DISCUSSION
PK-PD, CABP
The objective of these analyses was to evaluate the agreement by MIC between percent probabilities of PK-PD target attainment among simulated omadacycline-treated patients and observed clinical response among omadacycline-treated patients with CABP. PK-PD target attainment analyses, which were undertaken to provide support for omadacycline i.v.-to-p.o. dosing regimens, were carried out using two drug exposure measures and four sets of PK-PD targets for the same nonclinical endpoint. Drug exposure measures evaluated were total-drug ELF and free-drug plasma AUC values. For dose selection, it is important to consider effect site exposure (A 1-logThe results of PK-PD target attainment analyses on days 1 and 2 at the MICFor It is important to recognize the limitations of the above-described comparisons between simulated and clinical data. The assessments of clinical response by MIC were univariable and thus, did not consider other factors, such as underlying comorbidities, that may contribute to patient response. In addition, the comparisons, which were based on a limited number of patients, may be more susceptible to type II errors. These limitations likely obscured the ability to further discriminate between the results of PK-PD target attainment analyses and assessments of clinical response by MIC. Regardless, these data provide support for the premise that results of PK-PD target attainment based on the highest PK-PD target are not sufficiently predictive of clinical outcome, even if the PK-PD targets for a collection of isolates do not contain an extreme outlier, as was the case with the assessment for When using a fixed median PK-PD target, the PK-PD target attainment results may be overestimated, while the use of the maximum PK-PD target or other high percentiles, such as the second highest, for the PK-PD target distribution may lead to underestimated results. The risk of the latter is the selection of dosing regimens with higher total daily doses and, thus, poor safety profiles. The benefit of randomly assigning a PK-PD target is that high PK-PD targets are considered but according to a probability distribution of the expected occurrence of such targets. It should be noted that there are no current standard recommendations describing which approach for PK-PD targets for efficacy to assess when conducting PK-PD target attainment analyses. However, as described above, the use of randomly assigned PK-PD targets addresses the concern of appropriately considering higher PK-PD targets. Thus, we suggest that this approach be considered the standard for selecting PK-PD targets for efficacy when assessing the adequacy of dosing regimens and interpretive criteria for The assessment of nonclinical PK-PD data using Hill models relative to the distribution of PK-PD indices in simulated patients is another useful approach to evaluate the adequacy of selected dosing regimens. As shown in In addition to dose support, results of PK-PD target attainment analyses and assessments of clinical response by MIC were useful to support interpretive criteria decisions for In conclusion, results of the various assessments described herein served to provide support for omadacycline dosing regimens for the treatment of patients with CABP and decisions about the interpretive criteria for 