PHARMACODYNAMIC MODELING OF THE IN-VIVO INTERACTION BETWEEN CEFOTAXIME AND OFLOXACIN BY USING SERUM ULTRAFILTRATE INHIBITORY TITERS

The pharmacokinetics (PK) and pharmacodynamics (PD) of cefotaxime and ofloxacin and of their combination were examined in a three-period ran domized crossover study involving 12 healthy adults, The PK of cefotax ime and ofloxacin were modeled, PD was assessed from the predicted con centrations In serum and serum untrafiltrate inhibitory titers for 10 test organisms, An inhibitory sigmoid E-max model based on the probabi lity of bacterial growth was used, where Emas = 1 and EC50 is the conc entration resulting in a 50% probability of growth. The total body cle arance (CLT) and volume of distribution at steady state (V-ss) for cef otaxime were 0,236 liters/kg/h and 0.207 liters/kg, respectively, for the monotherapy and 0.231 liters/kg/h and 0.208 liter/kg for the combi nation therapy, Ofloxacin exhibited PK parameters of 0.143 liters/kg/h for CLT and 1.20 liters/kg for V-ss following the monotherapy and of 0.141 liters/kg/h for CLT and 1.16 liters/kg for V-ss following combin ation therapy. For the combination therapy, an interaction term, theta , defined the type and relative extent of interaction, The range of ob served theta values (-0.033 to 0.067) is consistent with an additive P D interaction according to standards similar to those used for the in vitro fractional inhibitory concentration index.