title: Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy subjects: results from two clinical trials.
abstract: OBJECTIVE
  Two phase I, open-label trials in healthy subjects assessed whether co-administration with CYP3A4/CYP2C19 inhibitors, itraconazole/fluconazole (study A), or CYP3A4 inducer, rifampicin (study B), affects the exposure, safety/tolerability and pharmacokinetics of selumetinib and its metabolite N-desmethyl selumetinib.
  
  
  METHODS
  In study A (n = 26), subjects received a single dose of selumetinib 25 mg and, after 4 days of washout, were randomized to treatment 1 (itraconazole 200 mg twice daily on days 1-11) or treatment 2 (fluconazole 400 mg on day 1 then 200 mg/day on days 2-11) plus co-administration of single-dose selumetinib 25 mg on day 8 (selumetinib staggered 4 h after itraconazole/fluconazole dose); Twenty-one days after discharge/washout, subjects received the alternate treatment. In study B (n = 22), subjects received a single dose of selumetinib 75 mg (day 1) then rifampicin 600 mg/day (days 4-14) plus a single dose of selumetinib 75 mg on day 12. Pharmacokinetic analysis and safety assessments were performed.
  
  
  RESULTS
  Selumetinib co-administered with itraconazole, fluconazole (selumetinib staggered 4 h after itraconazole/fluconazole dose), or rifampicin was well tolerated. Selumetinib exposure was higher when co-administered with itraconazole or fluconazole (area under the plasma concentration-time curve (AUC) increased by 49 and 53%, respectively; maximum plasma concentration (Cmax) increased by 19 and 26%, respectively) but lower when co-dosed with rifampicin (AUC and Cmaxdecreased by 51 and 26%, respectively) versus selumetinib dosed alone. Co-administration with itraconazole or rifampicin decreased N-desmethyl selumetinib AUC(0-t)(11 and 55%, respectively), and Cmax(25 and 18%, respectively), with fluconazole, AUC(0-t)increased by 40%, but there was no effect on Cmax.
  
  
  CONCLUSIONS
  Co-administration of CYP3A4/CYP2C19 inhibitors will likely increase exposure to selumetinib, while CYP3A4 inducers will likely reduce its exposure.
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Angela W
authors.initials: AW
authors.lastname: Dymond
authors.affiliation: AstraZeneca R&D, AstraZeneca Global Medicines Development, Da Vinci Building, Melbourn, Royston, Hertfordshire, SB8 6HB, UK. karen.so@astrazeneca.com.
authors.forename: Karen
authors.initials: K
authors.lastname: So
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: AstraZeneca, Gaithersburg, MD, 20878, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Covance Laboratories, Inc., Madison, WI, 53704, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Severin
authors.affiliation: Quintiles Phase I Services, Overland Park, KS, 66211, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mathews
authors.affiliation: Quintiles Phase I Services, Overland Park, KS, 66211, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Lisbon
authors.affiliation: AstraZeneca R&D, AstraZeneca Global Medicines Development, Da Vinci Building, Melbourn, Royston, Hertfordshire, SB8 6HB, UK.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Mariani
mesh_terms: D000293:Adolescent; D000328:Adult; D001562:Benzimidazoles / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D065689:Cytochrome P-450 CYP2C19 Inhibitors / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D064368:Healthy Volunteers; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048730:MAP Kinase Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D012293:Rifampin / Q000494:pharmacology; D055815:Young Adult
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D065689:Cytochrome P-450 CYP2C19 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065693:Cytochrome P-450 Enzyme Inducers; D017964:Itraconazole; D015725:Fluconazole; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; D012293:Rifampin
keywords: Cytochrome P450; Exposure; Induction; Inhibition; Pharmacokinetic profile; Selumetinib