New therapeutic options for persistent low-level viremia in patients with chronic hepatitis B virus infection: Increase of entecavir dosage

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.
Entecavir	5.3 ± 2.5	1	Yurdaydin et al[31], 2008
TAF	86.6	16	Gibson et al[32], 2016
Lamivudine	1491 ± 1033	281	Yurdaydin et al[31], 2008
CMX-157	1600	420	Pei et al[33], 2017
Tenofovir	2482 ± 1938	468	Yurdaydin et al[31], 2008
Adefovir	2636 ± 1549	497	Yurdaydin et al[31], 2008
Telbivudine	8950 ± 4803	1689	Yurdaydin et al[31], 2008

EC₅₀: Effective concentration of nucleos(t)ide analogs that results in 50% inhibition of HBV DNA production; TAF: Tenofovir alafenamide; CMX-157: Tenofovir conjugated with a lipid moiety.

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 events	Treatment 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 entecavir	A 1463004, A1463005	Pages 17 and18
(b) Entecavir 0.5 and 1.0 mg/d for current treatment	The 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 CHB	A1463002, A1463005, A1463014, A1463022, A1463027	Pages 23 and 24
(c) Exposure-response: HBV DNA changes for 0.1 up to 1.0 mg/d	HBV DNA changes for 0.1, 0.5, and 1.0 mg/d were reported	A1463004, A143005, A1463014, A1463017	Pages 11-17
(d) Pharmacokinetics of multiple doses	Entecavir multiple dose pharmacokinetic parameters from 0.5 to 20 mg/d were presented	A1463002, A1463033	Page 25
(e) Overall incidence of adverse events for doses 0.5 and 1.0 mg/d	No apparent dose-response relationship in the overall incidence of adverse events for doses of 0.5 and 1.0 mg/dwasfound	A 1463004, A1463005, A1403014,	Pages 18 and 19
(f) Doses and adverse events for multiple dose therapy, 0.5 mg up to 20 mg/d	The dose and adverse events with entecavir multiple doses, 0.5 mg up to 20 mg daily, were reported in nine clinical trials	A 1463001, A1463002, A1463003, A 1463004, A1463005, A1463010, A1463033, A1463034, A1463041	Pages 17, 21, and 23
(g) Cardiovascular safety	The 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 mg	A1463001, A1463002, A1463010, A1463033, A1463034, A1463041	Pages 21 and 23

NA: Nucleos(t)ide analogs; CHB: Chronic hepatitis B virus infection; HBV: Hepatitis B virus.

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)
20	545.6 ± 57.9	179.8 ± 34.8	1.0	142.5 ± 55.5
10	304.3 ± 35.6	99.9 ± 13.7	0.75	127.5 ± 41.8
5.0	145.8 ± 28.4	46.2 ± 6.4	0.88	91.3 ± 57.9
2.5	71.6 ± 10.3	22.8 ± 5.7	0.75	115.7 ± 37.2
1.0	26.38 ± 12	8.24 ± 16	0.75	148.89 ± 39.5
0.5	14.78 ± 17	4.23 ± 9	1.0	129.9 ± 17.28
0.1	2.5 ± 21	0.6 ± 29	1.0	127.69 ± 91.44

Data are presented as the mean ± SD. Source: A1463002 and A1463033 clinical studies; AUC: Area under the concentration-time curve.