title: The Effect of Single and Multiple Doses of Rifampin on the Pharmacokinetics of Doravirine in Healthy Subjects.
abstract: OBJECTIVE
  Doravirine is a novel, next-generation, non-nucleoside reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretrovirals. Doravirine is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein. Rifampin (rifampicin) is used for treating tuberculosis in patients who are co-infected with human immunodeficiency virus. Rifampin demonstrates organic anion-transporting polypeptide 1B1 and P-glycoprotein inhibition after single-dose administration and CYP3A and P-glycoprotein induction after multiple-dose administration. The objective of this study was to evaluate the effects of co-administration of single and multiple doses of rifampin on doravirine pharmacokinetics.
  
  
  METHODS
  In period 1 of this open-label, two-period, fixed-sequence study in healthy adults, subjects received single-dose doravirine 100 mg; blood samples for measuring plasma concentration were collected pre-dose and up to 72 h post-dose. In period 2, following a 7-day washout, subjects received doravirine 100 mg and rifampin 600 mg on day 1, rifampin 600 mg daily on days 4-18, with doravirine 100 mg co-administered on day 17; blood samples were collected pre-dose and up to 72 h post-dose on day 1 and up to 48 h post-dose on day 17. Safety assessments included adverse events, physical examinations, vital signs, and clinical laboratory measurements.
  
  
  RESULTS
  Ten subjects completed the study. Doravirine area under the concentration-time curve from time zero extrapolated to infinity and plasma concentration at 24 h post-dose were comparable in the presence and absence of single-dose rifampin [geometric mean ratios (90% confidence intervals)] of 0.91 (0.78-1.06) and 0.90 (0.80-1.01), respectively. Doravirine maximum plasma concentration increased when co-administered with single-dose rifampin vs. doravirine alone, geometric mean ratio (90% confidence interval): 1.40 (1.21-1.63). Reductions in doravirine geometric mean ratios (90% confidence interval), area under the concentration-time curve from time zero extrapolated to infinity: 0.12 (0.10-0.15), plasma concentration at 24 h post-dose: 0.03 (0.02-0.04), maximum plasma concentration: 0.43 (0.35-0.52), and apparent terminal half-life were observed when co-administered with multiple-dose rifampin vs. doravirine administered alone. Doravirine was well tolerated. Adverse events were mild and resolved by study completion.
  
  
  CONCLUSIONS
  Doravirine co-administration with single-dose rifampin indicated that inhibition of organic anion-transporting polypeptide uptake transporters and P-glycoprotein has little impact on doravirine pharmacokinetics. Long-term co-administration of rifampin or other strong CYP3A inducers with doravirine will likely reduce its efficacy.
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA. ka_yee@merck.com.|, 770 Sumneytown Pike, WP75B-100, West Point, PA, 19486, USA. ka_yee@merck.com.
authors.forename: Ka Lai
authors.initials: KL
authors.lastname: Yee
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Sauzanne G
authors.initials: SG
authors.lastname: Khalilieh
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Rosa I
authors.initials: RI
authors.lastname: Sanchez
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: Matt S
authors.initials: MS
authors.lastname: Anderson
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Manthos
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Judge
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: John
authors.initials: J
authors.lastname: Brejda
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Joan R
authors.initials: JR
authors.lastname: Butterton
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011728:Pyridones / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage* / Q000494:pharmacology; D014230:Triazoles / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065701:Cytochrome P-450 CYP3A Inducers; D027381:Liver-Specific Organic Anion Transporter 1; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C000592662:doravirine; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin