741 Safety, tolerability and antiviral activity of pradefovir mesylate in patients with chronic hepatitis B virus infection: 48-week analysis of a phase 2 study

Lee, K.S.; Lim, S.G.; Chuang, Wan‐Long; Hwang, Shinn-Jang; Cho, M.; Lai, Ming Yang; Chao, YC; Chang, Ting Ting; Han, Kelong; Lee, C.M.; Um, Soon-Ho; Yeon, J.E.; Yang, Shwu Huey; Teo, Eng Kiong; Peng, Chiung‐Yu; Lin, Helen; Huo, T. I.; Nguyen, Tran; Chen, T.Y.; Hu, Ke–Qin; Xu, Yanping; Sullivan-Bólyai, John Z.

doi:10.1016/s0168-8278(06)80742-7

Cited by 13 publications

(9 citation statements)

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“…Preclinical evaluation of pradefovir in rats showed a 12-fold improvement in the liver/kidney ratio for 21 over 19 combined with a good oral bioavailability (42%) as a mesylate salt formulation (Reddy et al, 2008 ). A 48-weeks Phase II trial involving chronically infected HBV patients further confirmed that pradefovir mesylate (dosed at 5–30 mg/day) was well-tolerated and significantly more active than 19 (dosed at 10 mg/day), without producing significant changes in kidney function markers (Lee et al, 2006 ). Although further clinical evaluation of 21 was discontinued in USA and Europe due to the potential carcinogenic effect observed in animal studies, a Phase III trial for the treatment of patients with chronic HBV infections is currently ongoing in China to determine (ClinicalTrials.gov Identifier: NCT04543565; Recruitment Status: Recruiting) (Zhang et al, 2020 ).…”

Section: Anti-hepadnaviral and Anti-retroviral Nucleoside Phosphonatementioning

confidence: 94%

Overview of Biologically Active Nucleoside Phosphonates

Groaz

Jonghe

2021

Front. Chem.

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The use of the phosphonate motif featuring a carbon-phosphorous bond as bioisosteric replacement of the labile P–O bond is widely recognized as an attractive structural concept in different areas of medicinal chemistry, since it addresses the very fundamental principles of enzymatic stability and minimized metabolic activation. This review discusses the most influential successes in drug design with special emphasis on nucleoside phosphonates and their prodrugs as antiviral and cancer treatment agents. A description of structurally related analogs able to interfere with the transmission of other infectious diseases caused by pathogens like bacteria and parasites will then follow. Finally, molecules acting as agonists/antagonists of P2X and P2Y receptors along with nucleotidase inhibitors will also be covered. This review aims to guide readers through the fundamentals of nucleoside phosphonate therapeutics in order to inspire the future design of molecules to target infections that are refractory to currently available therapeutic options.

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Section: Anti-hepadnaviral and Anti-retroviral Nucleoside Phosphonatementioning

confidence: 94%

Overview of Biologically Active Nucleoside Phosphonates

Groaz

Jonghe

2021

Front. Chem.

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“…53,54 In a randomized, open-label, parallel-group, multicenter study comparing pradefovir dosed at 5, 10, 20, and 30 mg/day and adefovir dipivoxil dosed at 10 mg/day for 48weeks, pradefovir was reported to be safe, well-tolerated and had significantly greater anti-HBV activity than adefovir dipivoxil. 53 Notably, the only adverse effects reported were minor or mild with most of them being associated with the patient cohort placed on 30 mg/day dosing. Intriguingly, another open-label clinical study that aimed at comparing the long-term safety profiles of pradefovir and adefovir dipivoxil was terminated due to adverse findings from nonclinical carcinogenicity studies.…”

Section: Pronucleotide Clinical Candidatesmentioning

confidence: 99%

Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates

et al. 2016

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Nucleoside monophosphates and monophosphonates have been known for a long time to exert favorable pharmacological effects upon intracellular delivery. However, their development as drug molecules has been hindered by the inherent poor druglike properties of the monophosphate and monophosphonate groups. These include inefficient cellular uptake and poor in vivo stability, with this latter drawback being most relevant to monophosphates than monophosphonates. To address these limitations, numerous monophosphate and monophosphonate prodrug strategies have been developed and applied in the discovery of nucleoside monophosphate and monophosphonate prodrugs that can treat viral infections and cancer. The approval of sofosbuvir, a nucleoside monophosphate prodrug, highlighted the success to be had by employing these prodrug technologies in the discovery of nucleotide therapeutics. In this Miniperspective, we discuss the different key monophosphate and monophosphonate nucleoside prodrugs that entered clinical development, some of which may in the future be approved to treat various human diseases.

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“…In line with the need for further metabolization, the AUC variation was higher on prade-fovir compared to adefovir (Lee et al 2006). The antiviral activity in that phase II study was more pronounced on pradefovir doses of 10 mg and higher.…”

Section: Pradefovir a Liver-targeted Adefovirmentioning

confidence: 79%

“…The open-label phase II trials compared pradefovir (5, 10, 20, or 30 mg) with 10 mg adefovir in chronically HBV-infected patients, who were treated for 24 to 48 weeks (Lee et al 2006, Lin et al 2006) This study included 47, 49, 48, 48, and 50 patients into the pradefovir 5, 10, 20 and 30 mg arm and the 10 mg adefovir arm respectively. After 24 and 48 weeks, a viral reduction was described to be 3.39, 4.22, 4.33, and 5.02 log copies per ml for the pradefovir mesylate dose of 5, 10, 20, and 30 mg, respectively, compared with 3.66 with 10 mg adefovir dipivoxil after 24 weeks (Lee et al 2006) and 4.09, 4.84, 4.89, 5.54 log copies per ml for the pradefovir mesylate dose of 5, 10, 20, and 30 mg, respectively, compared to 4.19 on 10 mg adefovir dipivoxil after 48 weeks (Lin et al 2006). However, pradefovir was recently put on hold concerning its further development based on increased tumor incidence in animal studies (Tillmann 2007).…”

Section: Pradefovir a Liver-targeted Adefovirmentioning

confidence: 99%

The treatment of chronic hepatitis B: Focus on adefovir-like antivirals

Tillmann

2008

TCRM

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Several options for the treatment of hepatitis B have been licensed in the last years: interferon, pegylated interferon, lamivudine, adefovir, entecavir, and telbivudine. In addition tenofovir has been licensed in the EU and is expected to be licensed in the USA in 2008. The antivirals can be divided into “lamivudine-like” and “adefovir-like”, which clinically differ in their capacity to induce “YMDD” mutants, which are the hallmark of lamivudine resistance. The differing resistance profile makes them good combination partners, even in the absence of synergy in antiviral potency.

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741 Safety, tolerability and antiviral activity of pradefovir mesylate in patients with chronic hepatitis B virus infection: 48-week analysis of a phase 2 study

Cited by 13 publications

References 0 publications

Overview of Biologically Active Nucleoside Phosphonates

Overview of Biologically Active Nucleoside Phosphonates

Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates

The treatment of chronic hepatitis B: Focus on adefovir-like antivirals

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