DOSE OPTIMIZATION OF CEFTRIAXONE-SULBACTAM COMBINATION IN ADULTS USING IN VITRO SYSTEMS, PK/PD MODELING AND STOCHASTIC SIMULATIONS APPROACHES
Journal Title: International Journal of Pharmacy and Pharmaceutical Sciences - Year 2016, Vol 8, Issue 7
Abstract
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. Lastly, the recommendation of dose adjustments for patients with renal impairment was also presented.Results: 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.Conclusion: FDC dosage regimen of 1.5g BD or 3g OD was recommended for mild to moderate infections; whereas 3g BD was required for severely infected patients.Keywords: PK/PD modeling, Monte-carlo simulations, Ceftriaxone, Sulbactam, Dose optimization
Authors and Affiliations
Vishnu Dutt Sharma, Aman Singla, Manu Chaudhary, Manish Taneja
Keywords
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