Does weight impact anidulafungin pharmacokinetics?

Pharmacolog

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

Antifungal therapy: drug-drug interactions at your fingertips-authors' response

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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 muM) 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 muM for itraconazole, 5 and 12 muM for hydroxyitraconazole, 3 and 6 muM for posaconazole, and 3 and 11 muM for isavuconazole, respectively. BSEP was strongly inhibited by itraconazole and hydroxyitraconazole (3 and 17 muM, respectively). Fluconazole and voriconazole did not inhibit any transport for >60%. Micafungin uniquely inhibited all transporters, with strong inhibition of MRP4 (4 muM). Anidulafungin and caspofungin showed strong inhibition of BCRP (7 and 6 muM, respectively). Amphotericin B only weakly inhibited BCRP-mediated transport (127 muM). 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

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 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 6 mg/l. Intrapatient variability was large (94.1% for IV, 88.5% for PO). Dose increases 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

Altered micafungin pharmacokinetics in intensive care unit patients

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