title: Simulation of the impact of rifampicin on once-daily darunavir/ritonavir pharmacokinetics and dose adjustment strategies: a population pharmacokinetic approach.
abstract: OBJECTIVE
  Treatment of HIV/TB coinfection is challenging due to potent drug-drug interactions between antiretrovirals and rifampicin. The effect of rifampicin on darunavir/ritonavir has not been studied. Population pharmacokinetic modelling was applied to investigate the interaction and generate alternative doses to inform clinical trial design.
  
  
  METHODS
  Darunavir/ritonavir concentrations were modelled simultaneously, including data from three studies in HIV patients (n = 51, 7 female). The darunavir/ritonavir-rifampicin interaction was assumed to mimic that previously observed with lopinavir/ritonavir. Daily darunavir/ritonavir 800/100 mg was simulated as a reference (n = 1000; -rifampicin). Simulations with apparent oral clearance increased by 71% and 36% and relative bioavailability decreased by 20% and 45% for darunavir and ritonavir, respectively, were performed for +rifampicin, 600 mg once daily (n = 1000). Darunavir/ritonavir 1200/200 mg once daily, 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily +rifampicin were simulated. Darunavir parameters for each dose +rifampicin were compared with -rifampicin by geometric mean ratio (90% CI).
  
  
  RESULTS
  A maximum effect model, with ritonavir inhibiting darunavir clearance, best described the relationship between the drugs. Compared with -rifampicin, simulated darunavir AUC0-24 was 57%, 26%, 1% and 16% lower for 800/100 mg once daily, 1200/200 mg once daily, 1600/200 mg once daily and 800/100 mg twice daily +rifampicin, respectively; but 39% higher with 1200/150 mg twice daily +rifampicin.
  
  
  CONCLUSIONS
  Darunavir/ritonavir 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily could potentially overcome reduced darunavir concentrations with rifampicin. In the absence of clinical data, modelling and simulation may be useful to predict drug-drug interactions and aid optimal dose selection.
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK laurad@liverpool.ac.uk.
authors.forename: Laura
authors.initials: L
authors.lastname: Dickinson
authors.affiliation: Faculty of Medicine, Imperial College, London, UK Department of HIV & GU Medicine, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Winston
authors.affiliation: Faculty of Medicine, Imperial College, London, UK St Stephen's Centre, Chelsea & Westminster Foundation Trust, London, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
mesh_terms: D000328:Adult; D019540:Area Under Curve; D003198:Computer Simulation; D000069454:Darunavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019438:Ritonavir; D012293:Rifampin; D000069454:Darunavir