Impact of dose adaptations following voriconazole therapeutic drug monitoring in pediatric patients.

Voriconazole is the mainstay of treatment for invasive aspergillosis in immunocompromised pediatric patients. Although Therapeutic Drug Monitoring (TDM) of voriconazole is recommended, it remains unknown if TDM-based dose adaptations result in target attainment. Patients <19 years from two pediatric hematologic-oncology wards were retrospectively identified based on unexplained high voriconazole trough concentrations (Cmin > 6 mg/l). Patient demographics, clinical characteristics, treatment, voriconazole dosing information, voriconazole Cmin before and after adjustment based on TDM were obtained. Twenty-one patients, median (range) age 7.0 (1.2-18.5) years, were identified in two centers. First Cmin (3.1 mg/l [0.1-13.5]) was obtained after 3 days (1-27) of treatment. The median of all Cmin (n = 485, median 11 per patient) was 2.16 mg/l (0.0 (undetectable)-28.0), with 24.1% of Cmin < 1 mg/l, 48.9% 1-4 mg/l, 9.3% 4-6 mg/l, and 17.7% > 6 mg/l. Intrapatient variability was large (94.1% for IV, 88.5% for PO). Dose increases at Cmin < 1 mg/l resulted in an increased Cmin in 76.4%, with 60% between 1 and 4 mg/l. Dose decreases at Cmin > 6 mg/l resulted in a decreased Cmin in 80%, with 51% between 1 and 4 mg/l. Overall, in 45% of the cases (33 out of 55 and 12 out of 45) therapeutic targets were attained after dose adjustment. Fifty-five percent of initial Cmin was outside the therapeutic target of 1-4 mg/l, with multiple dose adaptations required to achieve therapeutic concentrations. Only 60% and 51% of dose adaptations following sub- and supra-therapeutic Cmin, respectively, did result in target attainment. Intensive and continuous TDM of voriconazole is a prerequisite for ensuring adequate exposure in pediatric patients.

Pharmacokinetics of Anidulafungin in Obese and Normal-Weight Adults.

In 2025, approximately one out of five adults will be obese. Physiological changes associated with obesity have been shown to influence the pharmacokinetics of drugs. Anidulafungin is frequently used in critically ill patients, and to achieve optimal efficacy, it is essential that its dose is appropriate for each patient's characteristics. We combined data from obese subjects with data from normal-weight subjects and determined an optimal dosing regimen for obese patients by population pharmacokinetic modeling. Twenty adults, 12 of which were normal-weight healthy subjects (median weight, 67.7 kg; range, 61.5 to 93.6 kg) and 8 of which were morbidly obese subjects (median weight, 149.7 kg; range, 124.1 to 166.5 kg) were included in the analysis. Subjects received a single dose of 100 mg anidulafungin intravenously over 90 min, upon which blood samples were obtained. Monte Carlo simulations were performed to optimize dosing in obesity. A three-compartment model and equal volumes of distribution described the data best. Total body weight was identified as a descriptor for both clearance and the volume of distribution, but the effect of weight on these parameters was limited. Simulations showed that with the licensed 100-mg dose, more than 97% of subjects with a weight above 140 kg will have an area under the concentration-time curve from 0 to 24 h of less than 99 mg · h/liter (the reference value for normal-weight individuals). We found that in obese and normal-weight subjects, weight influenced both of the anidulafungin pharmacokinetic parameters clearance and volume of distribution, implying a lower exposure to anidulafungin in (morbidly) obese individuals. Consequently, a 25% increase in the loading and maintenance doses could be considered in patients weighing more than 140 kg.

Inhibitory Potential of Antifungal Drugs on ATP-Binding Cassette Transporters P-Glycoprotein, MRP1 to MRP5, BCRP, and BSEP.

Inhibition of ABC transporters is a common mechanism underlying drug-drug interactions (DDIs). We determined the inhibitory potential of antifungal drugs currently used for invasive fungal infections on ABC transporters P-glycoprotein (P-gp), MRP1 to MRP5, BCRP, and BSEP in vitro Membrane vesicles isolated from transporter-overexpressing HEK 293 cells were used to investigate the inhibitory potential of antifungal drugs (250 µM) on transport of model substrates. Concentration-inhibition curves were determined if transport inhibition was >60%. Fifty percent inhibitory concentrations (IC50s) for P-gp and BCRP were both 2 µM for itraconazole, 5 and 12 µM for hydroxyitraconazole, 3 and 6 µM for posaconazole, and 3 and 11 µM for isavuconazole, respectively. BSEP was strongly inhibited by itraconazole and hydroxyitraconazole (3 and 17 µM, respectively). Fluconazole and voriconazole did not inhibit any transport for >60%. Micafungin uniquely inhibited all transporters, with strong inhibition of MRP4 (4 µM). Anidulafungin and caspofungin showed strong inhibition of BCRP (7 and 6 µM, respectively). Amphotericin B only weakly inhibited BCRP-mediated transport (127 µM). Despite their wide range of DDIs, azole antifungals exhibit selective inhibition on efflux transporters. Although echinocandins display low potential for clinically relevant DDIs, they demonstrate potent in vitro inhibitory activity. This suggests that inhibition of ABC transporters plays a crucial role in the inexplicable (non-cytochrome P450-mediated) DDIs with antifungal drugs.

Antifungal therapy: drug-drug interactions at your fingertips.

The Information Age has revolutionized the ability of healthcare professionals (HCPs) to oversee a substantial body of clinically relevant information literally at one's fingertips. In the field of clinical pharmacology, this may be particularly useful for managing drug-drug interactions (DDIs). A thorough understanding of the underlying mechanisms of DDIs allows the HCP to predict such interactions and avoid those of greatest clinical significance. Specifically, successful treatment with antifungal agents is complicated by the high potential to interact with other concomitant medications. We describe here the development of a real-time knowledge base of DDIs with antifungal agents, providing expert recommendations to HCPs on how to handle DDIs with these drugs. This new resource will facilitate rapid identification, quantification and classification of these DDIs by clinicians with varying levels of experience and resources worldwide, ultimately improving patient safety and strengthening health systems.

Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients.

Micafungin is considered an important agent for the treatment of invasive fungal infections in the intensive care unit (ICU). Little is known on the pharmacokinetics of micafungin. We investigated micafungin pharmacokinetics (PK) in ICU patients and set out to explore the parameters that influence micafungin plasma concentrations. ICU patients receiving 100 mg of intravenous micafungin once daily for suspected or proven fungal infection or as prophylaxis were eligible. Daily trough concentrations and PK curves (days 3 and 7) were collected. Pharmacokinetic analysis was performed using a standard two-stage approach. Twenty patients from the ICUs of four hospitals were evaluated. On day 3 (n = 20), the median (interquartile range [IQR]) area under the concentration-time curve from 0 to 24 h (AUC0-24) was 78.6 (65.3 to 94.1) mg · h/liter, the maximum concentration of drug in serum (Cmax) was 7.2 (5.4 to 9.2) mg/liter, the concentration 24 h after dosing (C24) was 1.55 (1.4 to 3.1) mg/liter, the volume of distribution (V) was 25.6 (21.3 to 29.1) liters, the clearance (CL) was 1.3 (1.1 to 1.5) liters/h, and the elimination half-life (t1/2) was 13.7 (12.2 to 15.5) h. The pharmacokinetic parameters on day 7 (n = 12) were not significantly different from those on day 3. Daily trough concentrations (day 3 to the end of therapy) showed moderate interindividual (57.9%) and limited intraindividual variability (12.9%). No covariates of the influence on micafungin exposure were identified. Micafungin was considered safe and well tolerated. We performed the first PK study with very intensive sampling on multiple occasions in ICU patients, which aided in resolving micafungin PK. Strikingly, micafungin exposure in our cohort of ICU patients was lower than that in healthy volunteers but not significantly different from that of other reference populations. The clinical consequence of these findings must be investigated in a pharmacokinetic-pharmacodynamic (PK-PD) study incorporating outcome in a larger cohort. (This study is registered at ClinicalTrials.gov under registration no. NCT01783379.).

Does Weight Impact Anidulafungin Pharmacokinetics?

Bodyweight has been shown to influence anidulafungin exposure, but data from obese patients are lacking. We determined anidulafungin pharmacokinetics (100-mg single dose) in eight morbidly obese subjects (body mass index >40 kg/m(2)). Anidulafungin exposure was on average 32.5 % lower compared with the general patient population, suggesting dose increases may be required in this population.

Impact of special patient populations on the pharmacokinetics of echinocandins.

Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.

Drug-interactions of azole antifungals with selected immunosuppressants in transplant patients: strategies for optimal management in clinical practice.

The management of drug-drug interactions (DDIs) between azole antifungals (fluconazole, itraconazole, posaconazole and voriconazole) and immunosuppressants (cyclosporine, tacrolimus, everolimus and sirolimus) in transplant patients remains challenging, as the impact of altered immunosuppressant concentrations puts the patient at high risk for either toxicity or transplant rejection. As a result, it is a complex task for the clinician to maintain immunosuppressant concentrations within the desired therapeutic range and this requires a highly individualized patient approach. We provide important tools for adequate assessment of the drug interactions that cause this pharmacokinetic variability of immunosuppressants. A stepwise approach for the evaluation and subsequent management options, including a decision flow chart, are provided for optimal handling of these clinically relevant DDIs.