Assessment of the pharmacokinetic interaction between eltrombopag and lopinavir-ritonavir in healthy adult subjects

Abstract

Eltrombopag is an orally bioavailable thrombopoietin receptor agonist that is approved for the treatment of chronic idiopathic thrombocytopenic purpura. It is being developed for other medical disorders that are associated with thrombocytopenia. Patients with human immunodeficiency virus (HIV) may suffer from thrombocytopenia as a result of their HIV disease or coinfection with hepatitis C virus (HCV). HIV medications, particularly ritonavir (RTV)-boosted HIV protease inhibitors, are involved in many drug interactions. This study evaluated the potential drug-drug interaction between eltrombopag and lopinavir (LPV)/RTV. Forty healthy adult subjects enrolled in this open-label, three-period, single-sequence crossover study received a single 100-mg dose of eltrombopag (period 1), LPV/RTV at 400/100 mg twice daily (BID) for 14 days (period 2), and LPV/RTV at 400/100 mg BID (2 doses) with a single 100-mg dose of eltrombopag administered with the morning LPV/RTV dose (period 3). There was a 3-day washout between periods 1 and 2 and no washout between periods 2 and 3. Serial pharmacokinetic samples were collected during 72 h in periods 1 and 3 and during 12 h in period 2. The coadministration of 400/100 mg LPV/RTV BID with a single dose of 100 mg eltrombopag decreased the plasma eltrombopag area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) by 17%, on average, with no change in plasma LPV/RTV exposure. Adverse events (AEs) reported in period 2 were consistent with known LPV/RTV AEs, such as diarrhea, abdominal pain, nausea, vomiting, rash, and fatigue. No subjects withdrew due to AEs, and no serious AEs were reported. These study results suggest that platelet counts should be monitored and the eltrombopag dose adjusted accordingly if LPV/RTV therapy is initiated or discontinued.

Figures

Fig 1

Median plasma eltrombopag concentration-time profiles. ♢, Eltrombopag at 100 mg (n = 40); ♦, eltrombopag at 100 mg plus 400/100 mg LPV/RTV twice daily (n = 40).

Fig 2

Median plasma lopinavir and ritonavir concentration-time profiles. ■, Lopinavir in 400/100-mg LPV/RTV doses twice daily (n = 40); □, lopinavir in 400/100-mg LPV/RTV doses twice daily plus 100 mg eltrombopag (n = 40); Δ, ritonavir in 400/100-mg LPV/RTV doses twice daily (n = 40); ▲, ritonavir in 400/100-mg LPV/RTV doses twice daily plus 100 mg eltrombopag (n = 40).