Hepatitis Delta Virus Kinetics under the Prenylation Inhibitor Lonafarnib Suggest HDV-Mediated Suppression of HBV Replication

Yurdaydın, Cihan; Borochov, N.; Kalkan, Çağdaş; DebRoy, Swati; Karataylı, Ersin; Haynes-Williams, Vanessa; Karataylı, Senem Ceren; Canini, Laetitia; Uprichard, Susan L.; Bozdayi, AM; Choong, Ingrid; Cory, David G.; Heller, Theo; Cotler, S.J.; İdilman, Ramazan; Glenn, Jeffrey S.; Dahari, Harel

doi:10.1016/s0168-8278(16)01079-5

Cited by 6 publications

(3 citation statements)

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“…However, since we recently reported that an LNF dose of 200 mg bid was associated with poor gastrointestinal tolerability, higher monotherapy LNF doses may not be a feasible therapeutic approach. Interestingly, HDV kinetic data from a subsequent phase 2 study has shown encouraging results with LNF 100 mg bid plus ritonavir . Ritonavir boosting provides a potential means to decrease LNF doses in the gastrointestinal tract, thereby limiting adverse effects, while increasing its postabsorbed concentration and antiviral efficacy.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics modeling of lonafarnib in patients with chronic hepatitis delta virus infection

Canini

Koh

Cotler

et al. 2017

Hepatology Communications

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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)

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics modeling of lonafarnib in patients with chronic hepatitis delta virus infection

Canini

Koh

Cotler

et al. 2017

Hepatology Communications

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“…Interestingly, HDV kinetic data from a subsequent phase 2 study has shown encouraging results with LNF 100 mg bid plus ritonavir. (10) Ritonavir boosting provides a potential means to decrease LNF doses in the gastrointestinal tract, thereby limiting adverse effects, while increasing its postabsorbed concentration and antiviral efficacy. Specifically, in the phase 2 LOna farnib With and without Ritonavir (LOWR) HDV-1 study, the serum LNF concentrations with LNF 100 mg bid plus ritonavir 100 mg once a day were up to 6,000 ng/mL compared to 900 ng/mL with LNF 100 mg bid (clinical trial: NCT02430181).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics Modeling of Lonafarnib in Patients with Chronic Hepatitis Delta Virus Infection

Canini¹,

Koh²,

Cotler³

et al. 2016

Journal of Hepatology

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“…8,16,17 This inverse relationship of HBV and HDV viral load has been also hinted at in a small lonafarnib study with HBV/HDV-coinfected patients. 18 Thus, the observed transient HBV-DNA increase cannot be (at least fully) explained by a concurrent HDV-RNA reduction.…”

Section: Patients With Transient Hbv-dna Increase During Therapy Hamentioning

confidence: 92%

A transient early HBV‐DNA increase during PEG‐IFNα therapy of hepatitis D indicates loss of infected cells and is associated with HDV‐RNA and HBsAg reduction

Anastasiou

Yurdaydın

Maasoumy

et al. 2020

Journal of Viral Hepatitis

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HBV-DNA levels are low or even undetectable in the majority HDV-infected patients. The impact of PEG-IFNα on HBV-DNA kinetics in HDV-infected patients has not been studied in detail. We analysed data of a prospective treatment trial where 120 HDV-RNA-positive patients were randomized to receive PEG-IFNα-2a plus tenofovir-disoproxil-fumarate (PEG-IFNα/TDF, n = 59) or placebo (PEG-IFNα/PBO; n = 61) for 96 weeks. At week 96, HBV-DNA was still quantifiable in 71% of PEG-IFNα/PBO-treated patients but also in 76% of PEG-IFNα/TDF-treated patients, despite low HBV-DNA baseline values. Surprisingly, a transient HBV-DNA increase between weeks 12 and 36 was observed in 12 in PEG-IFNα/TDF-treated and 12

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Hepatitis Delta Virus Kinetics under the Prenylation Inhibitor Lonafarnib Suggest HDV-Mediated Suppression of HBV Replication

Cited by 6 publications

References 0 publications

Pharmacokinetics and pharmacodynamics modeling of lonafarnib in patients with chronic hepatitis delta virus infection

Pharmacokinetics and pharmacodynamics modeling of lonafarnib in patients with chronic hepatitis delta virus infection

Pharmacokinetics and Pharmacodynamics Modeling of Lonafarnib in Patients with Chronic Hepatitis Delta Virus Infection

A transient early HBV‐DNA increase during PEG‐IFNα therapy of hepatitis D indicates loss of infected cells and is associated with HDV‐RNA and HBsAg reduction

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