Abstract
The prenylation inhibitor lonafarnib (LNF) is a potent antiviral agent providing a breakthrough for the treatment of hepatitis delta virus (HDV). The current study used a maximum likelihood approach to model LNF pharmacokinetic (PK) and pharmacodynamic (PD) parameters and predict the dose needed to achieve 99% efficacy using data from 12 patients chronically infected with HDV and treated with LNF 100 mg twice daily (bid) (group 1) or 200 mg bid (group 2) for 28 days. The LNF‐PK model predicted average steady‐state LNF concentrations of 860 ng/mL and 1,734 ng/mL in groups 1 and 2, respectively, with an LNF absorption rate ka = 0.43/hour and elimination rate ke = 0.045/hour. The PK/PD model identified an average delay of 0.56 hours and an LNF concentration that decreases HDV production by 50%, EC50 = 227 ng/mL, with a Hill factor h = 1.48. The HDV half‐life in blood was 1.87 days, and the average steady‐state LNF efficacy in blocking HDV production was ɛ = 87.7% for group 1 and ɛ = 95.2% for group 2. A biphasic HDV decline with an average phase 1 decline (0.9 log10 IU/mL and 1.32 log10 IU/mL) was observed in groups 1 and 2, respectively. Phase 2 was not significantly (P = 0.94) different between the two groups, with an average slope of –0.06 log IU/mL/day. The model suggests an LNF dose of ∼610 mg bid would achieve ɛ = 99%. Conclusion: The first PK/PD modeling study in patients with chronic HDV indicates that a ∼3‐fold increase in LNF dose (∼610 mg bid) would achieve 99% antiviral efficacy. A ritonavir‐boosted LNF combination may provide a means to increase LNF efficacy with minimal side effects. The modeling findings provide an important advance in understanding HDV dynamics and the basis to optimize LNF therapy for hepatitis D. (Hepatology Communications 2017;1:288–292)
Highlights
A n estimated 15 million to 20 million people worldwide are chronically co-infected with hepatitis delta virus (HDV) and hepatitis B virus (HBV), which results in more severe liver disease progression than chronic HBV mono-infection.(1) Unlike the various therapeutic advancements in the field of chronic HBV and hepatitis C virus, there is still no satisfactory or U.S Food and Drug Administration-approved therapy for chronic delta hepatitis (CDH).(2) Guidelines have suggested peginterferon for the treatment of CDH(3); therapy is poorly tolerated and is limited by high relapse rates, even when treatment is extended for 5 years.(4)
LNF concentrations observed here in patients with chronic HDV were comparable to those observed in a dose escalation study of LNF for treatment of patients with solid tumors who received 25 mg to 300 mg bid(8) and after a single dose (100 mg) in healthy volunteers.(9) Cmax, Tmax, and AUC0!12h values computed in the current study were within the range observed during day 1 and day 14 of treatment in Castaneda et al(8) using 100 and 200 mg bid of LNF
Since we recently reported that an LNF dose of 200 mg bid was associated with poor gastrointestinal tolerability,(6) higher monotherapy LNF doses may not be a feasible therapeutic approach
Summary
A new investigational therapy involves the inhibition of the host function known as prenylation. Prenylation inhibition impacts a vital aspect of the HDV life cycle by disrupting the ability of the viral large delta antigen to interact with the hepatitis B surface antigen, a step that is required to form and secrete infectious HDV particles.(5) In a recently completed phase 2a. Supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Cancer Institute of the National Institutes of Health (NIH) and extramural NIH grant R01-AI078881 and by the United Kingdom Biotechnology and Biological Sciences Research Council (grant reference 1698:BB/L001330/1). Lonafarnib was provided by Eiger Biopharmaceuticals, Inc. under a clinical trial agreement with the NIDDK. Lonafarnib pharmacokinetic studies (performed by Quest Pharmaceutical Services, Newark, DE) was contracted through Eiger Biopharmaceuticals, Inc. under a clinical trial agreement with the NIDDK. Lonafarnib pharmacokinetic studies (performed by Quest Pharmaceutical Services, Newark, DE) was contracted through Eiger Biopharmaceuticals, Inc. under a clinical trial agreement with the NIDDK. *These authors contributed to this work
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