DOSE OPTIMIZATION OF CEFTRIAXONE-SULBACTAM COMBINATION IN PEDIATRIC USING IN-VITRO SYSTEMS AND STOCHASTIC SIMULATIONS APPROACHES

Increase in complexity and cost associated with pediatric safety and efficacy studies have reduced the interest of pharmaceutical companies to study bio-therapeutics in pediatric population. Dose recommendations are being made as per patient body weight or body surface area, with the assumption of linearity in body size dose adjustments. In the present study, newer approach i.e. flat fixed age-based dosing is explored. Stochastic simulations were performed on once-a-day (OD) and twice-a-day (BD) dosage regimens of a fixed dose combination (FDC) of ceftriaxone/sulbactam (2/1) to identify a promising dose range that can effectively evaluate exposure-response (E-R) relationships of the FDC against bacterial infection in pediatric population. Selected dose range of 60-120 mg/kg of FDC was evaluated against ESBL infection using in-vitro systems (dilution method and hollow fiber method). Effect of dose, dose frequency, severity of infection and age groups were analyzed in age-based subgroups i.e. neonates, infant, child and toddler. Recommended dose for infants, child and toddler were 75-120 mg/kg based on severity of infection. However, physiologically-induced reduction in drug’s clearance in neonates had resulted in lower dose recommendation against bacterial infection. Neonate dose of 120 mg/kg OD was best among all the exposures tested and its potential dose-related toxicity can be reduced either by reducing the doses (in mild infection) or by fractionating the dose into BD regimen (in severe infection). The E-R relationships of 120 mg/kg OD and BD dosage regimens in neonates were confirmed using in-vitro hollow fiber system