A translational pharmacokinetic/pharmacodynamic model to characterize bacterial kill in the presence of imipenem-relebactam

• Main Authors: Pratik Bhagunde, Zufei Zhang, Fred Racine, Donna Carr, Jin Wu, Katherine Young, Matthew L. Rizk
• Format: Article
• Language: English
• Published: Elsevier 2019-12-01
• Series: International Journal of Infectious Diseases
• Online Access: http://www.sciencedirect.com/science/article/pii/S1201971219303522

Objectives: Relebactam is a small molecule β-lactamase inhibitor under clinical investigation for use as a fixed-dose combination with imipenem/cilastatin. Here we present a translational pharmacokinetic/pharmacodynamic mathematical model to support optimal dose selection of relebactam. Methods: Data derived from in vitro checkerboard and hollow fiber infection studies of imipenem-resistant strains of Pseudomonas aeruginosa were incorporated into the model. The model integrates the effect of relebactam concentration on imipenem susceptibility in a semi-mechanistic manner using the checkerboard data and characterizes the bacterial time-kill profiles from the hollow fiber infection model data. Results: Simulations demonstrated that the ratio of the area under the concentration-time curve for free drug to the minimum inhibitory concentration (fAUC/MIC) was the pharmacokinetic driver for relebactam, with a target fAUC/MIC = 7.5 associated with 2-log kill. At a clinical dose of 250 mg relebactam, greater than 2-log reductions in bacterial load are projected for imipenem-resistant strains with an imipenem/relebactam MIC ≤ 4 μg/mL. Conclusions: The study confirms that the pharmacokinetic/pharmacodynamic driver for relebactam is fAUC/MIC, that an fAUC/MIC ratio of 7.5 is associated with 2-log kill in vitro, and that a 250 mg clinical dose of relebactam achieves this target value when delivered in combination with imipenem/cilastatin. Keywords: Imipenem, Relebactam, Translational, PK/PD, Dose selection