A Novel Mechanism-Based Pharmacokinetic-Pharmacodynamic Model Describing Ceftazidime-Avibactam (CAZ-AVI) Efficacy Against β-lactamase-Producing Klebsiella pneumoniae and Pseudomonas aeruginosa Isolates
Anders N. Kristoffersson (1) Caterina Bissantz (2), Rusudan Okujava (2), Andreas Haldimann (2), Kenneth Bradley (2), Thierry Lavé (2), Claudia Zampaloni (2), Elisabet I. Nielsen(1)
(1) Department of Pharmaceutical Biosciences, Uppsala Universitet, Uppsala, Sweden (2) Hoffmann LaRoche LtD., Basel, Switzerland
Objectives: To develop a mechanism based PKPD model describing the interaction between the diazabicyclootance (DBO) β-lactamase inhibitor Avibactam (AVI) and ceftazidime (CAZ) in order to enable comparative evaluation with other β-lactamase inhibitors in clinical development.
Methods: Static in vitro time-kill data was generated for the KPC-3 producing Klebsiella pneumoniae strain NCTC13438 over 24h, testing CAZ alone, AVI alone, CAZ-AVI (CAZ + 4mg/L AVI), and growth control. The CFU counts and the drug concentrations were measured over the course of the experiment. The model structure was externally evaluated using extensive literature data of three Pseudomonas aeruginosa strains [1]. The modelling was performed in NONMEM7.3 [2], guided by visual predictive checks (VPC) and a p-value of 0.001 for parameter inclusion. Parameter uncertainty was determined by SIR [3], as implemented in PsN [4]. Inter strain variability (ISV) for P. aeruginosa were added on relevant parameters and MIC values investigated as covariates.
Results: The AVI and CAZ dynamics were modelled for NCTC13438: the CFU count influenced CAZ degradation by an Emax-function, and AVI inhibition of β-lactamase activity was modelled by an Imax-function with IC50 fixed to a measured value. For P. aeruginosa no IC50 was available, and instead the reported half-lives of CAZ were used [1]. The bacterial dynamics were modelled with a two-state two-subpopulation model [5]. The CAZ effect was described by a sigmoidal Emax-function with the EC50 scaled by the CAZ MIC, and regrowth explained by a higher EC50 for the second subpopulation. For NCTC13438 a direct antibacterial effect of AVI was evident, and modelled by a slope function affecting the main subpopulation, and fast regrowth explained by the lack of AVI effect on the second subpopulation. In addition, as described for aztreonam [6], a potentiation of CAZ by AVI was observed and modelled by an Emax-function. For P. aeruginosa no direct antibacterial effect of AVI was found, however ISV on the AVI EC50 of the potentiation effect was required to fit the data adequately.
Conclusions: A novel PKPD model for the DBO- β-lactam combination CAZ-AVI was successfully developed to describe the longitudinal effect on K. pneumonia and P. aeruginosa. The model enables comparison of the effect of AVI with other DBO- β-lactam inhibitors in simulation, and may be an aid in translating PKPD results from in vitro to animal and human.
References:
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[6]Sy, S. et al. Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms. CPT Pharmacomet. Syst. Pharmacol. n/a-n/a (2017). doi:10.1002/psp4.12159
