherapeutic models were used to compare the analytical performances of the three analytical techniques. Statistical inter-method correlation analysis was performed using non-parametric correlation rank tests. The study's economic component combined calculations relative to the depreciation of the equipment and the estimated cost of an AQC unit of work. In any case, analytical validation parameters of the three techniques were satisfactory, and strong correlations between the two spectroscopic techniques vs. HPLC were found. In addition, Raman spectroscopy was found to be superior as compared to the other techniques for numerous key criteria including a complete safety for operators and their occupational environment, a non-invasive procedure, no need for consumables, and a low operating cost. Finally, Raman spectroscopy appears superior for technical, economic and environmental objectives, as compared with the other invasive analytical methods.

Comparison of Raman spectroscopy vs. high performance liquid chromatography for quality control of complex therapeutic objects: model of elastomeric portable pumps filled with a fluorouracil solution.

This study compares the performance of a reference method of HPLC to Raman spectroscopy (RS) for the analytical quality control (AQC) of complex therapeutic objects. We assessed a model consisting of a widely used anticancer drug, i.e., 5-fluorouracil, which was compounded in a complex medical device, i.e., an elastomeric portable infusion pump. In view of the main objective, the two methods provided excellent results for the analytical validation key criteria, i.e., trueness, precision and accuracy, ranging from 7.5 to 50mg/mL and in either isotonic sodium or 5% dextrose. The Spearman and Kendall correlation tests (p-value<1×10(-15)) and the statistical studies performed on the graphs confirm a strong correlation in the results between RS and the standard HPLC under the experimental conditions. The selection of a spectral interval between 700 and 1400cm(-1) for both the characterization and quantification by RS was the result of a gradual process optimization, combining matrix and packaging responses. In this new application, we demonstrate at least eight benefits of RS: (a) operator safety, (b) elimination of disposables, (c) elimination of analysis waste, which contributes to the protection of the environment, (d) a fast analytical response of less than 2min, (e) the ability to identify the solubilizing phase, (f) reduction of the risk of errors because no intrusion or dilution are needed, (g) negligible maintenance costs and (h) a reduction in the budget dedicated to technician training. Overall, we indicate the potential of non-intrusive AQC performed by RS, especially when the analysis is not possible using the usual techniques, and the technique's high potential as a contributor to the safety of medication.

Liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of the tyrosine kinase inhibitor, midostaurin, in plasma from patients with advanced systemic mastocytosis.

We developed and validated quantitative bioanalytical liquid chromatography-tandem mass spectrometry assay for the protein kinase inhibitor, midostaurin. Plasma samples were pre-treated using a protein precipitation with methanol containing midostaurin-d5 as an internal standard. After centrifugation, 5µL of the supernatant was injected into the chromatographic system. The system consisted of a 3.5µm particle bonded octadecyl silica column, with gradient elution using a mixture of 0.1% (v/v) formic acid in acetonitrile and 10mM ammonium formate in water with 0.1% formic acid. The analyte was quantified using the selected reaction-monitoring mode of a triple quadrupole mass spectrometer equipped with a heated electrospray interface. The assay was validated in a 75-2500ng/mL calibration range. For quality control, within-day and between-day precisions were 1.2-2.8%, and 1.2-6.9%, respectively. The ß-expectation tolerance limit (accuracy) met the limits of acceptance ±15% (±20% for the LLQ). The drug was sufficiently stable under all relevant analytical conditions. The assay has successfully been used to assess drug levels for therapeutic drug monitoring in patients presenting advanced systemic mastocytosis and treated with the promising midostaurin.

Physicochemical and microbiological stabilities of hydrocortisone in InOrpha suspending agent studied under various conditions.

Hydrocortisone is principally used as replacement therapy in adrenocortical deficiency states. In pediatric practice, posology ranges from 10 to 20 mg/m2 per day, divided in three doses, for the purpose of mimicking the nycthemeral cycle. Hydrocortisone is marketed in France in tablet form that contains 10 mg of the active ingredient. This galenic formulation is not suitable for pediatric use, and often requires a grinding operation or a dose fractionation to facilitate administration. To overcome this difficulty, the objective of this study was to develop and evaluate the physicochemical and microbiological stabilities of hydrocortisone in a sugar-free, alcohol-free, and paraben-free InOrpha suspending agent. The studied samples were formulated into a 2-mg/mL suspension and stored in glass bottles at two temperature conditions, between 2 degrees C to 8 degrees C and at room temperature). Two series of twelve samples were tested for physicochemical stability using high-performance liquid chromatography as well as for a microbiological status for 28 days (daily opening of the bottles from day 0 of compounding) and for 56 days (first opening at day 28 from compounding and daily opening for 28 consecutive days). The high-performance liquid chromatography method developed is linear, accurate, precise, and robust. On the other hand, a forced degradation study has demonstrated the selectivity and specificity of the method validated as stability indicating. In both storage conditions, high-performance liquid chromatography analysis showed that tested samples had concentrations ranging within 90% to 110% of the initial concentration for 28 consecutive days upon daily bottle opening and, for a maximum of 42 days with a first opening at day 28 from the compounding time. Microbiological status remained stable throughout the course of the study. Based on the data collected, the study led to the development of a new galenic formulation of hydrocortisone suitable for pediatric use which can be safely stored under refrigerated conditions or at room temperature for a maximum of 42 consecutive days.