title: Pharmacokinetic modelling of serum and bronchial concentrations for clarithromycin and telithromycin, and site-specific pharmacodynamic simulation for their dosages.
abstract: OBJECTIVE
  Clinical pharmacokinetic profiles of clarithromycin and telithromycin in bronchopulmonary sites have not been fully characterized. 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.
  
  
  METHODS
  Previously 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.
  
  
  CONCLUSIONS
  Population 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 of 250 and 500 mg, respectively. For telithromycin, once-daily doses of 600 and 800 mg achieved a ≥90% probability in ELF against Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis isolates but not Haemophilus influenzae isolates.
  
  
  CONCLUSIONS
  These results should provide a better understanding of the bronchial pharmacokinetics of clarithromycin and telithromycin, while also providing useful information about their dosages for respiratory tract infections based on site-specific pharmacodynamic evaluation. Further studies in a large number of patients are needed to confirm our findings and clarify their therapeutic implications.
authors.affiliation: Department of Clinical Pharmacotherapy, Hiroshima University, Hiroshima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ikawa
authors.forename: E
authors.initials: E
authors.lastname: Kikuchi
authors.forename: J
authors.initials: J
authors.lastname: Kikuchi
authors.forename: M
authors.initials: M
authors.lastname: Nishimura
authors.forename: H
authors.initials: H
authors.lastname: Derendorf
authors.forename: N
authors.initials: N
authors.lastname: Morikawa
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001419:Bacteria / Q000187:drug effects; D001980:Bronchi / Q000378:metabolism; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D048628:Ketolides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000382:microbiology; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D017291:Clarithromycin; C106791:telithromycin
keywords: macrolides; modelling; pharmacodynamics; pharmacokinetics; simulation