Pratik Bhagunde1, Zufei Zhang2, Fred Racine2, Donna Carr2, Jin Wu2, Katherine Young2, Matthew L Rizk3. 1. Sanofi US, 55 Corporate Drive, Bridgewater, NJ, 08807, USA. 2. Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ, 07033, USA. 3. Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ, 07033, USA. Electronic address: matthew_rizk@merck.com.
Abstract
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 250mg relebactam, greater than 2-log reductions in bacterial load are projected for imipenem-resistant strains with an imipenem/relebactam MIC≤4μg/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 250mg clinical dose of relebactam achieves this target value when delivered in combination with imipenem/cilastatin.
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 250mg relebactam, greater than 2-log reductions in bacterial load are projected for imipenem-resistant strains with an imipenem/relebactam MIC≤4μg/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 250mg clinical dose of relebactam achieves this target value when delivered in combination with imipenem/cilastatin.
Authors: Ivan Titov; Richard G Wunderink; Antoine Roquilly; Daniel Rodríguez Gonzalez; Aileen David-Wang; Helen W Boucher; Keith S Kaye; Maria C Losada; Jiejun Du; Robert Tipping; Matthew L Rizk; Munjal Patel; Michelle L Brown; Katherine Young; Nicholas A Kartsonis; Joan R Butterton; Amanda Paschke; Luke F Chen Journal: Clin Infect Dis Date: 2021-12-06 Impact factor: 9.079
Authors: Munjal Patel; Francesco Bellanti; Naveen M Daryani; Nadia Noormohamed; David W Hilbert; Katherine Young; Pooja Kulkarni; William Copalu; Ferdous Gheyas; Matthew L Rizk Journal: Clin Transl Sci Date: 2021-10-27 Impact factor: 4.689