English to Russian Medical Medical: Pharmaceuticals Clinical Trials

Dose fractionation studies of P. aeruginosa infections in neutropenic mice determined that an appropriate value of the critical threshold concentration of*bactam was ** mg/L (Study *****). This value, which was conservative relative to CT = *number* mg/L obtained for Enterobacteriaceae as described above, was chosen for the probability of target attainment (PTA) analyses. The time for which the *bactam CT of *number* mg/L needed to be maintained was equal to the magnitude appropriate for the PK/PD index of *zidime, which was *number*% of the dosing interval during which free drug concentrations exceed the MIC (fT>MIC) (of *drug combination*). This magnitude of *number*% fT>MIC was chosen for *zidime, as it has been repeatedly adopted as the pivotal value used in PTA calculations for *zidime [link] and in setting interpretive criteria for *zidime susceptibility-testing [link]. A period of *number*% fT>*number* mg/L for *bactam also yielded 1-log kill in the neutropenic mouse thigh infection model with P. aeruginosa, and was higher than the *number*% fT>*number* mg/L that yielded 2-log kill in neutropenic mouse lung infection with P. aeruginosa. The magnitudes of the *bactam and *zidime PK/PD indices enabled Monte Carlo simulation of population PK in human patients that substantiated the dose used in Phase 3 clinical trials. The dose and administration were designed to achieve pharmacodynamic exposure targets of *zidime and *bactam against *drug combination* MIC of up to, and including, *number* mg/L (the MIC90 of P. aeruginosa) in more than *number*% of patients modelled.

ACRONYMS:

CT Critical threshold concentration

% fT>CT Percentage of the dosing interval that the free drug concentration (of *bactam) is greater than the critical threshold concentration (for *bactam)

% fT>MIC Percentage of the dosing interval that the free drug concentration (of *zidime) is greater than the minimum inhibitory concentration (for *drug combination*)

PTA Probability of PK/PD target attainment

Спасибо!