Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints

ABSTRACT Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 μg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 μg/mL (tested with a fixed vaborbactam concentration of 8 μg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.

. Percent probabilities of PK-PD target attainment by meropenem-vaborbactam MIC on day 1 based on the assessment of the meropenem free-drug plasma %T>MIC ≥ 30% target and MIC data for collections of isolates among simulated patients with cUTI or AP by eGFR and absolute eGFR groups after administration of meropenemvaborbactam dosing regimens for the U.S. FDA and EMA submissions, overlaid on the meropenem-vaborbactam MIC distributions for Enterobacterales (top), KPC-producing Enterobacterales (middle), and P. aeruginosa (bottom) isolates Figure S2. Percent probabilities of PK-PD target attainment by meropenem-vaborbactam MIC on day 1 based on the assessment of the meropenem free-drug plasma %T>MIC ≥ 35% target and MIC data for collections of isolates among simulated patients with cUTI or AP by eGFR and absolute eGFR groups after administration of meropenemvaborbactam dosing regimens for the U.S. FDA and EMA submissions, overlaid on the meropenem-vaborbactam MIC distributions for Enterobacterales (top), KPC-producing Enterobacterales (middle), and P. aeruginosa (bottom) isolates Figure S3. Percent probabilities of PK-PD target attainment by meropenem-vaborbactam MIC on day 1 based on the assessment of the meropenem free-drug plasma %T>MIC ≥ 45% target and MIC data for collections of isolates among simulated patients with cUTI or AP by eGFR and absolute eGFR groups after administration of meropenemvaborbactam dosing regimens for the U.S. FDA and EMA submissions, overlaid on the meropenem-vaborbactam MIC distributions for Enterobacterales (top), KPC-producing Enterobacterales (middle), and P. aeruginosa (bottom) isolates Explanation for Figure S4 The steps of the algorithm, which were applied by using sets of meropenem and vaborbactam free-drug plasma PK-PD targets associated with net bacterial stasis and 1-and 2-log10 CFU reductions from baseline for the assessment of meropenemvaborbactam dosing regimens, are described below.
• If the meropenem MIC value for the isolate was less than or equal to the meropenemvaborbactam MIC value, then the given meropenem free-drug plasma %T>MIC was calculated using the meropenem MIC value and compared to the meropenem freedrug plasma %T>MIC target for the same bacterial reduction endpoint.
o If the calculated meropenem free-drug plasma %T>MIC was at least equal to the meropenem free-drug plasma %T>MIC target, PK-PD target attainment was classified as achieved, o and if not, as not achieved. • If the meropenem MIC value for the isolate was greater than the meropenemvaborbactam MIC value, the given meropenem free-drug plasma %T>MIC was calculated using the meropenem MIC value and compared to the meropenem freedrug plasma %T>MIC target.
o If the calculated meropenem free-drug plasma %T>MIC was at least equal to the meropenem free-drug plasma %T>MIC target, PK-PD target attainment was classified as achieved.
o If not, the vaborbactam free-drug plasma AUC:MIC ratio (calculated using the meropenem-vaborbactam MIC value) was calculated in order to assess whether or not the meropenem-vaborbactam, MIC value can be used.  If the calculated vaborbactam free-drug plasma AUC:MIC ratio was at least equal to the vaborbactam free-drug plasma AUC:MIC ratio target for a given endpoint, the meropenem free-drug plasma %T>MIC (using the meropenemvaborbactam MIC value) was calculated and compared to the meropenem freedrug plasma %T>MIC target.
• If the calculated meropenem free-drug plasma %T>MIC was at least equal to the meropenem free-drug plasma %T>MIC target, PK-PD target attainment was classified as achieved, • and if not, as not achieved.  If the calculated vaborbactam free-drug plasma AUC:MIC ratio was less than the vaborbactam free-drug plasma AUC:MIC ratio target, PK-PD target attainment was classified as not achieved (given that the meropenem free-drug plasma %T>MIC target had not been achieved using the meropenem MIC value).
8 Figure S4. Algorithm to calculate percent probabilities of PK-PD target attainment for meropenem-vaborbactam dosing regimens evaluated