title: Dolutegravir and elvitegravir plasma concentrations following cessation of drug intake.
abstract: OBJECTIVE
  To evaluate dolutegravir and elvitegravir/cobicistat pharmacokinetics in HIV-negative volunteers up to 10 days after drug cessation.
  
  
  METHODS
  Healthy volunteers received 50 mg of dolutegravir once-daily for 10 days, then underwent a 9 day wash-out period, and then received elvitegravir/cobicistat as part of Stribild(®) (245 mg of tenofovir, 200 mg of emtricitabine, 150 mg of elvitegravir and 150 mg of cobicistat) for 10 days. Serial pharmacokinetic (PK) sampling occurred prior to the final dose of each course and at regular intervals for up to 216 h (10 days) after drug cessation. Concentrations were determined by LC-MS/MS, and PK parameters were illustrated as geometric mean and 90% CI.
  
  
  RESULTS
  Seventeen volunteers completed the study. For dolutegravir, plasma terminal elimination t1/2 to the last measurable concentration (within 216 h) was longer than its t1/2 within the dosing interval (0-24 h): 14.3 h (12.9-15.7 h) versus 23.1 h (19.7-26.6 h); conversely, the terminal elimination t1/2 for elvitegravir was lower than its t1/2 within the dosing interval (0-24 h): 10.8 h (9.7-13.0 h) versus 5.2 h (4.7-6.1 h). Dolutegravir concentrations were above the protein-adjusted (PA) IC90 (64 ng/mL) in 100% of subjects after 36 and 48 h and in 94% after 60 and 72 h. All subjects had detectable dolutegravir concentrations at 96 h, a mean of 23.5% above the IC90. Elvitegravir concentrations were above the PA IC95 (45 ng/mL) in 100% of subjects at 24 h, 65% at 36 h but 0% after 48 h.
  
  
  CONCLUSIONS
  Our data show marked differences in the elimination rates of dolutegravir and elvitegravir following treatment interruption, which is likely to impact the extent to which drug doses can be delayed or missed. They suggest that clinical differences may emerge in patients who have suboptimal adherence.
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, UK University of Liverpool, Liverpool, UK.
authors.forename: Emilie
authors.initials: E
authors.lastname: Elliot
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Alieu
authors.initials: A
authors.lastname: Amara
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, UK University of Liverpool, Liverpool, UK.
authors.forename: Akil
authors.initials: A
authors.lastname: Jackson
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, UK.
authors.forename: Graeme
authors.initials: G
authors.lastname: Moyle
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, UK Imperial College, London, UK marta.boffito@chelwest.nhs.uk.
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016903:Drug Monitoring; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000099226:Dolutegravir; C509700:elvitegravir