title: Use of a physiologically based pharmacokinetic model to simulate drug-drug interactions between antineoplastic and antiretroviral drugs.
abstract: Co-administration of antineoplastics with ART is challenging due to potential drug-drug interactions (DDIs). However, trials specifically assessing such DDIs are lacking. Our objective was to simulate DDIs between the antineoplastics erlotinib and gefitinib with key antiretroviral drugs and to predict dose adjustments using a physiologically based pharmacokinetic (PBPK) model.
  
  
  
  In vitro data describing chemical properties and pharmacokinetic processes of each drug and their effect on cytochrome P450 isoforms were obtained from the literature. Plasma drug-concentration profiles were simulated in a virtual population of 50 individuals receiving erlotinib or gefitinib alone or with darunavir/ritonavir, efavirenz or etravirine. Simulated pharmacokinetic parameters and the magnitude of DDIs with probe drugs (midazolam, maraviroc) were compared with literature values. Erlotinib and gefitinib pharmacokinetics with and without antiretrovirals were compared and dose-adjustment strategies were evaluated.
  
  
  
  Simulated parameters of each drug and the magnitude of DDIs with probe drugs were in agreement with reference values. Darunavir/ritonavir increased erlotinib and gefitinib exposure, while efavirenz and etravirine decreased erlotinib and gefitinib concentrations. Based on our predictions, dose-adjustment strategies may consist of once-daily dosing erlotinib at 25 mg and gefitinib at 125 mg with darunavir/ritonavir; or erlotinib at 200 mg and gefitinib at 375 mg with etravirine. The interaction with efavirenz was not overcome even after doubling erlotinib or gefitinib doses.
  
  
  
  PBPK models predicted the in vivo pharmacokinetics of erlotinib, gefitinib and the antiretrovirals darunavir/ritonavir, efavirenz and etravirine, and the DDIs between them. The simulated dose-adjustments may represent valuable strategies to optimize antineoplastic therapy in HIV-infected patients.
authors.affiliation: Lluita contra la Sida Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.|Universitat Autónoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Moltó
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Rajith
authors.initials: R
authors.lastname: Rajoli
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: Universitat Autónoma de Barcelona (UAB), Barcelona, Spain.|PKPD Modeling and Simulation, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau - Institut d'Investigacio Biomedica Sant Pau, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Valle
authors.affiliation: Lluita contra la Sida Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Miranda
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.affiliation: Lluita contra la Sida Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.|Universitat Autónoma de Barcelona (UAB), Barcelona, Spain.|Universitat de Vic (UVic), Vic, Spain.|IrsiCaixa Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077156:Gefitinib; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008954:Models, Biological; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib