A-012. Safety and Pharmacokinetics (PK) of Repeat-Dose Micafungin (MICA) in Neonates
Session: Poster Session: Antifungal Pharmacokinetics/Dynamics
Saturday, October 25, 2008: 12:00 AM
Room: Hall C
Background: Disseminated candidiasis and hematogenous Candida meningoencephalitis (HCME) are leading causes of morbidity and mortality in premature infants. Experimental models of HCME and human bridging studies of echinocandin therapy suggest that relatively high weight-based dosages are required for successful therapy. We therefore determined the safety and PK of high dose MICA in infants at risk of invasive fungal infections. Methods: Open-label PK and safety of repeated dose IV MICA were assessed in young infants > 48 hours of age and < 120 days of life. Infants <1000 grams (g) received 10 mg/kg/day while infants ≥ 1000 g received 7 mg/kg/day once daily for 4-5 consecutive days. Plasma samples were drawn on day 4. MICA concentrations were measured using validated liquid chromatography with tandem mass spectrometric detection. Results: 13 infants were enrolled; 7 received 7 mg/kg and 6 received 10 mg/kg. Mean baseline weight and gestational age were 2101 g and 688 g, and 30 wks and 25 wks in the 7 mg/kg and 10 mg/kg groups, respectively. 12/13 infants were < 34 wks, 1 was 40 wks, gestational age. Adverse events (AE) occurred in 12/13 infants; drug-related AEs occurred in 3 infants (increased alkaline phosphatase, phlebitis, hypokalemia, temperature elevation). No deaths occurred. Median PK values for the 7 and 10 mg/kg groups, respectively, were: AUC, 258.1 and 291.2 µg*h/mL; Clss 0.45 and 0.57 mL/min/kg; Cmax, 23.3 and 24.9 µg/mL; and Vdss, 341.4 and 542.8 mL/kg. Conclusions: MICA doses up to 10mg/kg were well tolerated and provided exposure adequate for CNS coverage, as suggested by animal data. These data also suggest a single dose level of MICA may be appropriate for neonates, regardless of weight.
Antonio Arrieta1, Daniel Benjamin Jr2, David Kaufman, MD, Donald Buell4, Laura Kovanda4, Leah Arnold4, Lisa Castro5, P Smith6, Pablo J. Sanchez, MD7, Taiji Sawamoto4, Thomas Walsh, MD, FIDSA8, William Hope9 and  D. K. Benjamin Jr,
Cape Cod Associates Role(s): Grant Investigator, Received: Research Grant.
Astellas Role(s): Grant Investigator, Received: Research Grant.
Biosynexus Role(s): Grant Investigator, Received: Research Grant.
Medicines Company Role(s): Other, Received: Educational Grant.
Pfizer Role(s): Grant Investigator, Received: Research Grant.
Rockeby Role(s): Grant Investigator, Received: Research Grant., (1)CHOC, (2)Duke University, Horsham, United Kingdom, (3)Astellas Pharma US Inc, (4)Children's Mercy, (5)Duke University, (6)UT Southwestern, Dallas, TX, (7)National Cancer Institute, Bethesda, MD, (8)Univ of Manchester