Pharmacokinetic modelling of serum and bronchial concentrations for clarithromycin and telithromycin, and site‐specific pharmacodynamic simulation for their dosages

This study aimed to describe in more detail the pharmacokinetics of the two macrolides in epithelial lining fluid (ELF) of human bronchi and to evaluate their pharmacodynamic target attainment at this site. MethodsPreviously reported drug concentration data for serum and ELF were simultaneously fitted to a three‐compartment pharmacokinetic model using nonmem program. The model parameter estimates were used for site‐specific pharmacodynamic simulation. Results and discussionPopulation mean parameters for clarithromycin were as follows: distribution volumes of central, peripheral and ELF compartments (V1/F, V2/F and V3/F) = 204·7, 168·9 and 67·1 L; clearance (CL/F) = 34·4 L/h; absorption rate constant (Ka) = 0·680 1/h; transfer rate constants connecting compartments (K12, K21, K13 and K31 = 0·0193, 0·434, 0·667 and 0·260 1/h, respectively). Mean parameters for telithromycin were as follows: V1/F, V2/F and V3/F = 370·3, 290·3 and 213·8 L; CL/F = 89·5 L/h; Ka = 0·740 1/h; K12, K21, K13 and K31 = 0·0026, 1·044, 0·758 and 0·158 1/h, respectively. Using these parameters, the mean ELF/serum ratio in the area under drug concentration–time curve (AUC) was 7·80 for clarithromycin and 8·05 for telithromycin. Clarithromycin achieved a ≥ 90% probability of attaining a pharmacodynamic target [AUC/minimum inhibitory concentration (MIC) = 100] in ELF against bacterial isolates for which MICs were ≤0·5 and ≤1 mg/L for twice‐daily doses...
Source: Journal of Clinical Pharmacy and Therapeutics - Category: Drugs & Pharmacology Authors: Tags: Pharmacokinetics Source Type: research