title: A Two-Way Steady-State Pharmacokinetic Interaction Study of Doravirine (MK-1439) and Dolutegravir.
abstract: Doravirine, a non-nucleoside reverse-transcriptase inhibitor in development for the treatment of patients with human immunodeficiency virus-1 infection, has potential to be used concomitantly in antiretroviral therapy with dolutegravir, an integrase strand transfer inhibitor. The pharmacokinetic interactions between these drugs were therefore assessed.
  
  
  
  Oral formulations of doravirine and dolutegravir were dosed both individually and concomitantly once daily in healthy adults. Twelve subjects (six were male), 23-42 years of age, were enrolled and 11 completed this phase I, open-label, three-period, fixed-sequence study per protocol; one subject was discontinued for a positive cotinine test at admission to period 2. In period 1, dolutegravir 50 mg was administered for 7 days. After a 7-day washout, doravirine 200 mg was dosed for 7 days in period 2, followed (without washout) by both doravirine and dolutegravir simultaneously for 7 days in period 3. Plasma samples were taken to determine dolutegravir and doravirine concentrations.
  
  
  
  The steady-state concentration 24 h post-dose (C24) of dolutegravir was not substantially altered by co-administration of doravirine multiple doses; area under the plasma concentration-time curve from dosing to 24 h post-dose (AUC0-24), maximum concentration (Cmax), and C24geometric mean ratios were 1.36, 1.43, and 1.27, respectively. The pharmacokinetics of doravirine was not affected by multiple doses of dolutegravir (geometric mean ratios: 1.00, 0.98, and 1.06 for AUC0-24, C24, and Cmax, respectively). Both drugs were generally well tolerated.
  
  
  
  The results of this study demonstrate that concomitant administration of doravirine and dolutegravir in healthy subjects causes no clinically significant alteration in the pharmacokinetic and safety profiles of the two drugs, thereby supporting further evaluation of co-administration of these agents for human immunodeficiency virus-1 treatment.
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA. matt_anderson@merck.com.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Anderson
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA.
authors.forename: Sauzanne
authors.initials: S
authors.lastname: Khalilieh
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA.
authors.forename: Ka Lai
authors.initials: KL
authors.lastname: Yee
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Liu
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Rizk
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA.
authors.forename: Vedangi
authors.initials: V
authors.lastname: Shah
authors.affiliation: PAREXEL, Baltimore, MD, USA.
authors.forename: Azra
authors.initials: A
authors.lastname: Hussaini
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Ivy
authors.initials: I
authors.lastname: Song
authors.affiliation: ViiV Healthcare, Research Triangle Park, NC, USA.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Ross
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA.
authors.forename: Joan R
authors.initials: JR
authors.lastname: Butterton
mesh_terms: D000328:Adult; D019540:Area Under Curve; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005215:Fasting / Q000378:metabolism; D005260:Female; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D014230:Triazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; D000099226:Dolutegravir; C000592662:doravirine