Pharmacokinetics of Anidulafungin in Critically Ill Intensive Care Unit Patients with Suspected or Proven Invasive Fungal Infections.

Echinocandins, such as anidulafungin, are the first-line treatment for candidemia or invasive candidiasis in critically ill patients. There are conflicting data on the pharmacokinetic properties of anidulafungin in intensive care unit (ICU) patients. Adult ICU patients (from 3 hospitals) receiving anidulafungin for suspected or proven fungal infections were included in the present study. Patients were considered evaluable if a pharmacokinetic curve for day 3 could be completed. Twenty-three of 36 patients (7 female and 16 male) were evaluable. The median (range) age and body weight were 66 (28 to 88) years and 76 (50 to 115) kg, respectively. Pharmacokinetic sampling on day 3 (n = 23) resulted in a median anidulafungin area under the concentration-time curve from 0 to 24 h (AUC0-24) of 72.1 (interquartile range [IQR], 61.3 to 94.0) mg · h · liter-1, a median daily trough concentration (C24) of 2.2 (IQR, 1.9 to 2.9) mg/liter, a median maximum concentration of drug in serum (Cmax) of 5.3 (IQR, 4.1 to 6.0) mg/liter, a median volume of distribution (V) of 46.0 (IQR, 32.2 to 60.2) liters, and a median clearance (CL) of 1.4 (IQR, 1.1 to 1.6) liters · h-1 Pharmacokinetic sampling on day 7 (n = 13) resulted in a median AUC0-24 of 82.7 (IQR, 73.0 to 129.5) mg · h · liter-1, a median minimum concentration of drug in serum (Cmin) of 2.8 (IQR, 2.2 to 4.2) mg/liter, a median Cmax of 5.9 (IQR, 4.6 to 8.0) mg/liter, a median V of 39.7 (IQR, 32.2 to 54.4) liters, and a median CL of 1.2 (IQR, 0.8 to 1.4) liters · h-1 The geometric mean ratio for the AUCday7/AUCday3 term was 1.13 (90% confidence interval [CI], 1.03 to 1.25). The exposure in the ICU patient population was in accordance with previous reports on anidulafungin pharmacokinetics in ICU patients but was lower than that for healthy volunteers or other patient populations. Larger cohorts of patients or pooled data analyses are necessary to retrieve relevant covariates. (This study has been registered at ClinicalTrials.gov under identifier NCT01438216.).

A validated HPLC-MS/MS method for simultaneously analyzing curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetra-hydrocurcumin and piperine in human plasma, urine or feces.

Background: The spice curcumin is supposed to have many different beneficial health effects. To understand the complete pharmacokinetics of curcumin we need an analytical method to determine curcumin and its metabolites in human plasma, urine or feces. We have developed an HPLC-MS/MS method for the simultaneous analysis of curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and piperine in human plasma, urine or feces. Methods: Sample pretreatment involved a simple liquid-liquid extraction with tert-butyl methyl ether. Conjugated curcumin and analogs can be measured after enzymatic hydrolysis. Reversed-phase chromatography with a linear gradient of 50-95% methanol in 0.1% formic acid was used. Total run time is 15 min. The method was validated with regards to stability, specificity, sensitivity, linearity, accuracy, repeatability and reproducibility. The applicability of the method was tested using actual patients samples. Results: The LLOQ in plasma, urine and feces for curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and piperine ranged from 1 to 5 nM. Whereas all compounds could be quantified on a linear range between 2 and 400 nM. Plasma and feces recovery of curcumin was 97.1 ± 3.7% and 99.4 ± 16.2%, whereas urine showed a recovery of 57.1 ± 9.3%. All compounds had acceptable in-between day or between day variability in the different matrixes. Conclusion: A HPLC-MS/MS method was developed and validated for the simultaneous quantification of curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and piperine in human plasma, urine or feces. This method will aid in critically verifying the pharmacokinetics of curcumin made by supplement manufacturers and help us to provide insight in the claimed bioavailability of curcumin supplements.

Analysis of cyclosporin A, tacrolimus, sirolimus, and everolimus in dried blood spot samples using liquid chromatography tandem mass spectrometry.

In the last few years, an increasing number of dried blood spot (DBS) sampling assays have been developed. With this increase, more insight is gained in the factors that possibly influence the performance of DBS assays. We have developed an assay for four commonly used immunosuppressants; some of them are possibly concomitantly prescribed: cyclosporin A (CsA), tacrolimus (TcR), sirolimus (SiR), and everolimus (EvE). Chromatographic separation from possible ion suppression was obtained within the total runtime of 4.2 min. Trifluoroacetic acid and ammonium acetate were used as mobile phase additives. The linearity ranged from 23.6 to 787, 1.14 to 30.3, 1.34 to 35.8, and 1.26 to 33.7 µg/L, for CsA, TcR, SiR, and EvE, respectively. Between- and within-run accuracy and precision were all within 15 % and extensive validation for DBS samples, such as hematocrit, blood spot volume, and spot punch location was performed. None of these factors were found to be of influence on the performance of the DBS assay.

Potential drug interactions in cancer therapy: a prevalence study using an advanced screening method.

BACKGROUND: In cancer patients, drug interactions may intensify adverse events or reduce antitumour effects. We assessed the prevalence of potential drug interactions (PDIs) among ambulatory cancer patients on i.v. treatment using an advanced screening method. PATIENTS AND METHODS: Data on drugs used for comorbidities, anticancer agents, over-the-counter (OTC) drugs, and comorbidities were collected by means of a structured interview among the patients and review of medical charts. PDIs were identified using electronic (Drug Interaction Facts software, version 4.0) and manual screening methods (peer-reviewed reports). RESULTS: In this study, 278 patients were enrolled. We identified 348 PDIs. Of all patients, 161 (58%) had at least one PDI. Of all PDIs, 34% was classified as major and 60% as moderate. Coumarins, quinolones, antiepileptics, and hydrochlorothiazide were frequently part of a PDI. Interactions that potentially cause QT interval prolongation, gastrointestinal toxicity, and central nervous system depression were also common. In multivariate analysis, an increasing number of drugs [odds ratio (OR) = 1.4, confidence interval (CI) 1.23-1.52; P < 0.001] and the use of an OTC drug (OR = 0.56, CI 0.32-0.97; P = 0.045) were risk factors. CONCLUSIONS: PDIs are common in patients treated for an (haemato-) oncological disease. Screening for potential interactions should take place routinely before administering chemotherapy.

Correction to: Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization.

In the original publication of the article, the second author name has been misspelled.

Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies: a phase I exposure escalation study.

BACKGROUND: (Pre)clinical evidence is accumulating that intermittent exposure to increased doses of protein kinase inhibitors may improve their treatment benefit. In this phase I trial, the safety of high-dose, pulsatile sorafenib was studied. PATIENTS AND METHODS: High-dose sorafenib was administered once weekly in exposure escalation cohorts according to a 3 + 3 design. Drug monitoring was performed in weeks 1-3 and doses were adjusted to achieve a predefined target plasma area under the curve (AUC)(0-12 h). The effect of low gastric pH on improving sorafenib exposure was investigated by intake of the acidic beverage cola. RESULTS: Seventeen patients with advanced malignancies without standard treatment options were included. Once weekly, high-dose sorafenib exposure was escalated up to a target AUC(0-12 h) of 125-150 mg/L/h, achieving a twofold higher Cmax compared to standard continuous dosing. Dose-limiting toxicity was observed in three patients: grade 3 duodenal perforation (2800 mg sorafenib), grade 5 multiorgan failure (2800 mg sorafenib) and grade 5 biliary tract perforation (3600 mg sorafenib). The mean difference between observed and target AUC(0-12 h) was 45% (SD ± 56%) in week 1 using a fixed starting dose of sorafenib compared to 2% (SD ± 32%) in week 3 as a result of drug monitoring (P = 0.06). Dissolving sorafenib in cola, instead of water, did not improve sorafenib exposure. Clinical benefit with stable disease as the best response was observed in two patients. CONCLUSION: Treatment with high-dose, once weekly sorafenib administration resulted in dose-limiting toxicity precluding dose escalation above the exposure cohort of 125-150 mg/L/h. Drug monitoring was a successful strategy to pursue a target exposure.

Continuous infusion of lorazepam versus medazolam in patients in the intensive care unit: sedation with lorazepam is easier to manage and is more cost-effective.

OBJECTIVE: To evaluate the effectiveness of lorazepam and midazolam for long-term sedation of critically ill, mechanically ventilated patients. DESIGN: Double-blind, randomized, controlled study. SETTING: Medical intensive care unit in a university teaching hospital. PATIENTS: Sixty-four evaluable adult patients admitted to the intensive care department requiring mechanical ventilation for >3 days. INTERVENTIONS: Patients were randomized to receive blinded solutions of either lorazepam or midazolam by continuous infusion. The lowest dose that achieved an adequate sedation was infused. The maximum dose allowed for each drug was 60 mg/hr for midazolam and 4 mg/hr for lorazepam. Sedation was assessed initially and at least every 8 hrs thereafter on a seven-point scale if the sedation was adequate and every 2 hrs if it was not. MEASUREMENTS AND MAIN RESULTS: Measurements included the score on the sedation scale, the time between determination of the desired level of sedation and the achievement of that level, and plasma concentrations. It is significantly easier to reach a desired level of sedation with lorazepam than with midazolam. No difference in recovery was found in the 24 hrs after discontinuation of therapy. The fact that there are many factors influencing midazolam pharmacokinetics may explain the more difficult management of desired sedation levels. The equipotent dose of 10 mg of midazolam proved to be 0.7 mg of lorazepam in long-term sedation. The average cost for therapy with midazolam was approximately ten times more than that with lorazepam. CONCLUSIONS: Lorazepam is a useful alternative to midazolam for the long-term sedation of patients in the medical intensive care unit and provides easier management of the sedation level. Sedation with lorazepam offers a significant cost-savings.

Reversed-phase ion-pair HPLC method for the direct analysis of 1-OH midazolam glucuronide in human serum.

In recent years, it has become clear that the presence of high concentrations of 1-OH midazolam glucuronide is probably the cause of unexplained prolonged midazolam comas in patients with poor renal function. Until recently, only indirect methods for the analysis of this glucuronide were known, which had several disadvantages, such as a long analysis period (>6 hours). This article describes the validation of a method for the direct analysis of this compound in human serum, using reversed-phase ion-pair high-performance liquid chromatography (HPLC) in combination with solid phase extraction. The intraday and interday coefficients of variation have values below 6% for different possible serum concentrations. The limit of quantification (0.1 mg/L) is much lower than concentrations found in patients with a coma caused by the accumulation of 1-OH midazolam glucuronide. Recovery of 1-OH midazolam glucuronide is almost 100% at three different serum concentrations. Linearity is confirmed for normal serum levels (<1 mg/L) and for serum levels that might occur in patients with impaired renal function (<20 mg/L). Detection is performed at 254 nm with a diode array detector, which can also be used to check the peak purity in case of unexpected impurities.