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.

Incidence of Adverse Drug Reactions in COVID‐19 Patients in China: An Active Monitoring Study by Hospital Pharmacovigilance System

“…The safety monitoring data of other studies are mainly concentrated in patients with AIDS and healthy people. 18,19 For example, as seen in the Gonzalez-Garcia et al study, the most frequently reported AE in healthy adult subjects was diarrhea (26/40; 65%). 18 A randomized trial to evaluate the efficacy and safety of lopinavir/ritonavir in the treatment of HIV-1 infection reported that the incidence of diarrhea in moderate/severe AEs was 16%.…”

“…To evaluate the incidence, type, and risk factors associated with adverse drug reactions (ADRs) among patients with coronavirus disease 2019 (COVID- 19) by Hospital Pharmacovigilance System (CHPS). A retrospective analysis was performed on 217 patients with COVID-19 admitted to the First Hospital of Changsha in China, from January 17, 2020, to February 29, 2020.…”

“…In late December 2019, a cluster of cases with severe acute respiratory syndrome 2019 novel coronavirus pneumonia (SARS-CoV-2) infection in Wuhan, China, aroused worldwide concern. 1 As of March 9, 2020, over 100 countries reported laboratory-confirmed cases of coronavirus disease 2019 (COVID- 19), and > 110,000 cases have been diagnosed, with an estimated mortality risk of ~ 3%. 2 Unfortunately, no drug or vaccine has yet been approved to treat SARS-CoV-2 infection.…”

Co-administration of a commonly used Zimbabwean herbal treatment (African potato) does not alter the pharmacokinetics of lopinavir/ritonavir

“…Based on the intra-subject coefficient of variation of 15% for PK parameters for LPV, 19 a 5% consumer risk with 80% power, and assuming no difference between treatments, 16 subjects were necessary to demonstrate equivalence within the conventional acceptance range of 0.80–1.25 applied for bioequivalence studies. 20 …”

Prediction of Clinical Transporter‐Mediated Drug–Drug Interactions via Comeasurement of Pitavastatin and Eltrombopag in Human Hepatocyte Models

“…Clinical drug–drug interactions (DDIs) have been observed between eltrombopag and rosuvastatin (as a perpetrator 13 ) and lopinavir–ritonavir (as a victim 14 ). The main cause of the interaction of eltrombopag with rosuvastatin in vitro was the result of BCRP inhibition, with minimal inhibition of OATP1B1 5,15 .…”