Physiologically-Based Pharmacokinetic model for Ciprofloxacin in children with complicated Urinary Tract Infection

Abstract

In a recent multicenter population pharmacokinetic study of ciprofloxacin administered to children suffering from complicated urinary tract infection (cUTI), the apparent volume of distribution (V d ) and total plasma clearance (CL) were decreased by 83.6% and 41.5% respectively, compared to healthy children. To understand these differences, a physiologicallybased pharmacokinetic model (PBPK) for ciprofloxacin was developed for cUTI children. First, a PBPK model in adults was developed, modified incorporating age-dependent functions and evaluated with paediatric data generated from a published model in healthy children. Then, the model was then adapted to a cUTI paediatric population according to the degree of renal impairment (KF) affecting renal clearance (CL Renal, ) and CYP1A2 clearance (CL CYP1A2 ). Serum and urine samples obtained from 22 cUTI children were used for model evaluation. Lastly, a parameter sensitivity analysis identified the most influential parameters on V and CL. The PBPK model predicted the ciprofloxacin exposure in adults and children, capturing age-related pharmacokinetic changes. Plasma concentrations and fraction excreted unchanged in urine (f e ) predictions improved in paediatric cUTI patients once CL renal and CL CYP1A2 were corrected by KF. The presented PBPK model for ciprofloxacin demonstrates its adequacy to simulate different dosing scenarios to obtain PK predictions in a healthy population from 3 months old onwards. Model adaptation of CL Renal and CL CYP1A2 according to KF explained partially the differences seen in the plasma drug concentrations and f e vs time profiles between healthy and cUTI children. Nevertheless, it is necessary to further investigate the disease-related changes in cUTI to improve model predictions.

Development and application of a pediatric mechanistic kidney model

“…This file was further modified to include information on its metabolism by CYP1A2, as reported in other PBPK models. 9 , 24 The compound has been shown to be eliminated by biliary excretion 25 and possibly direct transintestinal elimination, 26 both of these were subsumed into a biliary clearance pathway. The fraction eliminated by renal, CYP1A2, and biliary were 60%, 30%, and 10%, respectively.…”

“…The drug undergoes renal elimination incorporating active tubular secretion by OAT3, 23 the input values for the Mech Kim model including the transporter mediated intrinsic clearance OAT3 was optimized to recapture the reported renal clearance of 21.5 L/h in the adult population (Simcyp value from unpublished meta‐analysis, Certara UK Limited). This file was further modified to include information on its metabolism by CYP1A2, as reported in other PBPK models 9,24 . The compound has been shown to be eliminated by biliary excretion 25 and possibly direct transintestinal elimination, 26 both of these were subsumed into a biliary clearance pathway.…”

“…However, this may not be the case; P-PBPK models that incorporate age-related changes in other renal routes, such as active tubular secretion and re-absorption, are less explored and instead have tended to use a more empirical approach for scaling these processes. 7,9,10 The development of a mechanistic kidney (Mech Kim) model, as part of a PBPK simulator, has been described previously. 11,12 In brief, the model links the physicochemical characteristics of a molecule and in vitro data with prior knowledge of renal physiology to predict the integrated effects of glomerular filtration, active and passive tubular secretion, intra-renal drug metabolism, active and passive tubular re-absorption, and the impact of covariates, such as age, sex, genetics, race, diet, concomitant drugs, and disease.…”

General clinical and methodological considerations on the extrapolation of pharmacokinetics and optimization of study protocols for small molecules and monoclonal antibodies in children

“…20,30 The unmet need for additional information on the disease-specific influence on model performance, as shown for example for midazolam, 40 was also stated in different studies, whereby this missing information is needed for further model refinement. 41 Given the scarcity of good quality paediatric data, the level of confidence in paediatric PBPK predictive performance is currently rather on the low to moderate end, posing a considerable challenge in predicting the PK especially in very young children (0-5 years) and in preterm neonates in particular. 19 clearance since both renal capacity and hepatic enzyme expression have reached adult levels.…”

Factors Affecting Successful Extrapolation of Ibuprofen Exposure from Adults to Pediatric Populations After Oral Administration of a Pediatric Aqueous Suspension

“…As PBPK models enable the creation of virtual subjects with different demographic characteristics and respective physiologies and the ethical challenges accompanying clinical studies in paediatrics, utilization of PBPK modeling in paediatric medicines development has proven to be a valuable tool for modeling age-dependent ADME processes and evaluate possible implications regarding drug exposure (9)(10)(11). In the literature, several studies have investigated agedependent oral drug absorption by employing a mechanistic model of the gastrointestinal tract (GI), such as the Advanced Compartmental Absorption and Transit (ACAT™) model (9,(12)(13)(14)(15)(16); however only few have attempted to simulate drug performance under different prandial and dosing conditions in paediatrics (17)(18)(19). Although different dosing conditions were addressed in these studies, the fed state conditions applied were mostly based on software default parameters (literature-based) for the paediatric subpopulation of interest.…”