title: Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects.
abstract: Doravirine is a novel, potent nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection that demonstrates a high genetic barrier to resistance and that has been well tolerated in studies to date. Doravirine is a candidate for patients switching from less-well-tolerated NNRTIs, such as efavirenz. While doravirine is a cytochrome P450 3A4 (CYP3A4) substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following a switch from efavirenz to doravirine were assessed. This was a 3-period, fixed-sequence, open-label study. Healthy adults were dosed with doravirine at 100 mg for 5 days once daily (QD) (period 1). Following a 7-day washout, efavirenz was administered at 600 mg QD for 14 days (period 2). Subsequently, doravirine was administered at 100 mg QD for 14 days (period 3). Blood samples were collected for pharmacokinetic analyses. Twenty healthy subjects were enrolled, and 17 completed the study. One day after efavirenz cessation, the doravirine area under the concentration-time curve from predosing to 24 h postdosing (AUC0-24), maximum observed plasma concentration (Cmax), and observed plasma concentration at 24 h postdosing (C24) were reduced by 62%, 35%, and 85%, respectively, compared with the values with no efavirenz pretreatment. These decreases recovered to 32%, 14%, and 50% for AUC0-24, Cmax, and C24, respectively, by day 14 after efavirenz cessation. The doravirine C24reached projected therapeutic trough concentrations, based on in vitro efficacy, on day 2 following efavirenz cessation. Geometric mean efavirenz concentrations were 3,180 ng/ml on day 1 and 95.7 ng/ml on day 15, and efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4. Though doravirine exposure was transiently decreased following efavirenz treatment cessation, dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed population.
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA ka_yee@merck.com.
authors.forename: Ka Lai
authors.initials: KL
authors.lastname: Yee
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Rosa I
authors.initials: RI
authors.lastname: Sanchez
authors.affiliation: Celerion, Lincoln, Nebraska, USA.
authors.forename: Patrice
authors.initials: P
authors.lastname: Auger
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Liu
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Ilias
authors.initials: I
authors.lastname: Triantafyllou
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.affiliation: Celerion, Lincoln, Nebraska, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Di Spirito
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Sauzanne G
authors.initials: SG
authors.lastname: Khalilieh
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D003521:Cyclopropanes; D004347:Drug Interactions; D005260:Female; D006261:Headache / Q000139:chemically induced; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D011728:Pyridones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014230:Triazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D011728:Pyridones; D014230:Triazoles; C000592662:doravirine; C098320:efavirenz
keywords: HIV; doravirine; drug interactions; efavirenz; pharmacokinetics