title: Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects.
abstract: BACKGROUND
  Doravirine is a novel non-nucleoside inhibitor of HIV-1 reverse transcriptase with potent activity against wild-type virus (95% inhibitory concentration 19 nM, 50% human serum). Doravirine has low potential to cause drug-drug interactions since it is primarily eliminated by oxidative metabolism and does not inhibit or significantly induce drug-metabolizing enzymes.
  
  
  METHODS
  The pharmacokinetics and safety of doravirine were investigated in two double-blind, dose-escalation studies in healthy males. Thirty-two subjects received single doses of doravirine (6-1,200 mg) or matching placebo tablets; 40 subjects received doravirine (30-750 mg) or matching placebo tablets once daily for 10 days. In addition, the effect of doravirine (120 mg for 14 days) on single-dose pharmacokinetics of the CYP3A substrate midazolam was evaluated (10 subjects).
  
  
  RESULTS
  The maximum plasma concentration (Cmax) of doravirine was achieved within 1-5 h with an apparent terminal half-life of 12-21 h. Consistent with single-dose pharmacokinetics, steady state was achieved after approximately 7 days of once daily administration, with accumulation ratios (day 10/day 1) of 1.1-1.5 in the area under the plasma concentration-time curve during the dosing interval (AUC0-24 h), Cmax and trough plasma concentration (C24 h). All dose levels produced C24 h>19 nM. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC time zero to infinity (AUC0-∞) and C24 h with no change in Cmax. Midazolam AUC0-∞ was slightly reduced by coadministration of doravirine (geometric mean ratio 0.82, 90% CI 0.70, 0.97). There was no apparent relationship between adverse event frequency or intensity and doravirine dose. No rash or significant central nervous system events other than headache were reported.
  
  
  CONCLUSIONS
  Doravirine is generally well tolerated in single doses up to 1,200 mg and multiple doses up to 750 mg once daily for up to 10 days, with a pharmacokinetic profile supportive of once-daily dosing. Doravirine at steady state slightly reduced the exposure of coadministered midazolam, to a clinically unimportant extent.
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA. matt_anderson@merck.com.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Anderson
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Gilmartin
authors.forename: Caroline
authors.initials: C
authors.lastname: Cilissen
authors.forename: Inge
authors.initials: I
authors.lastname: De Lepeleire
authors.forename: Luc
authors.initials: L
authors.lastname: Van Bortel
authors.forename: Marissa F
authors.initials: MF
authors.lastname: Dockendorf
authors.forename: Ernestina
authors.initials: E
authors.lastname: Tetteh
authors.forename: June K
authors.initials: JK
authors.lastname: Ancona
authors.forename: Rachael
authors.initials: R
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Joan R
authors.initials: JR
authors.lastname: Butterton
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C000592662:doravirine; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam