Comparative target site pharmacokinetics of immediate- and modified-release formulations of cefaclor in humans

Optimal dosing of beta-lactam antibiotics aims at maximizing the time at which drug levels in the interstitial space fluid (ISF)--the fluid that surrounds the causative microorganisms at the target site--exceed the minimal inhibitory concentration (MIC). One potentially attractive strategy to achieve this goal is to administer antibiotics as oral sustained-release formulations. The present study was designed to test the hypothesis that sustained-release formulations could lead to a more suitable pharmacokinetic profile in the ISF at the relevant target site. For this purpose, time versus cefaclor concentration profiles attained in the ISF were measured following administration of two formulations, an immediate- (500 mg IR) and a modified-release formulation in two different doses (500 mg MR and 750 mgMR) in a three-way crossover study of healthy male volunteers (n = 12). For the measurement of unbound cefaclor concentrations in the ISF of human skeletal muscle, the in vivo microdialysis technique was employed. For all three formulations, unbound cefaclor concentration in the ISF closely followed individual plasma concentration profiles in a dose-dependent pattern, with ISF to unbound plasma ratios ranging from 0.67 to 0.73. The mean residence time was found to be significantly longer for the MR formulations versus the IR formulation. The data of the present study indicate that time above MIC values at the target site can be substantially prolonged if an antibiotic is administered as a sustained-release product.