title: Effects of Tenapanor on Cytochrome P450-Mediated Drug-Drug Interactions.
abstract: Tenapanor (RDX5791, AZD1722) is an inhibitor of sodium/hydrogen exchanger isoform 3 in development for the treatment of constipation-predominant irritable bowel syndrome and the treatment of hyperphosphatemia in patients with chronic kidney disease on dialysis. We aimed to investigate whether tenapanor inhibits or induces cytochrome P450s (CYPs). In vitro experiments assessing the potential of tenapanor to affect various CYPs indicated that it could inhibit CYP3A4/5 (IC500.4-0.7 μM). An open-label, phase 1 clinical study (NCT02140268) evaluated the pharmacokinetics of the CYP3A4 substrate midazolam when administered with and without tenapanor. Healthy volunteers received a single oral dose of midazolam 7.5 mg on day 1 followed by tenapanor 15 mg twice daily on days 2 to 15, with an additional single 7.5-mg midazolam dose coadministered on day 15. Midazolam exposure was similar whether it was administered alone or with tenapanor (geometric least-squares mean ratio [90%CI] for [midazolam + tenapanor]/midazolam: area under the concentration-time curve, 107% [101% to 113%]; Cmax104% [89.6% to 122%]). Findings were similar for metabolites of midazolam. These results indicate that tenapanor 15 mg twice daily does not have a clinically relevant impact on CYP3A4 in humans and suggest that tenapanor can be coadministered with CYP3A4-metabolized drugs without affecting their exposure.
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Ardelyx Inc., Fremont, CA, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Rosenbaum
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Ahlqvist
authors.affiliation: AstraZeneca R&D, Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Rollison
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knutsson
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Bergur
authors.initials: B
authors.lastname: Stefansson
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Elebring
mesh_terms: D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D007546:Isoquinolines; D013449:Sulfonamides; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; C000599417:tenapanor
keywords: cytochrome P-450 CYP3A; cytochrome P-450 enzyme system; drug interactions; midazolam; tenapanor