Dose Optimization of Ceftriaxone-sulbactam Combination in Adults Using in Vitro Systems, Pk/pd Modeling and Stochastic Simulations Approaches

Objective: To optimize the dosage regimen of fixed-dose combination (FDC) of ceftriaxone/sulbactam (2/1 w/w) using in vitro system, pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte-Carlo simulations (MCS). Methods: One compartment in vitro system was used for identification of PK/PD driver that best correlates with therapeutic potential of FDC against ESBL positive E. coli infection. Using in vitro approach, the best exposure from dose escalation study was fractionated twice-a-day (BID) and thrice-a-day (TID) to determine a best dosage regimen of the FDC. In second approach i.e. in silico PK/PD modeling, dose response curve was constructed to estimate curve parameters (EC50 , γ, and Emax), which were then used to develop PK/PD model for the FDC. In the third approach, MCS were employed to evaluate the impact of different dosage regimen against mild-to-severe infections. Results: Lastly, the recommendation of dose adjustments for patients with renal impairment was also presented. Based on all three approaches, the best antibacterial effect was obtained from the exposure of 20 x MICcomb, which when fractioned to twice-daily dosing showed a maximum reduction in bacterial densities for severe infections. Dose reduction was recommended for patients with several renal impairments.