Clinical Pharmacokinetics and Pharmacodynamics of Micafungin

Abstract

Micafungin is a selective inhibitor of the synthesis of fungal 1,3-β-d-glucan, an essential component of the fungal cell wall. It is available as a powder for infusion only and is registered for the treatment of invasive and esophageal candidiasis in addition to prophylaxis of Candida infections in both adults and children. Average exposure after a single intravenous 100 mg dose in healthy adults is 133 mg h/L. Both exposure and maximum plasma concentration show linear dose proportional pharmacokinetics (PK) over a 0.15–8 mg/kg dose range. In healthy adults, the clearance (CL) is 10.4 mL/h/kg and volume of distribution is 0.2 L/kg; both are independent of the dose. Micafungin is metabolized by arylsulfatase, catechol-O-methyltransferase, and several cytochrome P450 (CYP) isoenzymes (3A4, 1A2, 2B6 and 2C), but no dose adjustments are necessary in patients with (severe) hepatic dysfunction. Exposure to micafungin is lower in hematology patients, and is even further lowered in critically ill patients (including burn patients) compared with healthy volunteers, which might have consequences for treatment efficacy. In children, an increased CL has been reported: 40–80 mL/h/kg in premature neonates and 20 mL/h/kg in children >4 months of age. Therefore, relatively higher doses of 4–10 mg/kg in premature neonates and 2–4 mg/kg in children with invasive candidiasis are used. However, these higher CLs may also be explained by the eightfold higher free fraction of unbound micafungin in premature neonates, meaning that an augmented dose might not be required.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0578-5) contains supplementary material, which is available to authorized users.

Pharmacokinetics and probability of target attainment for micafungin in normal-weight and morbidly obese adults

“…A two-compartment model with first order elimination best described the micafungin plasma concentrations, which is in line with previous reports. 5,12,[18][19][20] In our study, body weight was the size descriptor best explaining the inter-individual variability in clearance, where individual clearance (in L/h) is predicted using the power function 0.69 * (weight / 70) 0.74 . This relation is supported by previously reported clearances in normal-weight healthy subjects.…”

“…Micafungin exhibits linear pharmacokinetics and is metabolized by arylsulfatase, catechol-Omethyltransferase and several cytochrome P450 (CYP) isoenzymes: CYP3A4, CYP1A2, CYP2B6 and CYP2C. 5 Pharmacokinetic (PK)-Pharmacodynamic (PD) targets for micafungin have been defined in patients with invasive candidiasis or candidemia based on the AUC over the MIC. For all Candida species excluding C. parapsilosis a breakpoint between 5,000 and 12,000 showed a 98% success rate in response versus 87% if patients had an AUC/MIC ratio below 5,000.…”

Saliva for Precision Dosing of Antifungal Drugs: Saliva Population PK Model for Voriconazole Based on a Systematic Review.

“…Structural and chemical similarities (e.g., lipophilicity) of posaconazole to itraconazole, and high protein binding of posaconazole (>98%) and echinocandins (84-99.85%) (Hajdu et al, 1997;Paderu et al, 2007;Felton et al, 2014;Wasmann et al, 2018) may allow speculation for poor saliva penetration of these drugs.…”

Pre-Existing Liver Disease and Toxicity of Antifungals

“…Micafungin has a low hepatic extraction ratio with high protein binding in plasma, and while its total plasma concentration may decrease in some clinical cases, the unbound fraction of the drug is likely to remain stable [151,152]. A phase I parallel group open-label PK study of a single-dose of micafungin included 8 patients with Child–Pugh Score 7–9 hepatic dysfunction and did not find significant difference in unbound plasma concentration of the drug compared with healthy controls, while a lower AUC was found in the patients with hepatic impairment [153].…”