title: Lack of clinically significant pharmacokinetic interaction between the thrombopoietin receptor agonist eltrombopag and hepatitis C virus protease inhibitors boceprevir and telaprevir.
abstract: Eltrombopag is an orally bioavailable thrombopoietin receptor agonist approved for the treatment of thrombocytopenia associated with chronic immune (idiopathic) thrombocytopenic purpura and chronic hepatitis C virus (HCV) infection. This study evaluated the potential drug-drug interactions between eltrombopag and the HCV protease inhibitors boceprevir and telaprevir. In this open-label, 3-period, single-sequence, and crossover study, 56 healthy adult subjects were randomized 1:1 to cohort 1 (boceprevir) or 2 (telaprevir). The dosing was as follows: period 1, single 200-mg dose of eltrombopag; period 2, 800 mg boceprevir or 750 mg telaprevir every 8 hours (q8h) for 10 days; and period 3, single 200-mg dose of eltrombopag with either 800 mg boceprevir or 750 mg telaprevir q8h (3 doses). All doses were administered with food, and eltrombopag was administered specifically with low-calcium food. There was a 3-day washout between periods 1 and 2 and no washout between periods 2 and 3. Serial pharmacokinetic samples were collected for 72 h in periods 1 and 3 and for 8 h in period 2. The coadministration of eltrombopag increased the rate of boceprevir absorption, resulting in a 20% increase in the maximum concentration in plasma (Cmax), a 1-h-earlier time to Cmax (Tmax) for boceprevir, a 32% decrease in the concentration at the end of the dosing interval (Cτ), and no change in the area under the concentration-time curve over the dosing interval (AUC0-τ). The coadministration of eltrombopag did not alter telaprevir pharmacokinetics, and the coadministration of boceprevir or telaprevir did not alter eltrombopag pharmacokinetics. Dysgeusia, headache, and somnolence occurred in ≥2 subjects. One subject withdrew because of nausea, headache, dizziness, sinus pressure, and vomiting. There were no severe or serious adverse events. Dose adjustment is not required when eltrombopag is coadministered with boceprevir or telaprevir given the lack of clinically significant pharmacokinetic interaction.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA mary.b.wire@gsk.com.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Wire
authors.affiliation: PharStat, Research Triangle Park, North Carolina, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: Parexel, Baltimore, Maryland, USA.
authors.forename: Azra
authors.initials: A
authors.lastname: Hussaini
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Kleha
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Dickens
authors.initials: D
authors.lastname: Theodore
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001565:Benzoates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D018592:Cross-Over Studies; D004032:Diet; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D006834:Hydrazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D011392:Proline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011696:Purpura, Thrombocytopenic / Q000188:drug therapy; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D053628:Receptors, Thrombopoietin / Q000819:agonists; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001565:Benzoates; D006834:Hydrazines; D009842:Oligopeptides; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D015842:Serine Proteinase Inhibitors; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; C520809:eltrombopag; D002118:Calcium