title: Population pharmacokinetics of everolimus in cardiac recipients: comedications, ABCB1, and CYP3A5 polymorphisms.
abstract: BACKGROUND
  The aim of this study was, using routine drug monitoring data, to identify patient characteristics that may influence everolimus (EVE) pharmacokinetic parameters and to develop a population pharmacokinetic model to predict EVE whole blood concentrations in cardiac recipients.
  
  
  METHODS
  Fifty-nine patients were enrolled in the prospective study. Patient's characteristics were recorded including biological covariates and treatments. CYP3A5 and ABCB1 polymorphisms were determined. Seven hundred seventy-five EVE blood samples were collected for routine drug monitoring. Population pharmacokinetic modeling was carried out using the nonlinear mixed-effects modeling program. Results were analyzed according to a 1-compartment pharmacokinetic model with linear absorption and elimination. The model was evaluated using a bootstrap method and a visual predictive check procedure.
  
  
  RESULTS
  The pharmacokinetic of EVE in cardiac recipients was best described by a 1-compartment model. Interindividual variability was best described by an exponential error model and residual error by a proportional plus additive error model. Estimation of EVE apparent clearance (3.33 ± 0.20 L/h) and apparent volume of distribution (146 ± 33 L) were in accordance with previously published data. Bilirubinemia and cyclosporine significantly influenced EVE clearance. Some covariates that were expected to influence EVE clearance, for example, ABCB1 and CYP3A5 polymorphisms, were not evidenced. No covariates influenced the volume of distribution of EVE.
  
  
  CONCLUSIONS
  This study is the first population pharmacokinetic model of EVE in heart transplantation patients. It allows a better description of the pharmacokinetics of EVE. The present population pharmacokinetic model allows estimating a priori and a posteriori EVE concentrations in cardiac recipients and could limit the over and under drug exposure in this population.
authors.affiliation: Pharmacy Department, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris AP-HP, Paris, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Lemaitre
authors.forename: Elodie
authors.initials: E
authors.lastname: Bezian
authors.forename: Lauriane
authors.initials: L
authors.lastname: Goldwirt
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Shaida
authors.initials: S
authors.lastname: Varnous
authors.forename: Saik
authors.initials: S
authors.lastname: Urien
authors.forename: Marie
authors.initials: M
authors.lastname: Antignac
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010297:Paris; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D000068338:Everolimus; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus