title: Prediction of drug-drug interactions between various antidepressants and efavirenz or boosted protease inhibitors using a physiologically based pharmacokinetic modelling approach.
abstract: OBJECTIVE
  The rate of depression in patients with HIV is higher than in the general population. The use of antidepressants can have a beneficial effect, improving antiretroviral therapy adherence and consequently their efficacy and safety. Efavirenz and protease inhibitor boosted with ritonavir are major components of the antiretroviral therapy and are inducers and/or inhibitors of several cytochrome P450 (CYP) isoforms. Although antidepressants are prescribed to a significant proportion of patients treated with antiretrovirals, there are limited clinical data on drug-drug interactions. The aim of this study was to predict the magnitude of drug-drug interactions among efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants using an in vitro-in vivo extrapolation (IVIVE) model simulating virtual clinical trials.
  
  
  METHODS
  In vitro data describing the chemical characteristics, and absorption, distribution, metabolism and elimination (ADME) properties of efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants were obtained from published literature or generated by standard methods. Pharmacokinetics and drug-drug interaction were simulated using the full physiologically based pharmacokinetic model implemented in the Simcyp™ ADME simulator. The robustness of our modeling approach was assessed by comparing the magnitude of simulated drug-drug interactions using probe drugs to that observed in clinical studies.
  
  
  RESULTS
  Simulated pharmacokinetics and drug-drug interactions were in concordance with available clinical data. Although the simulated drug-drug interactions with antidepressants were overall weak to moderate according to the classification of the US FDA, fluoxetine and venlafaxine represent better candidates from a pharmacokinetic standpoint for patients on efavirenz and venlafaxine or citalopram for patients on boosted protease inhibitors.
  
  
  CONCLUSIONS
  The modest magnitude of interaction could be explained by the fact that antidepressants are substrates of multiple isoforms and thus metabolism can still occur through CYPs that are weakly impacted by efavirenz or boosted protease inhibitors. These findings indicate that IVIVE is a useful tool for predicting drug-drug interactions and designing prospective clinical trials, giving insight into the variability of exposure, sample size and time-dependent induction or inhibition.
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK. siccardi@liverpool.ac.uk
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.forename: Catia
authors.initials: C
authors.lastname: Marzolini
authors.forename: Kay
authors.initials: K
authors.lastname: Seden
authors.forename: Lisa
authors.initials: L
authors.lastname: Almond
authors.forename: Anna
authors.initials: A
authors.lastname: Kirov
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: David
authors.initials: D
authors.lastname: Back
mesh_terms: D000480:Alkynes; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D000069454:Darunavir; D004347:Drug Interactions; D006801:Humans; D008954:Models, Biological; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000480:Alkynes; D044966:Anti-Retroviral Agents; D000928:Antidepressive Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009842:Oligopeptides; D011725:Pyridines; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; C098320:efavirenz; D019438:Ritonavir; D000069454:Darunavir