Opinion Review
Copyright ©The Author(s) 2021.
World J Gastroenterol. Feb 28, 2021; 27(8): 666-676
Published online Feb 28, 2021. doi: 10.3748/wjg.v27.i8.666
Table 1 Relative potencies of various nucleos(t)ide analogs for inhibiting hepatitis B virus
Drug
EC50 (nM), mean ± SD
Difference (fold) from entecavir EC50
Ref.
Entecavir5.3 ± 2.51Yurdaydin et al[31], 2008
TAF86.616Gibson et al[32], 2016
Lamivudine1491 ± 1033281Yurdaydin et al[31], 2008
CMX-1571600 420Pei et al[33], 2017
Tenofovir2482 ± 1938468Yurdaydin et al[31], 2008
Adefovir2636 ± 1549497Yurdaydin et al[31], 2008
Telbivudine8950 ± 48031689Yurdaydin et al[31], 2008
Table 2 Summary of principal findings from Bergman’s review on the Food and Drug Administration website
Research project in Bergman’s review
Content of research project
Registration number of clinic studies
Page in Bergman’s review
(a) Treatment of emergent adverse eventsTreatment of emergent adverse events in the clinical studies in which entecavir doses from 0.5 to 40 mg/d were used to select the pivotal doses of entecavirA 1463004, A1463005Pages 17 and18
(b) Entecavir 0.5 and 1.0 mg/d for current treatmentThe dose and dose regimen of 0.5 mg/d for NA naïve patients and 1 mg/d for lamivudine refractory patients were determined to treat CHBA1463002, A1463005, A1463014, A1463022, A1463027Pages 23 and 24
(c) Exposure-response: HBV DNA changes for 0.1 up to 1.0 mg/dHBV DNA changes for 0.1, 0.5, and 1.0 mg/d were reportedA1463004, A143005, A1463014, A1463017Pages 11-17
(d) Pharmacokinetics of multiple dosesEntecavir multiple dose pharmacokinetic parameters from 0.5 to 20 mg/d were presentedA1463002, A1463033Page 25
(e) Overall incidence of adverse events for doses 0.5 and 1.0 mg/dNo apparent dose-response relationship in the overall incidence of adverse events for doses of 0.5 and 1.0 mg/dwasfoundA 1463004, A1463005, A1403014, Pages 18 and 19
(f) Doses and adverse events for multiple dose therapy, 0.5 mg up to 20 mg/dThe dose and adverse events with entecavir multiple doses, 0.5 mg up to 20 mg daily, were reported in nine clinical trialsA 1463001, A1463002, A1463003, A 1463004, A1463005, A1463010, A1463033, A1463034, A1463041Pages 17, 21, and 23
(g) Cardiovascular safetyThe studies for cardiovascular safety included in vitro investigations and six clinical studies, in which the safety of entecavir was assessed at doses of 0.5 mg/d to 20 mg/d and a single dose of 40 mgA1463001, A1463002, A1463010, A1463033, A1463034, A1463041Pages 21 and 23
Table 3 Pharmacokinetic parameters of entecavir multiple doses in Bergman’s review
Dose (mg/d)
AUC (ng/h/mL)
Cmax (ng/mL)
Tmax (h)
T1/2 (h)
20545.6 ± 57.9179.8 ± 34.81.0142.5 ± 55.5
10304.3 ± 35.699.9 ± 13.70.75127.5 ± 41.8
5.0145.8 ± 28.446.2 ± 6.40.8891.3 ± 57.9
2.571.6 ± 10.322.8 ± 5.70.75115.7 ± 37.2
1.026.38 ± 128.24 ± 160.75148.89 ± 39.5
0.514.78 ± 174.23 ± 91.0129.9 ± 17.28
0.12.5 ± 210.6 ± 291.0127.69 ± 91.44