Loretta Franceschi

Therapeutic Drug Monitoring of Linezolid: a Retrospective Monocentric Analysis

ABSTRACT The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [Cmin] and peak [Cmax] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC24]). The final database included 280 Cmin and 223 Cmax measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously (n = 58) or orally (n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for Cmin, 14.70 mg/liter [10.57 to 19.64] for Cmax, and 196.08 mg·h/liter [144.02 to 312.10 mg·h/liter] for estimated AUC24). Linezolid Cmin was linearly correlated with estimated AUC24 (r2 = 0.85). Optimal pharmacodynamic target attainment (defined as Cmin of ≥2 mg/liter and/or AUC24/MIC90 ratio of >80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as Cmin of ≥10 mg/liter and/or AUC24 of ≥400 mg·h/liter) was documented in about 12% of cases. A significantly higher proportion of cases with potential overexposure received cotreatment with omeprazole, amiodarone, or amlodipine. Our study suggests that the application of TDM might be especially worthwhile in about 30% of cases with the intent of avoiding either the risk of dose-dependent toxicity or that of treatment failure.

Tamoxifen and its main metabolites serum and tissue concentrations in breast cancer women.

Because of a possible relationship between tamoxifen (T) concentrations and clinical effects, we initiated a preliminary investigation on serum and tissue concentrations of T and its main active metabolites, and 4-hydroxytamoxifen, in women with positive breast cancer estrogen receptor. One hundred forty-eight patients were studied: 80 were admitted for monitoring of therapeutic serum drug concentrations, 22 had tissue concentrations taken at surgery, and 46 patients had uterine mucosa levels measured at diagnostic hysteroscopy. Steady-state serum concentrations were reached after 1 month of continuous treatment, with desmethyltamoxifen being the highest represented derivative from the third week onward. There was no relationship between dose (in mg/kg body weight) and steady-state serum concentrations during therapeutic drug monitoring of patients. The highest tissue concentrations were observed in breast lymph-nodes, cancer tissue, and uterine mucosa. On the basis of these data, we speculate that T and its active metabolites may exert both a defensive role (ie, an obstacle to the diffusion of malignant cells through the local lymphatic system) and a harmful one (induction of uterine malignancies).

Antifungal Prophylaxis with Posaconazole in Patients with Acute Myeloid Leukemia: Dose Intensification Coupled with Avoidance of Proton Pump Inhibitors Is Beneficial in Shortening Time to Effective Concentrations

ABSTRACT This study aimed to assess the influence of dose frequency and the presence or absence of cotreatment with proton pump inhibitors (PPIs) on the time to a target trough concentration (Cmin) of >700 ng/ml with posaconazole in the first 8 days of antifungal prophylaxis in hematological patients. This was a retrospective, observational study performed with 42 adult patients with acute myeloid leukemia who underwent posaconazole prophylaxis with 200 mg every 8 h (q8h) or 200 mg q6h after receiving induction chemotherapy and who had at least three subsequent therapeutic drug monitoring assessments during the first 8 days of treatment. The cohort was split into four groups (group 1, 200 mg q8h without PPI; group 2, 200 mg q8h with PPI; group 3, 200 mg q6h without PPI; group 4, 200 mg q6h with PPI). Rapid attainment of the target Cmin was obtained only in group 3 (P < 0.01) (median Cmin on day 4 of 935.5 ng/ml [interquartile range, 760.0 to 1,270.0 ng/ml] in group 3, versus 567.0 ng/ml [346 to 906 ng/ml] in group 1, 420.0 ng/ml [326.2 to 527.2 ng/ml] in group 2, and 514.0 ng/ml [403.7 to 564.7 ng/ml] in group 4). A linear accumulation of posaconazole over time was observed among patients in groups 1 and 3, regardless of the total daily dosage, differently from what occurred among those receiving PPI cotreatment (groups 2 and 4). Dose intensification (200 mg q6h) coupled with avoidance of PPI coadministration may represent a very powerful strategy to rapidly achieve effective concentrations with posaconazole in neutropenic hematological patients.

Pharmacokinetic Interaction Between Everolimus and Antifungal Triazoles in a Liver Transplant Patient

Objective: TO describe the management of a pharmacokinetic interaction between azole antifungals (fluconazole and voriconazole) and everolimus in a patient who underwent an orthotopic liver transplant. Case Summary: A 65-year-old male who received an orthotopic liver transplant experienced an iatrogenic retroperitoneal duodenal perforation on postoperative day 55. His condition was subsequently complicated by severe sepsis and acute renal failure. Intravenous fluconazole 400 mg, followed by 100 mg every 24 hours according to impaired renal function, was immediately started; to avoid further nephrotoxicity, immunosuppressant therapy was switched from cyclosporine plus mycophenolate mofetil to oral everolimus 0.75 mg every 12 hours. Satisfactory steady-state minimum concentration (Cmin) of everolimus was achieved (∼5 ng/mL). On day 72 posttransplant, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg every 12 hours on the first day, followed by 200 mg every 12 hours; to prevent drug toxicity, the everolimus dosage was promptly lowered to 0.25 mg every 24 hours. At that time, the everolimus Cmin averaged approximately 3 ng/mL. The concentration/dose ratio of everolimus (ie, Cmin reached at steady-state for each milligram per kilogram of drug administered) was markedly lower during fluconazole versus voriconazole cotreatment (mean ± SD, 3.49 ± 0.29 vs 11.05 ± 0.81 ng/mL per mg/kg/daily; p < 0.001). Despite intensive care, the patients condition continued to deteriorate and he died on day 84 posttransplant Discussion: Both azole antifungals were considered probable causative agents of an interaction with everolimus according to the Drug Interaction Probability Scale. The Interaction is due to the inhibition of CYP3A4–mediated everolimus clearance. Of note, prompt reduction of the everolimus dosage since the first azole coadministration, coupled with intensive therapeutic drug monitoring, represented a useful strategy to prevent drug overexposure. Conclusions: Our data suggest that during everolimus-azole cotreatment, a dose reduction of everolimus is needed to avoid overexposure. According to the different inhibitory potency of CYP3A4 activity, the reduction should be lower during fluconazole than during voriconazole cotreatment.

Stability of generic meropenem solutions for administration by continuous infusion at normal and elevated temperatures.

Abstract: Administration by continuous infusion may represent an effective tool for the treatment of multidrug-resistant gram-negative related infections with meropenem. Currently, no data on chemical stability of generic bioequivalent versions of meropenem over time are available. Triplicate samples of 5 mg/mL solutions of a generic meropenem formulation, Hospira, were evaluated for chemical stability at increasing temperatures (25°C, 30°C, 35°C, and 40°C) by means of a high-performance liquid chromatography technique over 4 separate days. Degradation of generic meropenem was both time and temperature dependent, and the aqueous solutions were stable for up to 8 hours in the temperature range between 25°C and 35°C, and for up to 5 hours at 40°C. Continuous infusion of generic meropenem Hospira may be applied in clinical settings with ambient temperature below 35°C, provided that the 5 mg/mL aqueous solution is reconstituted at most after 6–8 hours.

A simple method to monitor serum concentrations of fluoxetine and its major metabolite for pharmacokinetic studies

A rapid, selective and sensitive isocratic reversed-phase HPLC assay coupled with MS/MS detection for simultaneous quantification of fluoxetine and its major active metabolite in serum samples has been developed. Analytes were extracted with a simple three step liquid-liquid procedure and chromatographic separation was achieved on a C18 column. Because of its sensitivity, this HPLC/MS/MS method is suitable both for routine therapeutic drug monitoring and for pharmacokinetic studies, due to its low limits of quantification.

Development and Validation of a Liquid Chromatography–Tandem Mass Spectrometry Method for the Determination of Voriconazole and Posaconazole in Serum Samples

Posaconazole and voriconazole, two triazole antifungal agents, are used for the prophylaxis and treatment of invasive mycoses in patients with acute myeloid leukaemia and/or immunocompromised. Inter- and intra-patient variability of pharmacokinetics, drug-drug interactions, serum concentration related toxicity and success of therapy has stressed the need of frequently therapeutic drug monitoring of both drugs. Therefore, a rapid, selective and sensitive isocratic reversed-phase HPLC assay coupled with Mass spectrometry detection for quantification of posaconazole and voriconazole in serum samples has been developed. Analytes were extracted on solid-phase cartridges (SPE) and chromatographic separation was achieved on a C8 column and detected by mass spectrometry in positive ion mode with the select ion monitoring (SIM) mode. The total chromatographic running time was 6 minutes. The method was successfully used for a pharmacokinetic study but, thanks to its rapidity and selectivity, it’s also suitable for routinarly therapeutic drug monitoring (TDM).

The effects of oral smokeless tobacco administration on endurance performance

Background Smokeless tobacco is widely used by athletes to enhance performance. Nicotine is a central nervous system stimulant and acts on cardiocirculatory and metabolic systems, involving tissue blood flow and circulatory vasoreactivity. The aim of this study was to investigate the effects of the oral smokeless tobacco (Swedish snus (SS)) on the perception of fatigue and time to exhaustion (TTE) during moderate-intensity aerobic exercise. Methods Fourteen healthy non-tobacco male users were recruited for a double-blind, controlled crossover design (SS vs. snus placebo (SP)). Subjects were tested for 3 sessions: experimental session 1 (Exp1) consisted of an incremental test to determine the maximal aerobic power output (Wmax), whereas Exp2 and Exp3 consisted of exercising at 65%Wmax until exhaustion in SS or SP conditions. During Exp2 and Exp3, muscle and cerebral oxygenation was assessed by means of near-infrared spectroscopy, and the rating of perceived exertion (RPE) was recorded. Results Comparing SS with SP tests, significant differences (p < 0.05) were found in the values of cerebral (~3%) and muscular tissues oxygenation (~4%) in the first 30 min of exercise. The RPE values were not significantly different between the 2 conditions (SS vs. SP). No significant difference was found in TTE (SS: 54.25 ± 21.84 min; SP: 50.01 ± 17.03 min). Conclusion This study showed that muscular and cerebral oxygenation increased significantly with snus administration during an endurance exercise until exhaustion, but this did not affect fatigue perception and TTE. The results showed that snus could not be considered an ergogenic substance in non-tobacco users.

Fluoxetine Disposition in Patients with Chronic Hepatitis C Treated with Interferon-α

Background and ObjectivesCombination therapy with interferon-α and ribavirin is considered the treatment of choice for chronic hepatitis C. However, interferon-α may induce severe depression. It has been suggested that interferon-α is able to modify cytochrome P450 (CYP) 1A2 and 2D6 activity. We therefore decided to study the effects of the interferon-α-2b pegylated derivative on fluoxetine disposition in patients receiving combination chemotherapy for chronic hepatitis C.MethodsAfter approval by the institutional ethics committee, 20 adult patients with chronic hepatitis C, but with no history of other liver diseases, were prospectively admitted to the study, which included phenotyping by means of a dextromethorphan test and evaluation of fluoxetine and norfluoxetine pharmacokinetic parameters (the area under the serum concentration-time curve, maximum serum concentration, time to reach the maximum serum concentration and terminal elimination half-life) before and after 2 months of continuous peginterferon-α-2b therapy.ResultsThe only statistically significant difference we observed was a significant reduction in the terminal elimination half-life of fluoxetine (from 47.30 to 33.23 hours; p =0.014) after peginterferon-α-2b treatment.ConclusionThese data suggest that interferon-α may induce, rather than inhibit, the biotransformation of fluoxetine.