Avatrombopag for the treatment of immune thrombocytopenia and thrombocytopenia of chronic liver disease

Figures & data

Table 1 Comparison of the commercially-available thrombopoietin receptor agonists.^20,42,43

	Romiplostim	Eltrombopag	Avatrombopag	Lusutrombopag
Molecular structure	Peptide	Small molecule	Small molecule	Small molecule
TPO receptor site of action	Extracellular domain	Transmembrane domain	Transmembrane domain	Transmembrane domain
Route of administration	Subcutaneous	Oral	Oral	Oral
Dosing frequency^a	Weekly	Daily	Daily	Daily
Relevant food interactions	N/A	Yes	No	No
Current indications	Immune thrombocytopenia (adults and children)	Immune thrombocytopenia (adults and children) Hepatitis C-associated thrombocytopenia Severe aplastic anemia	Periprocedural thrombocytopenia in CLD patients Immune thrombocytopenia (adults)	Periprocedural thrombocytopenia in CLD patients

Note: ^aPer drug label. Modified with permission from Al-Samkari, H. Avatrombopag maleate for the treatment of periprocedural thrombocytopenia in patients with chronic liver disease. Drugs Today (Barc) 2018, 54(11): 647-655. © 2018 Clarivate Analytics.⁴⁴

Abbreviations: TPO, thrombopoietin; CLD, chronic liver disease; N/A, not applicable.

Figure 1 Molecular structure of avatrombopag.

Table 2 Primary and secondary efficacy endpoints in phase III trials of avatrombopag for the management of periprocedural thrombocytopenia in CLD

Primary or Secondary Endpoint	ADAPT-1 (Avatrombopag vs Placebo)		ADAPT-2 (Avatrombopag vs Placebo)
	Low baseline platelet count	High baseline platelet count	Low baseline platelet count	High baseline platelet count
Percentage of patients not requiring transfusion or rescue for bleeding (low baseline platelet count)	66% vs 23%	88% vs 38%	69% vs 35%	88% vs 33%
Percentage of patients achieving the target platelet count of ≥50×10^9/L on procedure day	69% vs 4.2%	88% vs 21%	67% vs 7%	93% vs 39%
Change in platelet count from baseline to procedure day	32.0×10^9/L vs 0.8×10^9/L	37.1×10^9/L vs 1.0×10^9/L	31.3×10^9/L vs 3.0×10^9/L	44.9×10^9/vs 5.9×10^9/L

Table 3 Prevalence of adverse events in avatrombopag trials

Study	Population and study type	Percentage experiencing at least one TEAE (drug vs placebo)	Most common TEAEs	Percentage experiencing at least one SAE (drug vs placebo)	Most common non-thrombocytopenia SAEs	Notes
Nomoto et al.^Citation29	Healthy subjects PK/PD	Japanese: 41.7% vs NR^a White: 20.8% vs NR	Headache	0% vs NR^a	N/A^a	Incidence of TEAEs was not dose dependent
Bussel et al.^Citation21	Chronic ITP Phase II	100% vs NR	Headache, fatigue, epistaxis, confusion, diarrhea, and arthralgia	19% vs NR	N/A^a	Four patients reported 5 thrombotic events
Jurczak et al.^Citation27	Chronic ITP Phase III	96.9% vs 58.8%	Headache, confusion, URTI, arthralgia, epistasis and fatigue	28.1% vs 5.9%	Headache, vomiting, severe thrombocytopenia
Terrault et al.^Citation26	CLD and thrombocytopenia Phase II	83.8% vs 75.7%	Nausea, fatigue, headache	17.2% vs 10.8%	Ascites, hepatic encephalopathy, gastrointestinal bleeding, infections
Terrault et al.^Citation9	CLD and thrombocytopenia Phase III	54% vs 55%	Abdominal pain, dyspepsia, nausea, pyrexia, dizziness, headache	7% vs 9%	Hyponatremia and gastrointestinal hemorrhage.	3 thrombotic events were reported, 1 in avatrombopag arm and 2 in placebo arm

Note: ^aStudies did not report/define SAEs.

Abbreviations: TEAE, treatment-emergent adverse event; SAE, serious adverse event; NR, not reported; N/A, not applicable.

Table 4 Summary of key pharmacokinetic parameters of avatrombopag

Parameter	Value
Median time to maximal concentration (Tmax)	5–8 hrs post-dose
Mean maximal concentration (Cmax)^a	166 ng/mL
Area under the time-concentration curve (AUC0-x)^a	4198 mg.hr/mL
Food effect	AUC0-x and Cmax not affected
Volume of distribution (VD)	180 L
Plasma protein binding	96%
Mean terminal half-life (t1/2)	16–19 hrs
Mean Clearance (CL)	6.9 L/hr
Metabolism	CYP2C9 and CYP3A4
Excretion	88% fecal, 6% urine

Notes: ^aFor healthy subjects administered 40 mg avatrombopag. Reproduced with permission from Al-Samkari, H. Avatrombopag maleate for the treatment of periprocedural thrombocytopenia in patients with chronic liver disease. Drugs Today (Barc) 2018, 54(11): 647-655. © 2018 Clarivate Analytics.⁴⁴

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