title: Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics.
abstract: Doravirine is a novel, potent, nonnucleoside reverse-transcriptase inhibitor currently in development for HIV-1 infection treatment. As a substrate for CYP3A-mediated metabolism, doravirine could potentially be affected by liver-function changes. As a portion of the HIV-1-infected population has varying degrees of liver impairment, we investigated the effect of moderate hepatic impairment on the pharmacokinetic profile and tolerability of single-dose doravirine 100 mg in otherwise healthy subjects. A total of 16 subjects aged 44-64 years took part in the open-label, single-dose trial: 8 with moderate hepatic impairment (Child-Pugh score, 7-9; 6 men, 2 women) and 8 healthy individuals (mean age and height matched with the impairment group; 6 men, 2 women). Subjects with hepatic impairment were required to have chronic, stable hepatic impairment with features of cirrhosis of any etiology. Blood sampling revealed that doravirine exposure was similar in both groups. The observed geometric least-squares mean ratio (90% confidence interval; moderately impaired/healthy subjects) was 0.99 (0.72-1.35) for AUC0-∞, 0.93 (0.74-1.18) for AUC0-24 h, 0.90 (0.66-1.24) for Cmax, and 0.99 (0.74-1.33) for C24 h. Geometric mean apparent terminal t½ was ∼18 hours for both groups, whereas median Tmaxwas 2 hours (range, 1-6 hours) and 2.5 hours (range, 1-3 hours) for impaired and healthy individuals, respectively. In addition, doravirine was generally well tolerated. The results demonstrate that moderate hepatic impairment does not have a clinically meaningful effect on doravirine pharmacokinetics. Therefore, dose adjustment should not be necessary in patients with both HIV-1 and moderate hepatic impairment.
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Sauzanne
authors.initials: S
authors.lastname: Khalilieh
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Ka Lai
authors.initials: KL
authors.lastname: Yee
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Liu
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Rosa I
authors.initials: RI
authors.lastname: Sanchez
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: Patrice
authors.initials: P
authors.lastname: Auger
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Ilias
authors.initials: I
authors.lastname: Triantafyllou
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Stypinski
authors.affiliation: Clinical Pharmacology of Miami, Inc., Miami, FL, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Lasseter
authors.affiliation: Orlando Clinical Research Center, Orlando, FL, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Marbury
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Iwamoto
mesh_terms: D000328:Adult; D019540:Area Under Curve; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011728:Pyridones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014230:Triazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C000592662:doravirine
keywords: CYP3A; clinical trial; doravirine; hepatic insufficiency; pharmacokinetics; phase 1