Kim Vanstraelen

Protein-Binding Characteristics of Voriconazole Determined by High-Throughput Equilibrium Dialysis

Plasma protein binding (PPB) can possibly alter the already variable pharmacokinetics of voriconazole. Voriconazole PPB was determined only once, being 58%, according to equilibrium dialysis (ED). We investigated voriconazole PPB more in detail, with a convenient and newer high-throughput ED assay (HT-ED), in human blank plasma spiked with voriconazole and in plasma from intensive care unit (ICU) patients treated with voriconazole. HT-ED was conducted in a 96-well plate, setup against phosphate-buffered saline. Voriconazole concentrations were measured by liquid chromatography-tandem mass spectrometry. The median PPB was 47.6% [interquartile range (IQR) 45.3%-50%] in vitro, and 49.6% (IQR 42.5%-52.5%) in ICU samples (p = 0.35), and is not depending on total voriconazole concentration (0.7-11.2 mg/L, p = 0.65). The drug mainly binds to albumin (25.5 ± 5.1%), and to a lesser extent to α-1-acid glycoprotein (AAG; 4.8 ± 1.2%). The HT-ED assay can be performed at 37 °C or 25 °C (p = 0.44) and in batch: PPB variations during freeze-thaw cycles (p = 0.13) and during frozen storage up to 12 months (p = 0.10) were not clinically relevant. Voriconazole PPB is approximately 50%, according to HT-ED. As albumin and AAG only account for approximately 30% of total voriconazole PPB, other plasma components could influence PPB and therefore efficacy or toxicity because of variations in unbound fractions.

Pharmacokinetics of Posaconazole Oral Suspension in Children Dosed According to Body Surface Area.

Background: Antifungal prophylaxis remains challenging in immunocompromised children as no clear consensus has yet been reached about which drug to be used. Posaconazole has a broad spectrum of activity, a favorable safety profile and excellent prophylactic activity in adults. However, a lack of pharmacokinetic studies in pediatric patients hampers routine implementation. This study investigates the pharmacokinetics of a newly introduced posaconazole dosing regimen based on the body surface area in pediatric hematologic patients. Methods: In this prospective pharmacokinetic study, 8 blood samples were taken during 1 dosing interval at steady state in children aged 13 years or younger with hematologic malignancy, who were treated prophylactically with posaconazole oral suspension at a dose of 120 mg/m2 3 times daily. Posaconazole plasma concentrations were determined using high-performance liquid chromatography fluorescence detection. Results: One hundred twelve samples were taken from 14 patients with a mean age of 6.7 ± 2.8 years. A median posaconazole daily dose of 100.0 mg (77.3–100.0) 3 times daily (tid), corresponding to a median of 117.9 mg/m2 (112.2–120.4) tid, resulted in mean trough posaconazole plasma concentrations of 0.85 ± 0.56 mg/L. Pharmacokinetic analysis revealed a clearance of 0.8 L/(h kg) (0.5–1.4). No invasive fungal infections or adverse events were encountered during treatment. Conclusions: Posaconazole is a promising antifungal agent to be used prophylactically in hematologic patients aged 13 years or younger. Administering posaconazole oral suspension in a dosage of 120 mg/m2 tid results in adequate posaconazole plasma exposure, without significant adverse events.

Impact of hypoalbuminemia on voriconazole pharmacokinetics in critically ill adult patients.

ABSTRACT Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/liter) on voriconazole pharmacokinetics in adult intensive care unit (ICU) patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples from ICU patients that had been spiked with voriconazole at concentrations of 1.5 mg/liter, 2.9 mg/liter, and 9.0 mg/liter (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/liter. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/liter. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (P < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (P = 0.05). We therefore propose to adjust the measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin plasma concentrations who show adverse events potentially related to voriconazole via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/liter for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/liter. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the adult saturated hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.

The Eagle-like effect of echinocandins: what’s in a name?

Despite several years of research, a lot of questions remain about the paradoxical attenuation of echinocandin activity against Candida and Aspergillus species at certain drug concentrations above the MIC values, the so-called paradoxical growth effect or Eagle-like effect. Although this phenomenon has been observed in several in vitro studies, confirming in vivo data are scarce. The clinical relevance remains unknown, although more and more data suggest that the clinical impact of this phenomenon might be heavily overrated. Detailed knowledge about the mechanisms responsible for this phenomenon and further research about the presence of the effect in the human body is necessary to decide whether the paradoxical growth effect of echinocandins can really interfere with an adequate treatment of invasive fungal diseases in clinical practice.

Factors Impacting Unbound Vancomycin Concentrations in Different Patient Populations

ABSTRACT The unbound drug hypothesis states that only unbound drug concentrations are active and available for clearance, and highly variable results regarding unbound vancomycin fractions have been reported in the literature. We have determined the unbound vancomycin fractions in four different patient groups by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and identified factors that modulate vancomycin binding. We have further developed and validated a prediction model to estimate unbound vancomycin concentrations. Vancomycin (unbound and total) concentrations were measured in 90 patients in four different hospital wards (hematology [n = 33 samples], intensive care unit [ICU] [n = 51], orthopedics [n = 44], and pediatrics [age range, 6 months to 14 years; n = 18]) by a validated LC-MS/MS method. Multiple linear mixed model analysis was performed to identify patient variables that were predictive of unbound vancomycin fractions and concentrations. The variables included in the model were patient age, ward, number of coadministered drugs with high protein binding, kidney function (estimated glomerular filtration rate [determined by Chronic Kidney Disease Epidemiology Collaboration formula]), alpha-1-acid glycoprotein, albumin, total bilirubin, IgA, IgM, urea, and total vancomycin concentrations. In the pediatric cohort, the median unbound vancomycin fraction was 81.3% (range, 61.9 to 95.9%), which was significantly higher (P < 0.01) than the unbound fraction found in the three adult patient cohorts (hematology, 60.6% [48.7 to 90.6%]; ICU, 61.7% [47.0 to 87.6%]; orthopedics, 56.4% [45.9 to 78.0%]). The strongest significant predictor of the unbound vancomycin concentration was the total drug concentration, completed by albumin in the pediatric cohort and albumin and IgA in the adult cohorts. Validation of our model was performed with data from 13 adult patients. A mean difference of 0.3 mg/liter (95% confidence interval [CI], −1.3 to 0.7 mg/liter; R2 = 0.99 [95% CI, 0.95 to 0.99]) between measured and calculated unbound vancomycin concentrations demonstrated that the predictive performance of our model was favorable. Unbound vancomycin fractions vary significantly between pediatric and adult patients. We developed a formula to estimate the unbound fraction derived from total vancomycin, albumin, and IgA concentrations in adult patients.

Chemotherapy-Induced Intestinal Mucosal Barrier Damage: a Cause of Falsely Elevated Serum 1,3-Beta-d-Glucan Levels?

ABSTRACT Blood citrulline and intestinal fatty acid binding protein were determined as biomarkers for intestinal mucositis. Biomarker levels were correlated with corresponding serum 1,3-beta-d-glucan levels in 56 samples obtained from 33 cases with underlying hematological malignancies receiving induction chemotherapy. No correlation between biomarkers of intestinal mucositis and BDG levels was observed. (This study has been registered at ClinicalTrials.gov under registration no. NCT01576653.)

STIMULATION OF THE IV TO ORAL SWITCH OF BIOAVAILABLE DRUGS BY PHONE CALLS IN A BELGIAN TERTIARY CARE HOSPITAL

Abstract Introduction: Early switch from intravenous to oral administration of drugs with an almost complete oral bioavailability, can have important benefits. Drugs with almost complete bioavailability, like clindamycin (Dalacin®), levofloxacin (Tavanic®) and paracetamol (Perfusalgan®/Dafalgan ®), are very suitable for an early intravenous to oral switch in patients whose gastrointestinal absorption is intact. The aim of this study was to investigate the impact of direct phone contact between pharmacist and clinician on the intravenous to oral switch and to evaluate the reasons, mentioned by clinicians, that prevented an early switch. Materials & Methods: The project was initiated in a Belgian 1900-bed tertiary care hospital with a poster, communicated through the hospital’s intranet and spread to every hospital ward. During one month, all prescriptions for intravenous clindamycin, levofloxacin and paracetamol were evaluated. The treating clinician was contacted by phone to evaluate if an intravenous to oral switch was possible. Results: Clinicians were contacted concerning 377 patients. For 58.7% of patients, the switch from intravenous to oral administration was made. In case of refusal, several reasons were mentioned by the clinician, some more appropriate than others. Conclusion: Despite several appropriate reasons preventing an early intravenous to oral switch, there are still some aberrant opinions circulating in the hospital environment. Active interventions of pharmacists to stimulate intravenous to oral switch, using phone contact with the treating clinicians, can possibly be an adequate technique to stimulate intravenous to oral switch, but this needs to be further optimized.