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 onecompartment chemostat in vitro infection models. H. influenzae 3113 was exposed to PD-0162819 concentrations of 0.5 to 16؋ the MIC (MIC ‫؍‬ 0.125 g/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 g/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. Steadily increasing bacterial resistance to existing antibiotics continues to be a major public health concern (3, 8). Because most new antibacterial agents represent chemical modifications of existing chemical classes of antibacterial agents (5), it is suspected that the limited options of chemically distinct antibiotics have led to extensive drug resistance among bacterial pathogens. Therefore, it is of the utmost importance to identify novel, safe, and effective antibacterial agents that work through unique antibacterial biological mechanisms. The discovery of a new chemical class of antibacterial compounds, the pyridopyrimidines, targeting bacterial biotin carboxylase (BC), was recently reported (14, 15) and offers the potential that this novel chemical class, targeting a unique antibacterial mechanism, can be developed into drugs effective against multidrug-resistant bacteria.Compared to the development of drugs from an existing chemical class, the discovery of a novel class of compounds presents extra challenges (1, 5). The translation of pharmacokinetic/ pharmacodynamic (PK/PD) relationships between animal infection models and human patients has been well established for several existing chemical classes across a variety of in...

Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase

“…[6][7][8][9][10][11] The first committed step in this pathway is catalyzed by an essential cytoplasmic acetyl-CoA carboxylase multienzyme complex 12 (see also Supporting Information Text S1), and inhibitors of the BC active site of this complex have shown antibacterial activity against several Gram-negative species. 5,[13][14][15][16][17] The BC active site is highly conserved across a number of bacterial pathogens, including P. aeruginosa, E. coli, and H. influenzae. 18 While 1 lacks the potency to become a therapeutic agent, it is a promising starting point for medicinal chemistry efforts because of its selective on-target activity, low molecular weight, and available co-crystal structures with BC that enable structure-based molecular design.…”

“…coli ( tolC , imp ) . BC is a member of the fatty acid biosynthesis pathway (Figure S1) and has attracted attention over the past decade as a promising target for the development of novel broad-spectrum antibiotics for Gram-negative bacterial infections. − The first committed step in this pathway is catalyzed by an essential cytoplasmic acetyl-CoA carboxylase multienzyme complex (see also Text S1), and inhibitors of the BC active site of this complex have shown antibacterial activity against several Gram-negative species. ,− The BC active site is highly conserved across a number of bacterial pathogens, including P. aeruginosa, E.…”

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“…In-vitro system: One-compartment dilution system: The in-vitro modeling of the FDC was done using a single-compartment chemostat infection system as described previously 10,11 . Briefly, the chemostat system assembly consisted of a 500 mL glass central reservoir chamber with ports for the addition and removal of media via silicone tubes connected to peristaltic pumps, injection of drug (antibiotic combination) solution, and removal of medium samples.…”

Dose optimization of ceftriaxone-vancomycin combination using fractional inhibitory concentration kinetics in resistant bacteria

“…The three PK/PD indices that are routinely used for explaining the therapeutic efficacy in terms of achieving MIC and mechanism based action of antibiotics include: 1) % T>MIC time (% time for which the levels of antibiotic in serum/plasma exceed the MIC); 2) Area under the concentration-time curve (AUC)/MIC ratio; 3) Peak plasma concentration (C max )/MIC ratio [10][11][12]. Maximum literature for these kinds of PK/PD studies is available for single antibacterial agents [13,14]; the effect of combination therapy on the PK and PD, and subsequently on PK/PD indices is very limited [15].…”