Simulation of human plasma levels of beta-lactams in mice by multiple dosing and the relationship between the therapeutic efficacy and pharmacodynamic parameters.
A mathematical multiple dosing model was designed so that human plasma concentration-versus-time curves of beta-lactams are reproduced in mouse plasma. The pharmacokinetic parameters of FK037, a new injective cephalosporin, in volunteers and in the mice model were 6,966 and 6,894 ml, respectively, for Vc, 2.592 and 2.698/h for alpha, 0.2875 and 0.3027/h for beta, and 0.9079 and 1.0506 for K21. Therefore, real pharmacokinetics of humans were reproduced in mice by this method. The 8-hour therapeutic efficacy (the decrease of the viable counts in the lung) against pneumonia with Staphylococcus aureus and Pseudomonas aeruginosa in mice was well correlated with the time above MIC value, but not with AUC, Cmax or AUC above MIC. These results indicate that this model was valuable to evaluate the beta-lactam antibiotics for predicting their clinical efficacy and that the time above MIC is an important factor in selecting beta-lactam agents and determining dosage in pulmonary infection.
Hatano
K
K
Department of Chemotherapy, Fujisawa Pharmaceutical Co., Ltd, Osaka, Japan.
Wakai
Y
Y
Watanabe
Y
Y
Mine
Y
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015296:Ceftizoxime / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002511:Cephalosporins / Q000627:therapeutic use; D004334:Drug Administration Schedule; D006801:Humans; D008433:Mathematics; D051379:Mice; D008813:Mice, Inbred ICR; D008954:Models, Biological; D011014:Pneumonia / Q000188:drug therapy; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C079769:cefoselis; D015296:Ceftizoxime