A simple, sensitive, and selective high-performance liquid chromatographic method for the simultaneous determination of voriconazole and posaconazole concentrations in human plasma was developed and validated. Quantitative recovery following liquid-liquid extraction with diethyl ether was achieved. Linearity ranged from 0.10 to 20.0 g/ml for voriconazole and from 0.05 to 10.0 g/ml for posaconazole. The intra-and interday coefficients of variation were less than 8.5%, and the lower limits of quantitation were <0.05 g/ml.Based on the increasing number of immunosuppressed patients, a rising incidence of Aspergillus infections has been observed (15,18). Voriconazole (VRC) and posaconazole (PSC), two broad-spectrum triazole derivatives, are the recommended antimycotics for either the treatment or the prophylaxis of invasive Aspergillus infections (4,8). Both inhibit the cytochrome P450-dependent 14␣-lanosterol demethylase, which is responsible for the synthesis of ergosterol, a key compound in the fungal cell membrane (19). VRC shows nonlinear pharmacokinetics in adults and is metabolized in the liver by CYP2C19, CYP3A4, and CYP2C9, resulting in a high interindividual variability of plasma levels (5). In contrast, PSC underlies no phase I metabolism but inhibits CYP3A4 (21). Currently, PSC is only available as an oral solution, and resorption depends strongly on gastric pH and nutrition. In order to manage possible drug interactions, to balance interindividual pharmacokinetic variability, and to ensure an effective exposure to VRC and PSC, therapeutic drug monitoring is recommended (16).Several methods for quantitation of VRC or PSC in human plasma by high-performance liquid chromatography (HPLC) have been reported (3, 6, 7, 9-14, 17, 20). Up to now, only one HPLC assay has been published for their simultaneous determination (1). This assay uses complex compositions of extractant and eluent, as well as high volumes of eluent; requires a long period of sample preparation; and is of poor sensitivity. Therefore, the aim of this work was to develop a rapid, sensitive, and economical HPLC method for the simultaneous determination of VRC and PSC in human plasma samples.VRC was provided by Pfizer (New York, NY) and PSC by Schering-Plough (Kenilworth, NJ). The internal standard (IS) quinoxaline and bovine serum albumin (BSA) powder were obtained from Sigma-Aldrich (Steinheim, Germany). Stock solutions of VRC (50.0 g/ml) and PSC (25.0 g/ml) were prepared in methanol and were diluted for the preparation of six combined working solutions (for VRC, 0.25, 0.50, 1.0, 2.0, 5.0, and 10.0 g/ml, and for PSC, 0.125, 0.25, 5.0, 1.0, 2.5, and 5.0 g/ml) and three combined quality control (QC) samples (for VRC, 0.50, 2.0, and 5.0 g/ml, and for PSC, 0.50, 2.5, and 5.0 g/ml). The IS working solution was prepared in methanol (20.0 g/ml). Each solution was stored at Ϫ20°C. For the preparation of plasma standard samples, BSA solutions (5%, wt/vol) were spiked with VRC, PSC, and IS (0.80 g/ml) to obtain the above-mentioned concentrations.Five-hu...
In clinical trials adverse events improve after dose reduction suggesting a dose-dependent toxicity. Given dose has a direct impact on the drug serum concentration, but the latter also can be influenced by multiple factors including interaction and metabolization. To enable the investigation of concentration related effects, an easy and sensitive assay for sorafenib drug monitoring is essential. Methods:A high performance liquid chromatography (HPLC) analysis involving an extraction with diethyl ether followed by separation on a Pinnacle™ DB C18 column and quantitation by UV absorbance at 260 nm was established. Sorafenib concentrations in samples of serum and peritoneal fluid have been determined. Results:The assay was validated for serum samples and is linear over the concentration range of 100 to 5000 ng/mL with a determination coefficient of >0.999. The limit of detection is 0.25 ng/mL. The intra-and inter-day coefficients of variation were below 3.03%. Sorafenib recovery in spiked probes of peritoneal fluid was above 85 %. Sorafenib concentrations in 44 serum samples and 14 probes of peritoneal fluid have been determined with a mean of 3328 and 1380 ng/mL respectively (standard deviation 2267 and 659 ng/ml). Conclusions:A sensitive and selective HPLC method for the determination of sorafenib in human serum was developed and also verified for peritoneal fluid. This method provides a useful tool for pharmacokinetic investigations as well as for therapeutic drug monitoring of sorafenib.
For posaconazole, drug monitoring is suggested, but the relevance of timing for the determination of posaconazole concentration (PC) remains unclear. We investigated the variation of PC before and 4 and 8 h after the administration of 400 mg of posaconazole. Mean concentrations were 645, 678, and 616 ng/ml. The differences between trough and maximum concentrations were below 20% in 17 and below 30% in 20 of 25 patients. Hence, untimed posaconazole plasma concentrations give reliable information for most patients.Posaconazole was shown to be effective in preventing invasive fungal infections (4, 21). Additionally, the compound is recommended for salvage therapy of invasive fungal infections (1, 15). Low posaconazole plasma concentrations have been associated with a reduced success rate of salvage therapy (22) and an increased risk of clinical failure in the prophylactic indication (8).Remarkable interindividual variation and low or undetectable plasma concentrations in a significant number of patients have been published (6,11,17). Posaconazole has a terminal elimination half-life of 15 to 35 h (6) and is only available for oral administration. Pharmacokinetics may be altered by numerous factors (2, 7, 13), e.g., absorption is impaired by reduced gastric acidity or diarrhea and can be improved by administration together with a fat-containing meal (6,12,18).Several assays for the determination of posaconazole concentration (PC) have been published (5, 9, 19), but for adequate therapeutic drug monitoring, additional issues have to be clarified. Particularly, the time point for sampling after the administration of the drug remains an open question. In clinical practice, the trough level is most often determined in the morning. In the case of suspected toxicity or a breakthrough infection, PC might be of immediate interest, and delaying sampling can become difficult. The purpose of this study is to evaluate first the impact of timing and then the intradaily variability of posaconazole plasma concentration.This study was conducted as an open, single-center trial, in accordance with the local ethical regulations. Patients with hematological malignancies, receiving posaconazole for any indication with a dosage of 400 mg twice a day (BID), were enrolled. Other doses and intervals, particularly 200 mg three times a day (TID), have been excluded, as higher doses and longer intervals are expected to cause a more pronounced variation in daily drug concentration. The aim of the study was to investigate the magnitude of variation in posaconazole drug concentrations at steady state. Therefore, patients were not enrolled before 7 days (mean, 31 days) of posaconazole administration, and patients with severe mucositis, gastrointestinal graft-versus-host disease (GVHD), or diarrhea (more than 3 times daily) were excluded.For pharmacokinetic sampling, blood was drawn in the morning, 12 (11 to 13) h after the last evening dose and before the first daily dose (C trough [C 0h ]), both at the time of maximum expected concentration (4 h ...
In this retrospective study, analyzing blood samples from daily clinical practice of patients in various clinical settings and with different indications for antifungal therapy, concomitant medication of lorazepam was associated with decreased posaconazole concentrations. Therefore, lorazepam but not temazepam might induce posaconazole clearance by glucuronidation.
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