The Effect of GS-548351 on the Pharmacokinetics of Midazolam Following Multiple Doses of ANS-6637 in Healthy Adults

J Clin Pharmacol. 2020 Dec;60(12):1598-1605. doi: 10.1002/jcph.1672. Epub 2020 Jun 23.


ANS-6637, a pro-drug of GS-548351, is a selective, reversible inhibitor of aldehyde dehydrogenase isoform 2 under development as an anticraving agent for the treatment of substance use disorders. In vitro testing indicates that GS-548351 is an inhibitor and inducer of cytochrome P450 family 3, subfamily A (CYP3A). In this phase 1 single-center, open-label, fixed-sequence drug-drug interaction study we assessed the impact of steady-state GS-548351 on single-dose pharmacokinetics of midazolam, an index substrate for CYP3A. Twelve healthy volunteers received 600 mg of ANS-6637 by mouth daily from study days 3 to 8 and a single 5-mg oral dose of midazolam on days 1 and 8. Pharmacokinetic samples were collected over 24 hours on days 1 and 8, then analyzed using liquid chromatography-tandem mass spectrometry. The prespecified no-effect range for the 90% confidence interval (CI) of the geometric mean ratio (GMR) of midazolam coadministered with ANS-6637 (day 8) compared with midazolam alone (day 1) was 0.7-1.43. There was an increase in midazolam AUC0-∞ (GMR [90%CI]) that was within the no-effect range (1.26 [1.12-1.425]) and an increase in midazolam Cmax that was outside the range (1.22 [1.03-1.45]). The AUC0-∞ (1.08 [0.91-1.27]) and Cmax (0.95 [0.75-1.2]) of 1-hydroxymidazolam, the primary metabolite of midazolam, were also within the no-effect range. A single grade 3 adverse event (alanine aminotransferase elevation) was identified and resolved following discontinuation of the study drug. Overall, multidose ANS-6637 was well tolerated and did not alter the PK of midazolam beyond a small increase in AUC0-∞ that is unlikely to be clinically significant.

Keywords: drug-drug interactions; opioid use; pharmacokinetics; substance use.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Intramural

MeSH terms

  • Administration, Oral
  • Adult
  • Aldehyde Dehydrogenase / antagonists & inhibitors
  • Area Under Curve
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Administration Schedule
  • Drug Interactions
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Half-Life
  • Healthy Volunteers
  • Humans
  • Male
  • Midazolam / administration & dosage
  • Midazolam / analogs & derivatives
  • Midazolam / blood
  • Midazolam / metabolism
  • Midazolam / pharmacokinetics*
  • Organic Chemicals / administration & dosage
  • Organic Chemicals / pharmacology*
  • Prodrugs / administration & dosage
  • Prodrugs / adverse effects
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*


  • Enzyme Inhibitors
  • GS-548351
  • Organic Chemicals
  • Prodrugs
  • 1-hydroxymethylmidazolam
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Aldehyde Dehydrogenase
  • Midazolam