Single- and Multiple-Dose Pharmacokinetics of the Antifungal Agent MK-0991 in Man.

J.A. STONE, S.D. HOLLAND, W.D. JU, Z. ZHANG, M. SCHWARTZ, V.L. HOAGLAND, K.E. MAZINA, T.L. HUNT, and S. WALDMAN

Abstract: 

The echinocandin, MK-0991 (L-743,872), is currently in Phase II/III clinical development as a parenteral antifungal agent. The pharmacokinetics of MK-0991 following one hour intravenous infusions in healthy male subjects were investigated in three Phase I studies. In an alternating two-panel (n=6 each), single rising dose study, plasma concentrations of MK-0991 increased proportionally with the dose received following infusions of 5 - 100 mg. Beta phase half-life was consistently 9-10 hours across the dose levels examined. An additional phase with longer half-life was evident at higher doses. The drug was cleared very slowly with an average plasma clearance of 11 ml/min. Multiple dose pharmacokinetics were investigated in two Phase I studies: a two-week, serial-panel (n=5 or 6 each) study of daily infusions of 15, 35 and 70 mg and a single-panel (n=10), three-week study of daily 70 mg infusions. Moderate accumulation was observed with daily dosing. The degree of drug accumulation and the time to steady-state were somewhat dose-dependent, such that the average accumulation for AUC_{0-24hr} was 25% at 15 mg q.d., 34% at 35 mg q.d. and 50% at 70 mg q.d in the initial two week study. In the three week study of 70 mg q.d., accumulation averaged 39% on Day 14 and 47% on Day 21. For the 70 mg daily dosing regimen, mean (+/- S.D.) trough (24 hour) concentrations were 1.36 +/- 0.30 and 2.66 +/- 0.55 micro g/ml on Days 1 and 14 of the two week study and were 1.34 +/- 0.35, 2.43 +/- 0.58 and 2.64 +/- 0.65 micro g/ml on Days 1, 14 and 21 of the three week study. This dosing regimen maintained plasma concentrations above the reported in vitro MICs of many clinically important fungi, including Candida and Aspergillus species, throughout the treatment period for most subjects. In conclusion, the pharmacokinetics of MK-0991 support the clinical evaluation of once daily dosing regimens for efficacy against Candida and Aspergillus.
1998

abstract No: 

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Full conference title: 

38th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 38th