Population Pharmacokinetic Analysis for Imipenem-Relebactam in Healthy Volunteers and Patients With Bacterial Infections

Abstract

Relebactam is a small-molecule β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin. The pharmacokinetics of relebactam and imipenem across 10 clinical studies were analyzed using data from adult healthy volunteers and patients with bacterial infections. Renal function estimated by creatinine clearance significantly affected the clearance of both compounds, whereas weight and health status were of less clinical significance. Simulations were used to calculate probability of joint target attainment (ratio of free drug area under the curve from 0 to 24 hours to minimum inhibitory concentration (MIC) for relebactam and percentage of time the free drug concentration exceeded the MIC for imipenem) for the proposed imipenem/relebactam dose of 500/250 mg, with adjustments for patients with renal impairment, administered as a 30-minute intravenous infusion four times daily. These dosing regimens provide sufficient antibacterial coverage (MIC ≤ 4 μg/mL) for all renal groups.

Figure 1

Impact of intrinsic factors on simulated steady‐state AUC _{0–24 hours} of imipenem and relebactam. ^aNormal renal function (CrCL 90 to < 150 mL/minutes); ^bCrCL 15 to < 30 mL/minutes; ^cCrCL 30 to < 60 mL/minutes; ^dCrCL 60 to < 90 mL/minutes. Unless otherwise specified, the weight for each group was 70–90 kg. The reference population refers to participants with normal renal function (CrCL 90 to < 150 mL/minutes) and weight 70–90 kg. Lower and upper clinical bounds are shown as solid lines for imipenem (0.6–2.0) and relebactam (0.4–2.5) based on imipenem 500 mg and relebactam 250 mg administered as a 30‐minute intravenous infusion dosed every 6 hours. AUC_{0–24 hours}, area under the plasma concentration‐time curve from 0 to 24 hours; CrCL, creatinine clearance; RI, renal impairment.

Figure 2

Percentage of participants achieving 6.5% fT > MIC for imipenem and fAUC_{0–24 hours}/MIC = 5.2 for relebactam with Pseudomonas aeruginosa (top) and Enterobacteriaceae (bottom) MIC distributions among isolates relevant to proposed indication from clinical phases 2/3 and surveillance data. Simulations used the recommended renal dose adjustments that are detailed in Table 2. Solid and dashed vertical lines represent European Committee on Antimicrobial Susceptibility Testing and Clinical and Laboratory Standards Institute breakpoint MICs, respectively. Solid horizontal line represents 90% probability of target attainment. CrCL, creatinine clearance; fAUC_{0–24 hours}/MIC, ratio of free drug area under the curve from 0 to 24 hours to MIC; fT > MIC, time the free drug concentration exceeds the MIC; MIC, minimum inhibitory concentration; PK, pharmacokinetic.

Figure 3

Percentage of participants achieving 6.5% fT > MIC (a) and 30% fT > MIC (b) for imipenem with Pseudomonas aeruginosa (left) and Enterobacteriaceae (right) MIC distributions among isolates relevant to proposed indication from clinical phases 2/3 and surveillance data. Solid and dashed vertical lines represent European Committee on Antimicrobial Susceptibility Testing and Clinical and Laboratory Standards Institute breakpoint MICs, respectively. Solid horizontal line represents 90% probability of target attainment. fT > MIC, time the free drug concentration exceeds the MIC; MIC, minimum inhibitory concentration; PK, pharmacokinetic.