Pradefovir Treatment in Patients With Chronic Hepatitis B: Week 24 Results From a Multicenter, Double-Blind, Randomized, Noninferiority, Phase 2 Trial.

BACKGROUND: Pradefovir is a liver-targeted prodrug of adefovir, a nucleoside/nucleotide analogue with antiviral activity against hepatitis B virus (HBV) DNA polymerase. This phase 2 study compared the efficacy and safety of oral pradefovir (30, 45, 60, or 75 mg) versus tenofovir disoproxil fumarate (TDF; 300 mg) and aimed to identify the most appropriate dose of pradefovir for the forthcoming phase 3 study. METHODS: Treatment-naive and experienced (not on treatment >6 months) patients with chronic hepatitis B were eligible. RESULTS: A total of 240 participants were randomized and treated in the study (48 per group). Approximately 80% were hepatitis B e antigen (HBeAg) positive, and 10% had liver cirrhosis. The reductions from baseline in HBV DNA levels achieved at week 24 were 5.40, 5.34, 5.33, and 5.40 log10 IU/mL, with pradefovir doses of 30-, 45-, 60-, and 75-mg, respectively, compared with 5.12 log10 IU/mL with TDF. However, HBeAg loss was attained by more participants who received 45-, 60-, or 75-mg pradefovir than by those receiving TDF (12%, 6%, and 9% vs 3%). The TDF group exhibited a more significant increase in serum creatinine than the pradefovir 30- and 45-mg groups, and serum phosphate levels were comparable among all groups. Most adverse events (AEs) were mild (grade 1). No treatment-related severe AEs were reported. Overall, AEs and laboratory abnormalities were comparable to those in the TDF group. CONCLUSIONS: Pradefovir and TDF exhibited comparable reductions in HBV DNA levels. All treatments were safe and well tolerated. CLINICAL TRIALS REGISTRATION: NCT00230503 and China Drug Trials CTR2018042.

Safety, pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects.

BACKGROUND: Pradefovir is efficiently converted to adefovir [9-(2-phosphonylmethoxyethyl) adenine (PMEA)], producing high hepatic PMEA concentration but low levels in the systemic circulation and kidney. The aim of this study is to evaluate the tolerability, adverse effect (AEs), pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir. METHODS: Fifty healthy subjects were divided into five groups and randomized within each group at a ratio of 3:1:1 to receive a single ascending dose of pradefovir (10, 30, 60, 90, or 120 mg), and 10 mg adefovir dipivoxil (ADP) or placebo. Blood and urine samples were collected and analyzed. A total of 1930 polymorphic loci were analyzed in 6 blood samples collected from the 90 mg pradefovir group. RESULTS: The single oral dose of pradefovir up to 120 mg was well tolerated. A total of 29 dose-limited mild AEs were reported in 17 subjects. The peak plasma concentration (C max) and area under the curve (AUC)0-48 of serum pradefovir ranged from (21.41 ± 12.98) to (447.33 ± 79.34) ng/mL and (46.10 ± 29.45) to (748.18 ± 134.15) ng h/mL across the dose range, respectively. The C max and AUC0-48 of serum PMEA ranged from 18.10 ± 4.96 to 312.33 ± 114.19 ng/mL and 72.65 ± 28.25 to 1095.48 ± 248.47 ng h/mL. Generally, no kidney impairment was observed. Pharmacogenetic analysis identified three metabolism-related single nucleotide polymorphism (SNP) locis, P450 (cytochrome) oxidoreductase [POR (rs6965343)], arylamine N-acetyltransferases [NAT1 (rs4986993)] and CYP2F1 (rs305968)], and one distribution-related loci, orosomucoid 2 [ORM2 (rs12685968)]. CONCLUSIONS: The single oral dose of pradefovir 10-120 mg was well tolerated. SNPs may be associated with variable rates of adverse events. TRIAL REGISTRATION NUMBER: CTR20140341.

Simultaneous determination of pradefovir, PMEA and tenofovir in HBV patient serum using liquid chromatography-tandem mass spectrometry and application to phase 2 clinical trial.

Pradefovir, a prodrug of PMEA, is under phase 2 clinical trial in China to evaluate its pharmacokinetic and pharmacodynamics after multiple-dose study, with adefovir dipivoxil and tenofovir disoproxil fumarate as positive control. A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of pradefovir, PMEA and tenofovir in HBV patient serum. Serum samples were pretreated via simple protein precipitation with methanol and entecavir was used as internal standard. Chromatographic separation was carried out on a Synergi(®) fusion-RP column (150mm×4.6mm) by gradient elution with methanol and 0.1% formic acid in water (v/v) at a flow rate of 1mL/min. The analytes were detected in multiple reaction monitoring mode with positive ion electrospray ionization at m/z 424.1/151.0, 274.1/162.2, 288.1/176.1, and 278.1/152.2for pradefovir, PMEA, tenofovir and IS, respectively. The assays were validated according to current bioanalytical guidelines including specificity, linearity (2.0-500ng/mL for pradefovir and PMEA, 4.0-1000ng/mL for tenofovir), accuracy and precision, extraction recovery, matrix effect and stability. The validated method has been successfully applied to the pharmacokinetic study of pradefovir, adefovir dipivoxil and tenofovir disoproxil fumarate in a set of HBV patients.

Factors limiting the extent of absolute bioavailability of pradefovir in rat.

1. Pradefovir was designed as an oral liver target prodrug of 9-(2-phosphonylmethoxyethyl) adenine (PMEA). Liver targeting arises through first pass hepatic metabolism by cytochrome P-450 3A4 (CYP3A4). For CYP3A4 primarily exists in intestines and liver, intestinal metabolism may impair its liver selectivity and oral bioavailability, and then impair its efficacy and safety. It was important to reveal details of the disposition of pradefovir in intestines and liver in a preclinical study. 2. The absolute bioavailability of pradefovir was 4.75% based on the intravenous and oral AUC0-24 h in rats. Pradefovir was stable in intestinal segments and microsomes. The fractions of the dose absorbed from the GI tract were 20.3% and 15.3% from intravenous and oral administration of pradefovir in rats and portal vein-cannulated rat models, respectively. The liver extraction ratio was predicted to be 49.2% from liver microsomes system, based on the monitoring substrate loss rate. Rat intestines' Ussing chamber experiment indicated that P-glycoprotein (P-gp) transporter and paracellular pathway may involve in intestinal transportation. 3. Activation of pradefovir mainly occurs in the liver. Low intestinal absorption was the main reason of low bioavailability of pradefovir in rats. The result was suggestive for the disposition of pradefovir in human intestine and liver.

Pradefovir：a new drug that targets to the liver for treatment of hepatitis B / 中国生化药物杂志

Objective To review pharmacological mechanism, pharmacokinetics, clinical research progress and prospects of pradefovir, a liver targeted medicine for hepatitis B.Methods The studies of pradefovir were summarized by searching literature databases of Web of Science,Elsevier ScienceDirect,Springer Link,Wiley Online Library, Pubmed, CNKI, Wanfang and VIP datebase.Results Pradefovir is a prodrug that targets to the liver, which absorbs rapidly by oral administration.Pradefovir could be quickly converted to adefovir with hepatic drug metabolizing enzyme CYP3A4. Compared with adefovir dipivoxil, it has shown smaller nephrotoxicity and larger liver targeting.Conclusion Pradefovir has shown favorable safety and effectiveness in the clinical study and has no durg resistance to be found.The approval Ⅲ clinical trial has been acquired of pradefovir in USA and has enteredⅠ clinical trial currently in our country, which has good prospects for clinical application in future.

Nuevos tratamientos para el manejo de la Hepatitis B / New treatments for the management of Hepatitis B

El tratamiento de hepatitis B está en fase de experimentación en espera de obtener medicamentos con mayor eficiencia y menor resistencia. La mayoría de los medicamentos, en experimentación, son análogos de nucleósidos y nucleóticos que inhiben competitivamente la polimerasa HBV. La emtricitrabina es un medicamento que potencialmente se podría utilizar en pacientes coinfectados con HIV con el inconveniente de la resistencia cruzada a lamivudina. El tenofovir es un medicamento prometedor en los pacientes coinfectados con HIV tanto los Hbe Ag negativo como los resistentes a lamivudina. Prodrogas como el pradefovir se visualizan como medicamentos más efectivos y con menos efectos adversos que la droga original. La mayoría de estos medicamentos requieren de más estudios para definir su rol en el tratamiento de la hepatitis B crónica.

Hepatitis B treatment is in the experimentation stage expecting to obtain more effective and less resistant treatments. Most treatments under experimentation are nucleoside and nucleotide analogues that competitively inhibit HBV polymerase. Emtricitabine is a drug that could be used in con-infected HIV patients with the inconvenience of cross-resistance to lamivudine. Tenofovir is a promising drug for co-infected HIV patients, not only for the HbeAg negative but also for those resistant to lamuvidine. Pro-drugs such as pradefovir are considered more effective and with less adverse effects than the original drug. Most of these drugs require more studies to define its role in the treatment of chronic hepatitis B.

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

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.