Pharmacokinetics in animals and humans of a first-in-class peptide deformylase inhibitor.
BB-83698, a potent and selective inhibitor of peptide deformylase, was the first compound of this novel antibacterial class to progress to clinical trials. Single- and/or multiple-dose studies with doses ranging from 10 to 50 mg of BB-83698/kg of body weight were done with mice, rats, and dogs. Intravenous pharmacokinetics were characterized by low to moderate clearances and moderate volumes of distribution for all species. In dogs, but not in rodents, central nervous system (CNS) effects were dose limiting for intravenously administered BB-83698 and were suspected to be related to a high maximum concentration of the agent in plasma (Cmax) rather than to total systemic exposure. Controlled infusion studies with dogs demonstrated that CNS effects could be avoided without compromising systemic exposure by reducing the Cmax. A randomized, double-blind, placebo-controlled, five-way-crossover, single-dose-escalation, phase I study to explore the safety, tolerability, and pharmacokinetics of intravenous BB-83698 at doses ranging from 10 to 475 mg was performed with healthy male volunteers. Systemic exposures were generally in linear relationships with administered doses in animals and humans. Pharmacokinetics were consistent, predictable, and exhibited good allometric scaling among all species (r2 >0.98). Moreover, BB-83698 dosing in humans proceeded to a predicted efficacious exposure (the area under the concentration-time curve/MIC ratio, up to 184) without any clinically significant adverse effects.
Ramanathan-Girish
Sandhya
S
Genesoft Pharmaceuticals, South San Francisco, California 94080, USA.
McColm
Juliet
J
Clements
John M
JM
Taupin
Phil
P
Barrowcliffe
Sue
S
Hevizi
John
J
Safrin
Sharon
S
Moore
Clive
C
Patou
Gary
G
Moser
Heinz
H
Gadd
Alison
A
Hoch
Ute
U
Jiang
Vernon
V
Lofland
Denene
D
Johnson
Kirk W
KW
D000328:Adult; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D019540:Area Under Curve; D002493:Central Nervous System Diseases / Q000139:chemically induced; D018592:Cross-Over Studies; D004285:Dogs; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
C481664:BB-83698; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D000581:Amidohydrolases; C084507:peptide deformylase