Eltrombopag, an oral thrombopoietin receptor agonist, has no impact on the pharmacokinetic profile of probe drugs for cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C9 and CYP2C19 in healthy men: a cocktail analysis.
OBJECTIVE
It is likely that the thrombopoietin receptor agonist eltrombopag will be administered concomitantly with other medications in the treatment of thrombocytopenia. Therefore the potential for eltrombopag to interact with cytochrome P450 activity was investigated.


METHODS
Twenty-four healthy men received eltrombopag 75 mg/day on days 3-9, midazolam 5 mg (a probe for CYP3A4) on days 1 and 8 and a probe cocktail on days 2 and 9 that included caffeine 100 mg (CYP1A2), flurbiprofen 50 mg (CYP2C9) and omeprazole 20 mg (CYP2C19).


RESULTS
Midazolam pharmacokinetic parameters were comparable before and after eltrombopag administration; geometric least squares (GLS) mean ratio (90% confidence intervals, CI) area under the curve from zero to infinity (AUC(0-infinity)) was 1.03 (0.94,1.12) and maximum plasma concentration (C(max)) was 0.98 (0.86,1.07). Metabolic indices for other CYP isozymes were also equivalent before and after eltrombopag. GLS mean ratio (90% CI) for the paraxanthine:caffeine concentration ratio at 8 h postdose was 0.97 (0.92,1.03), for conjugated + unconjugated and unconjugated 4-hydroxy-flurbiprofen recovery in urine over 0-8 h was 0.95 (0.93,0.97) and 0.93 (0.88,0.98), respectively, and for the plasma omeprazole:5-hydroxyomeprazole concentration ratio at 2- and 3-h postdose was 1.00 (0.93,1.08) and 1.02 (0.88,1.18), respectively.


CONCLUSIONS
Once-daily administration of eltrombopag 75 mg for 7 days did not alter CYP3A4, CYP1A2, CYP2C9 or CYP2C19 activity in healthy volunteers.
Jenkins
Julian
J
Oncology Medicine Development Center, GlaxoSmithKline Research & Development, Collegeville, PA 19426, USA. julian.m.jenkins@GSK.com
Williams
Daphne
D
Deng
Yanli
Y
Collins
David A
DA
Kitchen
Valerie S
VS
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002110:Caffeine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005480:Flurbiprofen / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D009853:Omeprazole / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053628:Receptors, Thrombopoietin / Q000819:agonists*
D001565:Benzoates; D006834:Hydrazines; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D002110:Caffeine; D005480:Flurbiprofen; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole; D008874:Midazolam; C520809:eltrombopag