Absence of a Pharmacokinetic Interaction Between Entecavir and Adefovir

Bifano, Marc; Yan, Jing‐He; Smith, Robert A.; Zhang, Duxi; Grasela, Dennis M.; LaCreta, Frank

doi:10.1177/0091270007304780

Cited by 16 publications

(7 citation statements)

References 18 publications

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“…The results of this study demonstrated that reducing the ETV dose in combination with ADV did not diminish the efficacy of viral suppression and did not increase the emergence of genotypic ETV‐R variants. Several previous studies had reported that a combination therapy of ETV plus ADV was well tolerated, did not showed a pharmacokinetic interaction, and produced additive antiviral effects against CHB in vitro [Delaney et al, ; Bifano et al, ]. These additive or synergistic antiviral effects attenuated the need for higher dose of ETV in combination with ADV, as shown in this study.…”

Section: Discussionsupporting

confidence: 76%

Comparison of the efficacies of entecavir 0.5 and 1.0 mg combined with adefovir in patients with chronic hepatitis B who had failed on prior nucleos(t)ide analogue treatments

Cho

Lee

et al. 2015

Journal of Medical Virology

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Entecavir (ETV) plus adefovir (ADV) combination therapy is one of the useful treatment option for the patients with chronic hepatitis B (CHB) who had failed on prior nucleos(t) ide analogue (NA) treatments. This study compared the efficacies of the combinations of ETV 0.5 mg plus ADV and ETV 1.0 mg plus ADV in patients who had failed on prior multiple NA treatments. This retrospective analysis included 148 consecutive patients with CHB infection in Korea (n = 37 with ETV 0.5 mg plus ADV and n = 111 with ETV 1.0 mg plus ADV). The virological and biochemical responses were compared between the two groups. The cumulative probability of viral suppression of ETV 0.5 mg plus ADV was not inferior to that of ETV 1.0 mg plus ADV (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.38-1.08; P = 0.094). The changes in serum HBV DNA level in the ETV 0.5 mg plus ADV group were not different between the two groups over 12 months. Moreover, no significant difference was observed in acquiring ETV-resistant variants between the two groups during the treatment (HR, 0.95; P = 0.953). This study suggests the proof-of-concept that the lower dose of NA in combination with other NA might be the theoretical option for rescue combination therapy in patients with CHB who had failed on prior multiple NA treatments in order to reduce systemic exposure and possible side effects of NA.

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Section: Discussionsupporting

confidence: 76%

Comparison of the efficacies of entecavir 0.5 and 1.0 mg combined with adefovir in patients with chronic hepatitis B who had failed on prior nucleos(t)ide analogue treatments

Cho

Lee

et al. 2015

Journal of Medical Virology

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“…25 Such combination treatments will likely be evaluated in patients with CHB who are currently undergoing treatment with SOC (nucleoside/nucleotide analogs; e.g., tenofovir and entecavir). These antiviral agents are typically eliminated by active renal transport utilizing the OAT system 26 and it is important to understand how the TLR7 agonist may be eliminated. In the current study, RO7011785 was eliminated by the kidneys with urinary recovery of unchanged drug of ~ 60-67% of the administered dose across all single dose levels.…”

Section: Discussionmentioning

confidence: 99%

A Single and Multiple Ascending Dose Study of Toll‐Like Receptor 7 Agonist (RO7020531) in Chinese Healthy Volunteers

Luk

Jiang

Glavini

et al. 2020

Clinical Translational Sci

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Toll-like receptor 7 (TLR7) agonists modulate broad spectrum immune activity and are evaluated in the treatment of human diseases, including cancer and chronic viral infection. RO7020531, an oral prodrug of a TLR7 agonist, is in clinical development as part of a curative regimen against chronic hepatitis B. We report the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO7020531 in healthy Chinese volunteers following single and multiple ascending doses (SAD and MAD). PK and PD samples were evaluated from four SAD cohorts and 3 MAD cohorts with 10 subjects each (8 active and 2 placebo). Safety and tolerability were monitored throughout the study. A total of 155 adverse events (AEs) were reported in 49 subjects. Fifty-one AEs in 18 subjects were assessed as treatment-related. Most of the AEs were mild; nine subjects experienced moderate AEs; there were no severe AEs. In two 150 mg MAD cohorts given every other day (q.o.d.), 7 of 20 subjects experienced pyrexia and were discontinued due to transient asymptomatic lymphopenia, which resolved 24-48 hours postdose. The PK of the active metabolite, RO7011785, increased linearly with dose from 40 mg to 170 mg. There was no PK accumulation following q.o.d. dosing. The PK profile is consistent with observations in white subjects in the global first-inhuman study. SADs and MADs of RO7020531 resulted in dose-dependent increases in TLR7 response markers at 100 mg or above. Flu-like symptoms were associated with higher interferon-α levels. RO7020531 was safe and acceptably tolerated in healthy Chinese volunteers with a multiple 150 mg q.o.d. dose regimen.Chronic hepatitis B (CHB) virus infection is a major global healthcare problem, with ~ 240 million now chronically infected, among whom approximately one-third are in China. 1,2 Nearly 25% of all patients with CHB develop serious liver diseases, such as cirrhosis and primary hepatocellular carcinoma. More than 887,000 people die every year due to the consequences of CHB. 2 CHB infection is defined by the persistence of hepatitis B surface antigen (HBsAg) in the blood > 6 months. The loss of HBsAg followed by seroconversion to anti-hepatitis

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“…ETV and ADV have some antiviral efficacy against LAM-resistant HBV with complementary resistance profiles (24,31). A study in healthy volunteers showed no evidence of a pharmacokinetic interaction between ETV and ADV, allowing both to be safely administered without the need for dose adjustment of either (3). An in vitro study showed modest synergy between these two agents (9).…”

mentioning

confidence: 99%

Randomized Trial of Entecavir plus Adefovir in Patients with Lamivudine-Resistant Chronic Hepatitis B Who Show Suboptimal Response to Lamivudine plus Adefovir

Lim

Lee

et al. 2012

Antimicrob Agents Chemother

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A substantial proportion of patients with lamivudine-resistant hepatitis B virus (HBV) show suboptimal virologic response during rescue combination treatment with lamivudine plus adefovir. In this randomized active-control trial, 90 patients with serum HBV DNA levels of >2,000 IU/ml after at least 24 weeks of treatment with lamivudine-plus-adefovir therapy for lamivudineresistant HBV were randomized to combination treatment with entecavir plus adefovir (ETV؉ADV, n ‫؍‬ 45) or continuation of lamivudine plus adefovir (LAM؉ADV, n ‫؍‬ 45) for 52 weeks. At baseline, patients' mean serum HBV DNA level was 4.60 log 10 IU/ml (standard deviation [SD], 1.03). All 90 patients completed 52 weeks of treatment. At week 52, the proportion of patients with serum HBV DNA levels of <60 IU/ml, the primary endpoint, was significantly higher in the ETV؉ADV group than in the LAM؉ADV group (n ‫؍‬ 13, 29%, versus n ‫؍‬ 2, 4%, respectively; P ‫؍‬ 0.004). The mean reduction in serum HBV DNA levels from baseline was significantly greater in the ETV؉ADV group than in the LAM؉ADV group (؊2.2 log 10 IU/ml versus ؊0.6 log 10 IU/ml, respectively; P < 0.001). At week 52, additional mutations causing resistance to adefovir or entecavir were analyzed in all patients with detectable HBV DNA by restriction fragment mass polymorphism assays and detected in none of the ETV؉ADV group but in 15% of patients in the LAM؉ADV group (P ‫؍‬ 0.018). Safety and adverse event profiles were similar in the two groups. In conclusion, entecavir-plus-adefovir combination therapy provides superior virologic response and favorable resistance profiles, compared with the continuing lamivudine-plus-adefovir combination, in patients with lamivudine-resistant HBV who fail to respond to lamivudine-plus-adefovir combination therapy.

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Absence of a Pharmacokinetic Interaction Between Entecavir and Adefovir

Cited by 16 publications

References 18 publications

Comparison of the efficacies of entecavir 0.5 and 1.0 mg combined with adefovir in patients with chronic hepatitis B who had failed on prior nucleos(t)ide analogue treatments

Comparison of the efficacies of entecavir 0.5 and 1.0 mg combined with adefovir in patients with chronic hepatitis B who had failed on prior nucleos(t)ide analogue treatments

A Single and Multiple Ascending Dose Study of Toll‐Like Receptor 7 Agonist (RO7020531) in Chinese Healthy Volunteers

Randomized Trial of Entecavir plus Adefovir in Patients with Lamivudine-Resistant Chronic Hepatitis B Who Show Suboptimal Response to Lamivudine plus Adefovir

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