Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers

Abstract

The pharmacokinetics (PK) and pharmacodynamics (PD) of cefotaxime and ofloxacin and of their combination were examined in a three-period randomized crossover study involving 12 healthy adults. The PK of cefotaxime and ofloxacin were modeled. PD was assessed from the predicted concentrations in serum and serum untrafiltrate inhibitory titers for 10 test organisms. An inhibitory sigmoid Emax model based on the probability of bacterial growth was used, where Emax = 1 and EC50 is the concentration resulting in a 50% probability of growth. The total body clearance (CL(T)) and volume of distribution at steady state (V(SS)) for cefotaxime were 0.236 liters/kg/h and 0.207 liters/kg, respectively, for the monotherapy and 0.231 liters/kg/h and 0.208 liters/kg for the combination therapy. Ofloxacin exhibited PK parameters of 0.143 liters/kg/h for CL(T) and 1.20 liters/kg for V(SS) following the monotherapy and of 0.141 liters/kg/h for CL(T) and 1.16 liters/kg for V(SS) following combination therapy. For the combination therapy, an interaction term, theta, defined the type and relative extent of interaction. The range of observed theta values (-0.033 to 0.067) is consistent with an additive PD interaction according to standards similar to those used for the in vitro fractional inhibitory concentration index.