A reference laboratory experience of clinically achievable voriconazole, posaconazole, and itraconazole concentrations within the bloodstream and cerebral spinal fluid.

Interest in antifungal therapeutic-drug monitoring has increased due to studies demonstrating associations between concentrations and outcomes. We reviewed the antifungal drug concentration database at our institution to gain a better understanding of achievable triazole drug levels. Antifungal concentrations were measured by high-performance liquid chromatography (HPLC), ultraperformance liquid chromatography and single-quadrupole mass spectrometry (UPLC/MS), or a bioassay. For this study, only confirmed human bloodstream (serum or plasma) and cerebral spinal fluid (CSF) concentrations of voriconazole, posaconazole, and itraconazole were analyzed. The largest numbers of bloodstream and CSF samples were found for voriconazole (14,370 and 173, respectively). Voriconazole bloodstream concentrations within the range of 1 to 5.5 µg/ml represented 50.6% of samples. Levels below the lower limit of quantification (0.2 µg/ml) were observed in 14.6% of samples, and 10.4% of samples had levels of ≥5.5 µg/ml. CSF voriconazole levels ranged from undetectable to 15.3 µg/ml and were <0.2 µg/ml in 11% of samples. Posaconazole bloodstream concentrations were ≥0.7 and ≥1.25 µg/ml in 41.6% and 18.9% of samples, respectively. Posaconazole was detected in only 4 of 22 CSF samples (undetectable to 0.56 µg/ml). Itraconazole levels, as measured by UPLC/MS, were ≥0.5 µg/ml in 43.3% and were undetectable in 33.9% of bloodstream samples. In contrast, when measured by a bioassay, itraconazole/hydroxyitraconazole bloodstream concentrations were ≥1.0 µg/ml in 72.9% of samples and were undetectable in 18% of samples. These results indicate that there is marked variability in bloodstream concentrations achieved with these three azoles. In addition, many levels within the bloodstream for each azole and for voriconazole and posaconazole in the CSF were undetectable or below thresholds associated with efficacy.

Pharmacokinetics of anidulafungin in pleural fluid during the treatment of a patient with Candida empyema.

Candida empyema is a serious complication of disseminated candidiasis. However, little is known about the intrapleural pharmacokinetics of echinocandins. We report the penetration of anidulafungin into the pleural fluid of a patient with Candida tropicalis empyema. The anidulafungin ratio for the area under the concentration-time curve from 0 h to the last measurement between pleural fluid and serum values was only 0.125 (12.5%), with pleural fluid concentrations ranging between 0.67 and 0.88 µg/ml.

Pharmacokinetics of liposomal amphotericin B in pleural fluid.

We report the penetration of liposomal amphotericin B into the pleural fluid of a patient with pulmonary zygomycosis and empyema. The ratio of area under the concentration-versus-time curve in pleural fluid (AUC(pleural fluid)) to that in serum (AUC(serum)) for liposomal amphotericin B over 24 h was 9.4%, with pleural fluid concentrations of 2.12 to 4.91 microg/ml. Given the relatively low level of intrapleural penetration of liposomal amphotericin B, chest tube drainage may be warranted for successful treatment of zygomycotic empyema.

Micafungin concentrations from brain tissue and pancreatic pseudocyst fluid.

We report the attainment of micafungin concentrations from brain tissue and pancreatic pseudocyst fluid from two patients with invasive candidiasis. Micafungin was present in low levels at both body sites, indicating limited penetration into central nervous system (CNS) tissue and pancreatic fluid. Further studies are needed to fully characterize its pharmacokinetics at these locations, as micafungin may potentially serve as an alternative antifungal therapy for CNS or pancreatic candidal infections for which the currently recommended first-line therapy fails.

Serial plasma voriconazole concentrations after allogeneic hematopoietic stem cell transplantation.

Plasma voriconazole concentrations vary considerably between patients receiving standard dosing, and trough voriconazole concentrations are known to affect efficacy and toxicity. Temporal variations in serial plasma voriconazole concentrations through the course of therapy in hematopoietic stem cell transplantation patients has not been carefully described. Paired voriconazole concentrations in 64 patients were studied to determine the predictability of the second concentration based on the first. The difference between the two values was < or = 5% in six patients. In 25 patients, the second concentration was higher by a median of 40%. In 33 patients, the subsequent concentration was lower by a median of 59%. For patients with an initial concentration of < 2 microg/ml, the correlation between the two values was poor (r = 0.24; P < 0.17). For those with an initial concentration of > or = 2 microg/ml, the correlation was good (r = 0.72; P < 0.0001). There was no relationship between the magnitude of the change and the time elapsing between the two measurements. Among the 43 patients who had an initial concentration of > or = 1 microg/ml, the two voriconazole measurements were strongly correlated (r = 0.66, P < 0.0001), but only 67% had a voriconazole serum concentration of > or = 1 microg/ml on the second measurement. No studied variables were reliable predictors in identifying concentrations above or below 1 or 2 microg/ml. Our data suggest that variations in voriconazole concentrations are unpredictable despite standard dosing, and the acceptability of a concentration on one occasion cannot be extrapolated to future concentrations in the same patient. This suggests that ongoing therapeutic drug monitoring and dose adjustment may be beneficial in patients requiring prolonged voriconazole therapy.

Accelerated metabolism of voriconazole and its partial reversal by cimetidine.

We report a case of accelerated metabolism of voriconazole during therapy for invasive pulmonary aspergillosis, resulting in subtherapeutic levels. Target voriconazole levels were restored with high dosages of voriconazole (up to 40 mg/kg of body weight/day) and the addition of cimetidine as a cytochrome P450 enzyme inhibitor.

Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients.

BACKGROUND: Low voriconazole levels have been associated with a higher failure rate in patients with confirmed fungal infections. METHODS: Steady-state plasma trough voriconazole levels were measured after at least 5 days of therapy in 87 patients with hematologic malignancies on 201 separate occasions (1-5 levels per patient; median, 2). Most patients (90%) had undergone allogeneic hematopoietic stem cell transplantation. The daily voriconazole dose, administered in 2 divided doses, was 200 mg (n = 4), 400 mg (n = 151), 500 mg (n = 20), 600 mg (n = 18), and 800 mg (n = 8); corresponding to 2.0-16.3 (median, 5.4) mg/kg. Plasma voriconazole levels were 0-12.5 microg/mL (median, 1.2). Voriconazole was undetectable (<0.2 mug/mL) in 15%. RESULTS: The correlation between dose and levels was weak (r = 0.14; P = .045). The median absolute daily drug dose (400 mg) was identical in groups of patients with levels of 0, 0.2 to 0.5, >0.5 to 2.0, >2.0 to 5.0, and >5.0. Whereas the daily drug dose in mg/kg was significantly higher when the levels were >5.0 microg/mL, there was no consistent relation between dose and level below that threshold. In adult patients getting standard doses of voriconazole orally, the drug levels are highly variable. Based on limited available data, between a quarter and two-thirds of these levels could potentially be associated with a lower likelihood of response or a higher likelihood of failure. CONCLUSIONS: Future voriconazole studies should incorporate prospective therapeutic drug monitoring and consideration should be given to checking levels in patients receiving the drug for confirmed, life-threatening fungal infections.

Absence of an active metabolite for the triazole antifungal pramiconazole.

Pramiconazole is an antifungal with high potential for the treatment of dermatophyte and yeast infections of the skin. It is currently not known whether pramiconazole is active alone as the parent agent or assisted by active metabolites. The in vitro metabolism as well as the metabolic stability of pramiconazole was investigated in subcellular liver fractions and isolated hepatocytes of several species. Results indicate that the metabolism of pramiconazole was slow, since the enzyme-mediated disappearance of pramiconazole was rather slow. To investigate whether pramiconazole was converted into an active metabolite in humans, serum samples from healthy volunteers receiving a daily dose of 100 or 200 mg pramiconazole for one week were assayed with an agar diffusion bioassay and liquid chromatography-tandem mass spectrometry. It was concluded that there was no active metabolite present in serum samples from healthy volunteers after oral dosing of pramiconazole.

Steady-state plasma concentrations of itraconazole after oral administration in Kemp's ridley sea turtles, Lepidochelys kempi.

Pharmacokinetic studies of antifungal agents in reptiles are uncommon. Itraconazole, which has been used prophylactically in juvenile sea turtles suffering from hypothermia (cold stunning) on a regular basis, was evaluated for steady-state plasma concentrations. Five Kemp's ridley sea turtles (Lepidochelys kempi) receiving itraconazole at several dosages in a rehabilitation program had blood collected within 24 hr to estimate dosing frequency. Subsequently, serial blood samples of Kemp's ridley sea turtles that were given itraconazole at several dosages for 30 days to treat cold stunning were collected at various intervals to evaluate itraconazole plasma concentrations. Tissue samples were collected from one Kemp's ridley that died during rehabilitation. Plasma concentrations of itraconazole (and of hydroxyitraconazole [OH-ITRA], one of its major bioactive metabolites) were determined using a modified, validated reverse-phase high-performance liquid chromatography technique. Itraconazole concentrations in tissues were determined by bioassay to be far greater than the plasma concentrations measured in any of the turtles. At a 15-mg/kg dosage, the half-life (t1/2) was 75 hr for itraconazole and 55 hr for OH-ITRA. All dosages produced adequate concentrations in some turtles, but consistent therapeutic concentrations were produced only at 15 mg/kg q72hr and 5 mg/kg s.i.d., with the latter producing the highest plasma concentrations.

Development and validation of a high-performance liquid chromatography assay for voriconazole.

An analytical method for the determination of voriconazole (UK-109,496; Pfizer) in plasma was developed and validated. The method utilizes solid-phase extraction technology and high-performance liquid chromatography. The lower limit of quantitation is 0.2 microg/ml, and the range of linearity tested was 0.2 to 10 microg/ml.

A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution.

To determine the effect of omeprazole on peak serum concentrations (C(max)) of itraconazole oral solution (IOS), we carried out a randomized, open-label, prospective, crossover study. Fifteen healthy, non-pregnant adults received a single dose of IOS 400 mg on two occasions, at least 7 days apart, with omeprazole 40 mg nightly for 7 days before either IOS dose 1 or 2. C(max), time to C(max) (T(max)) and AUC(0-8) were determined for itraconazole and its active metabolite, hydroxyitraconazole, for each dose and compared. Omeprazole did not significantly affect the C(max), T(max) or AUC(0-8) of itraconazole or hydroxyitraconazole when administered as IOS.