title: Daclatasvir 30 mg/day is the correct dose for patients taking atazanavir/cobicistat.
abstract: Atazanavir is boosted with the cytochrome P450 (CYP) 3A4 inhibitor ritonavir. When combined with the CYP3A4 substrate daclatasvir, the daclatasvir dosage should be reduced from 60 to 30 mg once daily. Recently, cobicistat was licensed as a CYP3A booster and used with atazanavir.
  
  
  
  To determine whether the fixed-dose combination of atazanavir/cobicistat has an influence on daclatasvir pharmacokinetics comparable to that of the separate agents atazanavir and ritonavir.
  
  
  
  A prospective, open-label, two-period, randomized, cross-over trial was performed in 16 healthy subjects (NCT02565888). Treatment consisted of 300/100 mg of atazanavir/ritonavir plus 30 mg of daclatasvir once daily (reference) and a second period of 300/150 mg of atazanavir/cobicistat plus 30 mg of daclatasvir once daily (test). A 24 h pharmacokinetic, steady-state curve was recorded for all drugs. Geometric mean ratios (GMRs) with 90% CI were calculated for daclatasvir and atazanavir AUCτand Cmaxto compare the effect of both treatments (test versus reference). Laboratory safety and adverse events were evaluated throughout the trial.
  
  
  
  All 16 healthy subjects completed the study. Median (range) age and BMI were 48.5 (21-55) years and 24.5 (19.0-29.2) kg/m2, respectively. Pharmacokinetic parameters of ritonavir and cobicistat were comparable to those in the literature. The GMRs (90% CI) of daclatasvir AUCτand Cmax(test versus reference) were 101% (92%-111%) and 97% (89%-106%), respectively. Atazanavir GMRs (90% CI) of AUCτand Cmaxwere 82% (75%-79%) and 74% (68%-81%), respectively. No serious adverse events were reported.
  
  
  
  Atazanavir/cobicistat and atazanavir/ritonavir had a similar influence on daclatasvir pharmacokinetics in healthy volunteers. Daclatasvir at 30 mg once daily is the correct dose when combined with atazanavir/cobicistat.
authors: Department of Pharmacy, Radboud Institute for Health Sciences (RHIS) and Radboud University Medical Center, Nijmegen, The Netherlands elise.smolders@radboudumc.nl.
authors: E J
authors: EJ
authors: Smolders
authors: Department of Pharmacy, Radboud Institute for Health Sciences (RHIS) and Radboud University Medical Center, Nijmegen, The Netherlands.
authors: E P H
authors: EP
authors: Colbers
authors: Department of Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: C T M M
authors: CT
authors: de Kanter
authors: Department of Pharmacy, Radboud Institute for Health Sciences (RHIS) and Radboud University Medical Center, Nijmegen, The Netherlands.
authors: K
authors: K
authors: Velthoven-Graafland
authors: Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: J P H
authors: JP
authors: Drenth
authors: Department of Pharmacy, Radboud Institute for Health Sciences (RHIS) and Radboud University Medical Center, Nijmegen, The Netherlands.
authors: D M
authors: DM
authors: Burger
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069446:Atazanavir Sulfate / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002219:Carbamates; D000069547:Cobicistat / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011759:Pyrrolidines; D019438:Ritonavir / Q000493:pharmacokinetics / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; D065692:Cytochrome P-450 CYP3A Inhibitors; D007093:Imidazoles; D011759:Pyrrolidines; D000069446:Atazanavir Sulfate; D014633:Valine; C549273:daclatasvir; D000069547:Cobicistat; D019438:Ritonavir