The Application Of Virtual Clinical Trials To Optimization Of Meropenem Pharmacokinetics In Children With Community-Acquired Pneumonia

Abstract

Abstract Meropenem is a carbapenem β-lactam antibiotic that is active against a very wide range of gram-positive and gram-negative aerobic and anaerobic bacteria. It is used to treat pneumococcal meningitis and other serious infections caused by susceptible gram-negative organisms resistant to other antibiotics, especially extended-spectrum β-lactamase that produce Klebsiella pneumoniae. The study of meropenem’s pharmacokinetics is important in guiding the choice of the correct meropenem dose according to the different ages and disease states of patients. Therefore, considering the shortage of paediatric pharmacokinetics studies, the important aim of this study was to optimize and develop the pharmacokinetics of meropenem in paediatric patients with pneumonia by using population-based pharmacokinetic (PBPK)modelling conducted with a virtual clinical trial simulator (Simcyp; Simcyp Ltd, UK). This study was divided into seven chapters, using a meropenem dose of 1000mg as a single dose and 500mg q8h administered to elderly adult patients with liver and renal failure. Meropenem’s pharmacokinetics parameterschange with advancing age and renal failure and liver impairment. There were increases in the average rates of AUC and Cmax, which were accompanied by deterioration of rates of GFR and CLr in cases of elderly patients and renal impairment due to the physiological change of the kidneys with age and lack of efficiency. Since the excretion of the drug is directly associated with the kidneys, adjustment of the dosage should be taken into account. In terms of liver disorder (Pugh A, B and C), the increases of AUC and Cmax rates was in the severity of the disease, and removing the drug from the body decreased twice as much in Pugh C patients compared with healthy. Meropenemwas administered to children in four age groups, population 1(age 0.5-2), population 2 (age 2-6), population3 (age 6-12)and population 4(age 12-18). All of the child populations were administered the drug as both single (40mg/kg) and multiple (20mg/kg q8h) doses to explore alterations in pharmacokinetics of the drug among these age groups. Significant differences were found among the four populations; the rates of AUC and Cmax decreased in adult children, accompanied by kidney growth and natural removal of the drug, compared with children aged between0.5-2 years old. In addition, this study investigated the effect of an inhibitor(meropenem) on the alteration of the pharmacokinetics of midazolam in adult and child populations and found that the PK parameters increased four times when meropenem was added with midazolam and then slowly removed. It was indicated that children aged between 05.-2 years old might suffer from serious side effects due to the ability of meropenem to inhibit CYP3A4.