title: Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study.
abstract: Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirine-atorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA sauzanne.khalilieh@merck.com.
authors.forename: Sauzanne
authors.initials: S
authors.lastname: Khalilieh
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
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: 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: Li
authors.initials: L
authors.lastname: Fan
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Noha
authors.initials: N
authors.lastname: Maklad
authors.affiliation: Pharma Medica Research Inc., St. Charles, Missouri, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Jordan
authors.affiliation: Pharma Medica Research Inc., Mississauga, ON, Canada.
authors.forename: Maureen
authors.initials: M
authors.lastname: Martell
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Iwamoto
mesh_terms: D000328:Adult; D019540:Area Under Curve; D000069059:Atorvastatin / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C000592662:doravirine; D000069059:Atorvastatin
keywords: CYP3A4; atorvastatin; doravirine; human immunodeficiency virus; hypercholesterolemia; pharmacokinetics