title: Use of in vitro to in vivo extrapolation to predict the optimal strategy for patients switching from efavirenz to maraviroc or nevirapine.
abstract: OBJECTIVE
  In clinical practice, antiretroviral regimens are often interrupted or modified for intolerance and toxicity. The objective of this study was to develop an in vitro to in vivo extrapolation (IVIVE) approach to describe the interaction when efavirenz is switched to either maraviroc or nevirapine and to test different switching scenarios to identify the best strategy.
  
  
  METHODS
  In vitro data describing the chemical and absorption, tissue distribution, metabolism and excretion (ADME) characteristics of efavirenz, maraviroc and nevirapine were obtained from the literature, and used to simulate plasma exposures of these drugs using the Simcyp Population-Based Simulator. The predicted maraviroc and nevirapine exposures were compared with data from clinical studies evaluating their exposures following a switch from efavirenz.
  
  
  RESULTS
  Model predictions for maraviroc and nevirapine exposure were in agreement with observed data. The simulations suggest that the waning efavirenz induction effect following discontinuation necessitated increasing maraviroc to 600 mg twice daily for 1 week after efavirenz cessation. Alternatively, adequate exposure of maraviroc was shown with a dose of 450 mg for 2 weeks. Efavirenz waning induction did not affect nevirapine exposure.
  
  
  CONCLUSIONS
  IVIVE modelling successfully predicted patient drug exposure. This modelling technique is able to inform the design of clinical studies, and allows assessment of pragmatic dosing strategies under complex therapeutic scenarios.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK, a.schipani@liv.ac.uk.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Schipani
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Gerry
authors.initials: G
authors.lastname: Davies
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000480:Alkynes; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic / Q000379:methods; D003198:Computer Simulation; D003510:Cyclohexanes / Q000008:administration & dosage / Q000493:pharmacokinetics; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D005260:Female; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D008954:Models, Biological; D019829:Nevirapine / Q000008:administration & dosage / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003510:Cyclohexanes; D003521:Cyclopropanes; D023581:HIV Fusion Inhibitors; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; D019829:Nevirapine; C098320:efavirenz; D000077592:Maraviroc