title: Dolutegravir plasma concentrations according to companion antiretroviral drug: unwanted drug interaction or desirable boosting effect?
abstract: Studies in healthy volunteers have shown that the recently approved HIV integrase inhibitor dolutegravir has limited drug-to-drug interaction profile. Here we carried out a pharmacokinetic survey in HIV-infected patients given dolutegravir as part of their antiretroviral therapy.
  
  
  
  Dolutegravir plasma trough concentrations were measured in 78 HIV-infected patients given the drug in combination with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or abacavir/lamivudine. Drug concentrations were assessed by high performance liquid chromatography method with UV-detection.
  
  
  
  All patients were given dolutegravir at 50 mg once daily, with median trough drug concentrations of 1,096 (664-2,356) ng/ml (interindividual coefficient of variation: 85.3%). Patients given dolutegravir with atazanavir had significantly higher drug concentrations compared with those given darunavir, rilpivirine or abacavir/lamivudine (2,399 [1,929-4,070] versus 738 [552-1,048], 603 [432-1,373] or 1,045 [856-1,115] ng/ml; P<0.001 for all comparisons). By multivariate analyses, only companion antiretroviral drug resulted in significant association with dolutegravir plasma trough concentrations (P=0.012).
  
  
  
  Atazanavir coadministration significantly inhibited dolutegravir metabolism, ultimately resulting in a two- to fourfold increase in drug disposition compared with other antiretroviral drugs. This boosting effect of atazanavir could be used to optimize dolutegravir dosing in particular clinical settings.
authors.affiliation: Unit of Clinical Pharmacology, L. Sacco University Hospital, Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Cattaneo
authors.affiliation: Department of Infectious Diseases, L. Sacco University Hospital, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Minisci
authors.affiliation: Unit of Clinical Pharmacology, L. Sacco University Hospital, Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cozzi
authors.affiliation: Department of Infectious Diseases, L. Sacco University Hospital, Milan, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Riva
authors.affiliation: Department of Infectious Diseases, L. Sacco University Hospital, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Meraviglia
authors.affiliation: Clinical Pharmacology Unit, CNR Institute of Neuroscience, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università di Milano, Milan, Italy.|Scientific Institute IRCCS E. Medea, Parini, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.affiliation: Department of Infectious Diseases, L. Sacco University Hospital, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Galli
authors.affiliation: Department of Infectious Diseases, L. Sacco University Hospital, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasoni
mesh_terms: D019380:Anti-HIV Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D000069446:Atazanavir Sulfate / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018791:CD4 Lymphocyte Count; D000069454:Darunavir / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D004334:Drug Administration Schedule; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019259:Lamivudine / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012189:Retrospective Studies; D000068696:Rilpivirine / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D019562:Viral Load / Q000187:drug effects; D000099226:Dolutegravir; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D000069454:Darunavir; D015224:Dideoxynucleosides; D004338:Drug Combinations; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D019259:Lamivudine; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068696:Rilpivirine; D000099226:Dolutegravir; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir