Pharmacokinetics in animals and humans of a first-in-class peptide deformylase inhibitor

Abstract

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.

FIG. 1.

Chemical structure of first-in-class PDF inhibitor BB-83698. M_w, molecular weight.

FIG. 2.

Mean plasma drug concentration-time profiles following single 10-mg doses of BB-83698/kg administered i.v. to mice (three animals per time point) (open squares), rats (three animals per sex per time point) (open diamonds), and dogs (three animals of each sex) (open circles).

FIG. 3.

Mean plasma drug concentration-time profiles on day 1 (first dose) and day 5 (last dose) following 6-h i.v. infusions of 175 mg of BB-83698/kg for a total of 5 days. Following 6-h infusions of 175 mg of BB-83698/kg, two serial plasma samples were obtained at times up to 24 h on day 1 after the first dose (open circles), and two more were obtained on day 5 after the last dose (open squares). Plasma samples were analyzed by a validated LC/MS/MS method with appropriate QCs.

FIG. 4.

Mean plasma drug concentration-time profiles following i.v. infusions of BB-83698 (10 to 475 mg) to healthy male volunteers. The following dose levels, represented in the key, were tested (n = number of subjects): 10 mg (n = 9), 25 mg (n = 9), 50 mg (n = 9), 100 mg (n = 19), 200 mg (n = 20), 325 mg (n = 10), 400 mg (n = 10), and 475 mg (n = 10). Plasma samples were analyzed by a validated LC/MS/MS method.

FIG. 5.

Relationship plot for AUC_∞ versus dose following i.v. infusions of BB-83698 to healthy male volunteers. Data points represent, in order of increasing dose (10, 25, 50, 100, 200, 325, 400, and 475 mg), the mean AUC_∞s (±standard deviations) obtained at those dose levels. The solid line is the linear regression line predicted by the equation y = 0.11x (r² = 0.96).

FIG. 6.

Relationship plot for C_max versus dose following i.v. infusions of 10 to 475 mg of BB-83698 to healthy male volunteers. Data points represent, in order of increasing dose (10, 25, 50, 100, 200, 325, 400, and 475 mg), mean C_maxs (±standard deviations) obtained at those dose levels. The solid line is the linear regression line predicted by the equation y = 0.05x (r² = 0.99).

FIG. 7.

Linearized plots for CL (milliliters per minute) and V_ss (milliliters) as a function of body weight (BW; kilograms) for BB-83698 across three species (mouse, rat, and dog) along with predicted and observed CL values and V_sss for humans. Data points in the graph, shown as closed diamonds, represent, in order of increasing weight, average values of the pharmacokinetic parameters for mice, rats, and dogs, along with the predicted values for humans. Actual data values are included in the figure. The solid lines represent the lines of best fit to the linearized form of the allometric equation. The observed CL values and V_ss for healthy male volunteers after the 10-, 25-, and 475-mg doses are shown as open squares.