title: Physiology-based pharmacokinetics of caspofungin for adults and paediatrics.
abstract: OBJECTIVE
  Caspofungin (CAS) is an antifungal agent for intravenous application in adults and children. Our aim was the development and validation of a physiology-based pharmacokinetic (PBPK) model in order to predict the pharmacokinetics in different patient populations, particularly in paediatrics.
  
  
  METHODS
  A PBPK model for adults was built and validated with raw data of the two clinical trials CASLAMB and CASMTD. Afterwards, the model was scaled for paediatric patients under the consideration of known biochemical differences between adults and paediatrics.
  
  
  RESULTS
  The simulated results of the PBPK model were in good agreement with the observed values of the CASLAMB and CASMTD trial. Patients of the CASLAMB trial received CAS in combination with cyclosporine A (CsA), which leads to an increased AUC0-24h of CAS hypothetically due to an inhibition of the hepatic transport protein OATP1B1 by CsA. However, there was no difference in the transport rate of OATP1B1 between CASLAMB and CASMTD patients in the PBPK model, suggesting that CsA might not influence OATP1B1. Furthermore, the model was able to sufficiently predict the pharmacokinetics of paediatric patients compared to published data.
  
  
  CONCLUSIONS
  The final PBPK model of CAS without individualized parameter is able to predict the pharmacokinetics in different patient populations correctly. Thus, the model provides a basis for investigators to choose doses and sampling times for special populations such as infants and small children.
authors.affiliation: Institute of Pharmaceutical and Medical Chemistry - Department of Clinical Pharmacy, Westfaelische Wilhelms-University Muenster, Corrensstraße 48, 48149, Muenster, Germany, f_stad01@uni-muenster.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Stader
authors.forename: Gudrun
authors.initials: G
authors.lastname: Wuerthwein
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.forename: Joerg-Janne
authors.initials: JJ
authors.lastname: Vehreschild
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077336:Caspofungin; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D016572:Cyclosporine / Q000008:administration & dosage; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D054714:Echinocandins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D016014:Linear Models; D055666:Lipopeptides; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D019338:Polypharmacy; D011446:Prospective Studies; D011485:Protein Binding; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D016572:Cyclosporine; D000077336:Caspofungin