Thrombopoietin Receptor Agonists (TPO-RAs): Drug Class Considerations for Pharmacists

Abstract

The thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and lusutrombopag carry unique US Food and Drug Administration (US FDA)-and European Medicines Agency (EMA)-approved indications and may be used to increase platelet counts in a variety of conditions. Current indications for available TPO-RAs include treatment of chronic immune thrombocytopenia (ITP) in cases of insufficient response to prior treatment (avatrombopag, eltrombopag, romiplostim), management of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure (avatrombopag, lusutrombopag), management of severe aplastic anemia (eltrombopag), and management of thrombocytopenia associated with interferon-based therapy for hepatitis C (eltrombopag). Across current indications, pharmacists can assist in stabilizing platelet counts and help to reduce large undulations commonly seen when starting, stopping, or transitioning between these agents. If therapy modifications may benefit the patient, pharmacists should discuss possible changes with the patient's treatment team or treating physician. When used for ITP, romiplostim, eltrombopag, and avatrombopag stimulate TPO receptors on hematopoietic stem cells (also known as c-Mpl, or CD110) to promote platelet production; however, romiplostim is the only TPO-RA that binds at the same site as endogenous TPO. These subtle mechanistic differences may explain why switching TPO-RA may be clinically advantageous in some situations. As pharmacists are called to counsel patients on TPO-RA use, a deep understanding of potential adverse events and management strategies, as well as appropriate monitoring, will increase the likelihood that patients meet their goals of therapy in the shortest timeframe. Other uses of TPO-RAs are also discussed in this review, including use following hematopoietic stem cell transplant, use in myelodysplastic syndrome, and use in chemotherapy-induced thrombocytopenia. Key PointsThrombopoietin receptor agonists (TPO-RAs) offer different clinical opportunities based on their pharmacokinetic, pharmacodynamic, and mechanistic characteristics.

Case Report: Successful Avatrombopag Treatment for Two Cases of Anti-PD-1 Antibody-Induced Acquired Amegakaryocytic Thrombocytopenia

“…The standard treatment of AAT has not been defined, and the management is often thorny because of their refractoriness to possible treatment choices, including immunosuppressive therapy, rituximab, interleukin-11, recombinant human thrombopoietin (rh-TPO) and even some thrombopoietin receptor agonists (TPO-RAs). As a newly FDA approved TPO-RA for immune ITP, avatrombopag promotes platelet production by stimulating TPO receptor (c-Mpl) with high efficacy and safety (Deng et al, 2021;Gilreath et al, 2021). However, little is known about its effects in the treatment of AAT, especially anti-PD-1/PD-L1 antibody-induced AAT.…”

Avatrombopag Treatment of Severe Aplastic Anemia With Liver Injury: a Case Report

“…Many preclinical studies have con rmed the bene cial effect of TPO on the activation and maintenance of hematopoietic stem cells. Therefore, TPO-RAS seem to be ideal therapeutic agents for enhancing bone marrow function, which has greatly contributed to the progress of clinical treatment of SAA [5] . TPO-Ras simulates endogenous TPO, regulates the proliferation and maturation of megakaryocytes in bone marrow and increases platelet production [6,7] .…”

“…The TPO-RAS romiplostim, eltrombopag, avatarmbopag and lusutrombopag have unique indications approved by the US Food and Drug Administration (FDA) and the European Drug Administration (EMA) and may be used in a variety of conditions to increase platelet counts [5] . Romistine competes with endogenous TPO to bind the extracellular segment of TPO receptor; eltrombopag and avatrombopag are non competitively combined with endogenous TPO and have potential superimposed platelet raising effect [5] . Eltrombopag, a second-generation platelet receptor agonist, has been shown to be satisfactorily effective in the treatment of AA in numerous clinical trials.…”

Refractory primary immune thrombocytopenia (ITP): current clinical challenges and therapeutic perspectives

“…Like eltrombopag, avatrombopag is a small molecule that binds the transmembrane domain. Its absorption is not reduced by dietary fat or divalent cations (such as calcium); therefore, and unlike eltrombopag that must be taken on an empty stomach or at least 2 h after a meal, avatrombopag can be given with any food [ 66 ].…”