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.
Purpose: 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...
| Published in: | European Journal of Clinical Pharmacology Vol. 73; no. 2; pp. 175 - 185 |
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| Main Authors: | , , , , , , , |
| Format: | clinical trial research tables/charts Journal Article |
| Published: |
Springer Nature
Feb2017
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=120662217&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 120662217 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Feb2017 vid: 73 iid: 2 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 120662217 120662217 144019475 120662217 10.1007/s00228-016-2153-7 120662217 ppf: 175 ppct: 10 formats: fmt: @attributes: type: P tig: atl: 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. aug: au: Dymond, Angela Martin, Paul So, Karen Mariani, Gabriella Huang, Yifan Severin, Paul Mathews, David Lisbon, Eleanor affil: AstraZeneca , Alderley Park, Macclesfield Cheshire SK10 4TG UK sug: subj: Cytochrome P-450 Enzyme System Antagonists and Inhibitors Human Pharmacokinetics Random Assignment Rifampin Administration and Dosage ROC Curve Descriptive Statistics Data Analysis Software Clinical Trials ab: Purpose: 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 ( C ) increased by 19 and 26%, respectively) but lower when co-dosed with rifampicin (AUC and C decreased by 51 and 26%, respectively) versus selumetinib dosed alone. Co-administration with itraconazole or rifampicin decreased N-desmethyl selumetinib AUC (11 and 55%, respectively), and C (25 and 18%, respectively), with fluconazole, AUC increased by 40%, but there was no effect on C . Conclusions: Co-administration of CYP3A4/CYP2C19 inhibitors will likely increase exposure to selumetinib, while CYP3A4 inducers will likely reduce its exposure. pubtype: Academic Journal doctype: clinical trial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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