title: Pharmacokinetics and safety of twice-daily atazanavir 300 mg and raltegravir 400 mg in healthy individuals.
abstract: BACKGROUND
  Atazanavir plus raltegravir 300/400 mg twice daily is being explored as a ritonavir- and nucleoside-sparing treatment strategy. The pharmacokinetics and safety of this combination in healthy individuals were evaluated.
  
  
  METHODS
  A total of 22 healthy individuals received raltegravir 400 mg on days 1-5, atazanavir 300 mg on days 6-12 and atazanavir plus raltegravir 300/400 mg on days 13-26, twice daily with a light meal. Serial blood samples were collected 12 h after the morning dose on days 5, 12 and 26; safety assessments, clinical laboratory data and serial electrocardiograms (ECGs) at 0, 2 and 6 h were obtained.
  
  
  RESULTS
  Raltegravir coadministration reduced atazanavir geometric mean maximum plasma concentration (C(max)), area under the plasma concentration-time curve from 0 to 12 h post-dose (AUC(0-12)) and trough plasma concentration (C(min)) by 11%, 17% and 29%, respectively, compared with atazanavir alone. Geometric mean atazanavir C(min) was 817 ng/ml (range 250-1,550) with raltegravir coadministration. Atazanavir increased raltegravir geometric mean C(max), AUC(0-12) and C(min) by 39%, 54% and 48%, respectively. All adverse events were of mild or moderate intensity. Hyperbilirubinaemia and ECG PR increases with atazanavir were similar to those of atazanavir/ritonavir once daily. No corrected QT prolongations were noted. Mean QRS increase from baseline was 11.0 ms (range 2-25) after receiving atazanavir for 7 days; no further QRS increase was noted and no QRS interval was >120 ms with raltegravir coadministration. No ECG changes were observed with raltegravir alone.
  
  
  CONCLUSIONS
  Coadministration of atazanavir and raltegravir 300/400 mg twice daily decreased atazanavir AUC(0-12) and C(min) relative to atazanavir alone, and increased AUC(0-12) of raltegravir relative to raltegravir alone. Atazanavir and raltegravir alone and coadministered appeared safe and well-tolerated.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, R&D, Hopewell, NJ, USA. li.zhu@bms.com
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Joan
authors.initials: J
authors.lastname: Butterton
authors.forename: Anna
authors.initials: A
authors.lastname: Persson
authors.forename: Michele
authors.initials: M
authors.lastname: Stonier
authors.forename: Wendy
authors.initials: W
authors.lastname: Comisar
authors.forename: Deborah
authors.initials: D
authors.lastname: Panebianco
authors.forename: Sheila
authors.initials: S
authors.lastname: Breidinger
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.forename: Richard
authors.initials: R
authors.lastname: Bertz
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D013997:Time Factors; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D009842:Oligopeptides; D011725:Pyridines; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000069446:Atazanavir Sulfate