Gl. Drusano et al., Use of preclinical data for selection of a phase II/III dose for evernimicin and identification of a preclinical MIC breakpoint, ANTIM AG CH, 45(1), 2001, pp. 13-22
One of the most challenging issues in the design of phase II/III clinical t
rials of antimicrobial agents is dose selection. The choice is often based
on preclinical data from pharmacokinetic (PK) studies with animals and heal
thy volunteers but is rarely linked directly to the target organisms except
by the MIC, an in vitro measure of antimicrobial activity with many limita
tions. It is the thesis of this paper that rational dose-selection decision
s can be made on the basis of the pharmacodynamics (PDs) of the test agent
predicted by a mathematical model which uses four data sets: (i) the distri
bution of MICs for clinical isolates, (ii) the distribution of the values o
f the PK parameters for the test drug in the population, (iii) the PD targe
t(s) developed from animal models of infection, and (iv) the protein bindin
g characteristics of the test drug. In performing this study with the new a
nti-infective agent evernimicin, we collected a large number (n = 4,543) of
recent clinical isolates of gram-positive pathogens (Streptococcus pneumon
iae, Enterococcus faecalis and Enterococcus faecium, and Staphylococcus aur
eus) and determined the MICs using E-test methods (AB Biodisk, Stockholm, S
weden) for susceptibility to evernimicin, Population PK data were collected
from healthy volunteers (n = 40) and patients with hypoalbuminemia (n = 12
), and the data were analyzed by using NPEM III. PD targets were developed
with a neutropenic murine thigh infection model with three target pathogens
: S. pneumoniae (n = 5), E. faecalis (n = 2), and S. aureus (n = 4). Drug e
xposure or the ratio of the area under the concentration-time curve/MIC (AU
C/MIC) was found to be the best predictor of microbiological efficacy. Ther
e were three possible microbiological results: stasis of the initial inocul
um at 24 h (10(7) CFU), log killing (pathogen dependent, ranging from 1 to
3 log(10)), or 90% maximal killing effect (90% E-max). The levels of protei
n binding in humans and mice were similar. The PK and PD of 6 and 9 mg of e
vernimicin per kg of body weight were compared; the population values for t
he model parameters and population covariance matrix were used to generate
five Monte Carlo simulations with 200 subjects each. The fractional probabi
lity of attaining the three PD targets was calculated for each dose and for
each of the three pathogens. All differences in the fractional probability
of attaining the target AUC/MIC in this PD model were significant. For S.
pneumoniae, the probability of attaining all three PD targets was high for
both doses. For S. aureus and enterococci, there were increasing difference
s between the 6- and 9-mg/kg evernimicin doses for reaching the 2 log killi
ng (S. aureus), 1 log killing (enterococci), or 90% E-max AUC/MIC targets.
This same approach may also be used to set preliminary in vitro MIC breakpo
ints.