Safety, efficacy, and pharmacokinetics of pradefovir for the treatment of chronic hepatitis B infection

Highlights

• Pradefovir was associated with reduced serum PMEA levels compared to ADV.

• The antiviral activity of pradefovir was greater after pradefovir than ADV, and it was similar to that of TDF.

• Pradefovir demonstrated a favorable safety profile and excellent anti-HBV activity.

• Pradefovir could be a promising anti-HBV drug.

Abstract

Background & aims

Pradefovir is a liver targeted novel prodrug of adefovir (PMEA) developed to provide higher antiviral activity with reduced systemic toxicities. This study evaluated the tolerability, pharmacokinetics, and antiviral activity of pradefovir in patients with chronic hepatitis B (CHB) virus infection.

Methods

Non-cirrhotic, treatment-naïve subjects with CHB were divided into five groups (10 patients each) and randomized within each group in a ratio of 6:2:2 to receive an ascending dose of 30, 60, 75, 90, or 120 mg pradefovir, 10 mg adefovir dipivoxil (ADV), or 300 mg tenofovir disoproxil fumarate (TDF) once a day for 28 days.

Results

A total of 51 subjects were randomized and 49 subjects completed the study. The groups were well matched and included 39 males, of whom 71% were hepatitis B e-antigen-negative with a mean hepatitis B virus (HBV) DNA level of 6.4–7.16 log10 IU/mL. No subject experienced a serious adverse event or nephrotoxicity. The most frequently reported adverse event was asymptomatic reduction in blood cholinesterase levels in the pradefovir group which recovered without any treatment about 13 ± 7 days after drug discontinuation. This adverse event was not observed in the ADV and TDF groups.

The mean changes in serum HBV DNA were −2.78, −2.77, −3.08, −3.18, −3.44, −2.34, and −3.07 log10 IU/mL at 30, 60, 75, 90, and 120 mg pradefovir, 10 mg ADV and 300 mg TDF, respectively, with plateau levels reached with 60 mg pradefovir. Pradefovir and its metabolite PMEA showed linear pharmacokinetics proportional to the dose. The half-life of PMEA in the pradefovir group was 11.47–17.63 h.

Conclusions

Short-term use of pradefovir was well tolerated. A decline in HBV DNA levels was superior to TDF at higher doses of pradefovir. 30–60 mg pradefovir is recommended for CHB treatment.

Clinical trial number

CTR20150224.

Introduction

Chronic hepatitis B (CHB) virus infection affects more than 350 million individuals worldwide, with a high prevalence in Asian and Sub-Saharan African countries (Ott et al., 2012; Xiao et al., 2019). Persistent viral replication is an independent risk factor for the development of cirrhosis, hepatocellular carcinoma, and liver-related mortality (Chen et al., 2006, 2010; European Association For The Study Of The Liver, 2012; Liaw et al., 2012). Adefovir dipivoxil (ADV), a diester prodrug of the active moiety adefovir (PMEA) is effective in lamivudine-resistant CHB patients (Murakami et al., 2014; Marcellin et al., 2008). Long-term ADV use helps achieve and maintain viral suppression, regression of fibrosis, and reversal of cirrhosis in most patients (Wang et al., 2014), However, PMEA is actively transported into the renal proximal tubules and causes nephrotoxicity at ADV doses of 30–120 mg/day (Lee et al., 2010). Hence, ADV, is used at submaximal dose of 10 mg because of its renal toxicity.

Pradefovir, a hepatic targeted novel prodrug of PMEA developed by utilizing the HepDirectTM patented technology, enhances the delivery of PMEA to the liver. Different from ADV, the majority of pradefovir is metabolized to PMEA in the hepatocytes; it remains unchanged until penetration in to the hepatocytes, after which it is converted to PMEA by cytochrome P450 isozyme 3A4 (Dando and Plosker, 2003; Qaqish et al., 2003; Lin et al., 2006a). This selectively liver-activated prodrug enhances liver levels of the active metabolite adefovir diphosphate (ADV-DP) and decreases serum and renal concentrations. These features lead to a high PMEA concentration in the liver and very low concentration in the serum which reduces the renal and bone toxicities associated with ADV (Agarwal et al., 2018). The molecular weight of pradefovir is similar to that of ADV.

The well-tolerated oral single dose of pradefovir varies between 10 and 120 mg and does not cause significant kidney impairment in healthy subjects and the maximum concentration (C_max) and area under the plasma concentration-time curve from time 0–48 h (AUC_0–48) of serum PMEA ranges from 18 to 312 ng/mL and 72–1095 ng*h/mL, respectively (Ding et al., 2017). The clinical trials with pradefovir are currently on going. This phase Ib study is the first study conducted in China evaluating the efficacy and safety of pradefovir in CHB subjects.