title: Prediction of Pharmacokinetics and Pharmacodynamics of Doripenem in Pediatric Patients.
abstract: The aim of this paper was to predict the pharmacokinetics of doripenem in pediatrics from adult pharmacokinetic data and to investigate dosing regimens in pediatrics using Monte-Carlo pharmacokinetics/pharmacodynamics (PK/PD) simulations prior to the initiation of pediatric clinical trials. The pharmacokinetics in pediatrics was predicted by using a previously reported approach for β-lactam antibiotics. Monte-Carlo simulation was employed to assess dosing regimens in pediatrics based on the predicted pharmacokinetic profiles and the minimum inhibitory concentration (MIC) distributions of Haemophilus influenzae and Streptococcus pneumoniae, which frequently cause infectious pediatric diseases. The probabilities of attaining target time above MIC (40%T>MIC) were calculated for dosing regimens of 1-30 mg/kg with two or three times daily dosing (TID) based on simulations of 5000 pediatric patients and MICs. The results suggested 15 and 5 mg/kg TID would give approximately 90% or more probability of target attainment against Haemophilus influenzae and Streptococcus pneumoniae, respectively. The pediatric phase 3 study confirmed that pharmacokinetics in pediatrics could be well predicted by this method, indicating that the dosing regimen had been appropriately selected. The framework of dose selection for pediatric clinical trials based on predictions of pharmacokinetic profiles and PK/PD indices should be applicable to the development of other β-lactam antibiotics for pediatric use.
authors.affiliation: Clinical Pharmacology and Pharmacokinetics, Clinical Research Department, Shionogi & Co., Ltd.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Clinical Pharmacology and Pharmacokinetics, Clinical Research Department, Shionogi & Co., Ltd.
authors.forename: Toru
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Clinical Pharmacology and Pharmacokinetics, Clinical Research Department, Shionogi & Co., Ltd.
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimamura
authors.affiliation: Clinical Pharmacology and Pharmacokinetics, Clinical Research Department, Shionogi & Co., Ltd.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Wajima
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015780:Carbapenems / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D000077726:Doripenem; D006193:Haemophilus influenzae / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009010:Monte Carlo Method; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem
keywords: Monte Carlo; antiinfectives; clinical pharmacokinetics; doripenem; pediatric; pharmacodynamics