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

PurposeTwo 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.MethodsIn 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.ResultsSelumetinib 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 max) increased by 19 and 26%, respectively) but lower when co-dosed with rifampicin (AUC and C max decreased 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 C max (25 and 18%, respectively), with fluconazole, AUC(0–t) increased by 40%, but there was no effect on C max.ConclusionsCo-administration of CYP3A4/CYP2C19 inhibitors will likely increase exposure to selumetinib, while CYP3A4 inducers will likely reduce its exposure.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-016-2153-7) contains supplementary material, which is available to authorized users.

Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis

“…Additional safety and tolerability data for the Western studies are reported in detail elsewhere and include references [20–22]. …”

Population Pharmacokinetic and Exposure‐Response Analysis of Selumetinib and Its N‐desmethyl Metabolite in Patients With Non‐Small Cell Lung Cancer

“…N‐desmethyl selumetinib is metabolized through the same routes as the parent drug. In studies, selumetinib, N‐desmethyl selumetinib, and glucuronide conjugates of both were the major components identified in human plasma, and the amide metabolite was also detected in human plasma . N‐desmethyl selumetinib is an active metabolite, and shows a 3‐ to 5‐fold greater potency for MEK1 inhibition in vitro than the parent compound.…”

“…Selumetinib has a short half‐life (5‐7 hours), and its pharmacokinetic (PK) profile is approximately dose‐proportional from 25 mg to 150 mg in patients with advanced cancer . Cytochrome P450 (CYP) 1A2, 2C19, 3A4, and 3A5 are mainly responsible for the metabolism of selumetinib, with CYP1A2 being the enzyme primarily responsible for the formation of the N‐desmethyl metabolite . N‐desmethyl selumetinib is metabolized through the same routes as the parent drug.…”

“…11 Cytochrome P450 (CYP) 1A2, 2C19, 3A4, and 3A5 are mainly responsible for the metabolism of selumetinib, with CYP1A2 being the enzyme primarily responsible for the formation of the N-desmethyl metabolite. 12,13 N-desmethyl selumetinib is metabolized through the same routes as the parent drug. In studies, selumetinib, N-desmethyl selumetinib, and glucuronide conjugates of both were the major components identified in human plasma, and the amide metabolite was also detected in human plasma.…”

“…In studies, selumetinib, N-desmethyl selumetinib, and glucuronide conjugates of both were the major components identified in human plasma, and the amide metabolite was also detected in human plasma. 12,13 N-desmethyl selumetinib is an active metabolite, and shows a 3-to 5-fold greater potency for MEK1 inhibition in vitro than the parent compound. N-desmethyl selumetinib has relative lower exposure in vivo, with area under the plasma-drug concentrationtime curve (AUC) and maximum concentration of drug in plasma (C max ) typically <10% of the parent compound.…”