Efficacy of MK-991 (L-743,872), a semisynthetic pneumocandin, in murine models of Pneumocystis carinii.
In addition to its potent efficacy in animal models against Candida sp., Aspergillus fumigatus, and Histoplasma capsulatum, the clinical candidate pneumocandin MK-991 (formerly L-743,872) was also extremely potent against Pneumocystis carinii in models of immune-compromised animals. MK-991 was approximately 14 times more potent than the original natural product lead, pneumocandin B0. The 90% effective dose (ED90) of MK-991 for cyst clearance in the rat model for pneumocystis was 0.011 mg/kg of body weight when delivered parenterally for 4 days twice a day (b.i.d.). In a mouse model, under the same experimental parameters, the ED90 was 0.02 mg/kg. MK-991 was also effective orally, with an ED90 for cyst clearance of 2.2 mg/kg against acute infection in rats (b.i.d. for 4 days). Complete prevention of P. carinii development was achieved in immunocompromised mice at a daily oral dose of 2.25 mg/kg. As reported previously for other pneumocandins and echinocandins, MK-991 selectively prevented the development of P. carinii cysts. When used as a prophylactic agent, neither stage of the organism appeared in the lungs of animals. In response to an acute infection, cysts were eliminated rapidly, while trophozoite forms persisted. Despite good efficacy as an oral agent in murine models, the low oral absorption of this class may limit the use of MK-991 to parenteral therapy.
Merck Research Laboratories, Rahway, New Jersey 07065, USA. maryann_powles@merck.com
M A
MA
Powles
P
P
Liberator
J
J
Anderson
Y
Y
Karkhanis
J F
JF
Dropinski
F A
FA
Bouffard
J M
JM
Balkovec
H
H
Fujioka
M
M
Aikawa
D
D
McFadden
D
D
Schmatz
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000627:therapeutic use*; D000077336:Caspofungin; D054714:Echinocandins; D055666:Lipopeptides; D051379:Mice; D008809:Mice, Inbred C3H; D010455:Peptides; D010456:Peptides, Cyclic; D016720:Pneumocystis Infections / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D000077336:Caspofungin