title: Evaluation of pharmacokinetic/pharmacodynamic relationships of PD-0162819, a biotin carboxylase inhibitor representing a new class of antibacterial compounds, using in vitro infection models.
abstract: The present study investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationships of a prototype biotin carboxylase (BC) inhibitor, PD-0162819, against Haemophilus influenzae 3113 in static concentration time-kill (SCTK) and one-compartment chemostat in vitro infection models. H. influenzae 3113 was exposed to PD-0162819 concentrations of 0.5 to 16× the MIC (MIC = 0.125 μg/ml) and area-under-the-curve (AUC)/MIC ratios of 1 to 1,100 in SCTK and chemostat experiments, respectively. Serial samples were collected over 24 h. For efficacy driver analysis, a sigmoid maximum-effect (E(max)) model was fitted to the relationship between bacterial density changes over 24 h and corresponding PK/PD indices. A semimechanistic PK/PD model describing the time course of bacterial growth and death was developed. The AUC/MIC ratio best explained efficacy (r(2) = 0.95) compared to the peak drug concentration (C(max))/MIC ratio (r(2) = 0.76) and time above the MIC (T>MIC) (r(2) = 0.88). Static effects and 99.9% killing were achieved at AUC/MIC values of 500 and 600, respectively. For time course analysis, the net bacterial growth rate constant, maximum bacterial density, and maximum kill rate constant were similar in SCTK and chemostat studies, but PD-0162819 was more potent in SCTK than in the chemostat (50% effective concentration [EC(50)] = 0.046 versus 0.34 μg/ml). In conclusion, basic PK/PD relationships for PD-0162819 were established using in vitro dynamic systems. Although the bacterial growth parameters and maximum drug effects were similar in SCTK and the chemostat system, PD-0162819 appeared to be more potent in SCTK, illustrating the importance of understanding the differences in preclinical models. Additional studies are needed to determine the in vivo relevance of these results.
authors: Pfizer Global Research and Development, Ann Arbor, Michigan, USA. adam.ogden@pfizer.com
authors: Adam
authors: A
authors: Ogden
authors: Michael
authors: M
authors: Kuhn
authors: Michael
authors: M
authors: Dority
authors: Susan
authors: S
authors: Buist
authors: Shawn
authors: S
authors: Mehrens
authors: Tong
authors: T
authors: Zhu
authors: Deqing
authors: D
authors: Xiao
authors: J Richard
authors: JR
authors: Miller
authors: Debra
authors: D
authors: Hanna
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001710:Biotin / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002853:Chromatography, Liquid; D015169:Colony Count, Microbial; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006192:Haemophilus Infections / Q000188:drug therapy* / Q000382:microbiology; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D053719:Tandem Mass Spectrometry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D001710:Biotin; D019731:Carbon-Nitrogen Ligases; C019791:biotin carboxylase