Safety and Human Pharmacokinetics of AIC316, a Potent Helicase-Primase Inhibitor of Herpes Simplex Virus (HSV)

Birkmann, Alexander; Kropeit, Dirk; McCormick, David; Zimmermann, Holger; Ruebsamen‐Schaeff, Helga

doi:10.1016/j.antiviral.2011.03.014

Cited by 4 publications

(3 citation statements)

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“…Half-lives of 2.0–2.5 h determined for penciclovir after dosing with the prodrug famciclovir fall into the same range. − Against this background, results for pritelivir (at least 5 h in rodents and 22 h in non-rodents; section ) suggested a favorably prolonged exposure of humans. Indeed, a terminal elimination half-life of 60–70 h determined in human volunteers at the therapeutic dose level (100 mg, single dose) , and predictable in otherwise healthy subjects with genital herpes also confirms achievement of the first of the pharmacokinetic goals of the present development.…”

Section: Discussionsupporting

confidence: 73%

Discovery, Chemistry, and Preclinical Development of Pritelivir, a Novel Treatment Option for Acyclovir-Resistant Herpes Simplex Virus Infections

et al. 2022

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When the nucleoside analogue acyclovir was introduced in the early 1980s, it presented a game-changing treatment modality for herpes simplex virus infections. Since then, work has been ongoing to improve the weaknesses that have now been identified: a narrow time window for therapeutic success, resistance in immunocompromised patients, little influence on frequency of recurrences, relatively fast elimination, and poor bioavailability. The present Drug Annotation focuses on the helicase−primase inhibitor pritelivir currently in development for the treatment of acyclovir-resistant HSV infections and describes how a change of the molecular target (from viral DNA polymerase to the HSV helicase−primase complex) afforded improvement of the shortcomings of nucleoside analogs. Details are presented for the discovery process leading to the final drug candidate, the pivotal preclinical studies on mechanism of action and efficacy, and on how ongoing clinical research has been able to translate preclinical promises into clinical use.

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Section: Discussionsupporting

confidence: 73%

Discovery, Chemistry, and Preclinical Development of Pritelivir, a Novel Treatment Option for Acyclovir-Resistant Herpes Simplex Virus Infections

et al. 2022

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“…PK of pritelivir has been demonstrated in a single and multiple-dose ascending trial. [ 84 , 85 ] A dose-proportional increase in exposure (linear PK) has been observed. Terminal elimination half-life varied between 60–70 h and AUC of approximately 90.8 mg*h/L after a single 100 mg dose, with 75% bioavailability [ 85 ].…”

Section: Pritelivir and Amenamevirmentioning

confidence: 98%

“…The drugs are selective for HSV. Amenivir is also active against VZV, but pritelivir is inactive against other viruses such as CMV and VZV ( Figure 1 ) [ 18 , 81 , 84 ].…”

Section: Pritelivir and Amenamevirmentioning

confidence: 99%

Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients

et al. 2023

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Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have a narrow therapeutic window and show significant pharmacokinetic variability. Above that, immunocompromised patients have various comorbidities like impaired renal function and are exposed to polypharmacy. This scoping review discusses the current pharmacokinetic (PK) and pharmacodynamic (PD) knowledge of antiviral drugs for HSV and CMV treatment in immunocompromised patients. HSV and CMV treatment guidelines are discussed, and multiple treatment interventions are proposed: early detection of drug resistance; optimization of dose to target concentration by therapeutic drug monitoring (TDM) of nucleoside analogs; the introduction of new antiviral drugs; alternation between compounds with different toxicity profiles; and combinations of synergistic antiviral drugs. This research will also serve as guidance for future research, which should focus on prospective evaluation of the benefit of each of these interventions in randomized controlled trials.

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A Cutting‐Edge View on the Current State of Antiviral Drug Development

Clercq

2013

Medicinal Research Reviews

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Prominent in the current stage of antiviral drug development are: (i) for human immunodeficiency virus (HIV), the use of fixed-dose combinations (FDCs), the most recent example being Stribild(TM); (ii) for hepatitis C virus (HCV), the pleiade of direct-acting antivirals (DAAs) that should be formulated in the most appropriate combinations so as to obtain a cure of the infection; (iii)-(v) new strategies (i.e., AIC316, AIC246, and FV-100) for the treatment of herpesvirus infections: herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), respectively; (vi) the role of a new tenofovir prodrug, tenofovir alafenamide (TAF) (GS-7340) for the treatment of HIV infections; (vii) the potential use of poxvirus inhibitors (CMX001 and ST-246); (viii) the usefulness of new influenza virus inhibitors (peramivir and laninamivir octanoate); (ix) the position of the hepatitis B virus (HBV) inhibitors [lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate (TDF)]; and (x) the potential of new compounds such as FGI-103, FGI-104, FGI-106, dUY11, and LJ-001 for the treatment of filoviruses (i.e., Ebola). Whereas for HIV and HCV therapy is aimed at multiple-drug combinations, for all other viruses, HSV, CMV, VZV, pox, influenza, HBV, and filoviruses, current strategies are based on the use of single compounds.

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Safety and Human Pharmacokinetics of AIC316, a Potent Helicase-Primase Inhibitor of Herpes Simplex Virus (HSV)

Cited by 4 publications

References 0 publications

Discovery, Chemistry, and Preclinical Development of Pritelivir, a Novel Treatment Option for Acyclovir-Resistant Herpes Simplex Virus Infections

Discovery, Chemistry, and Preclinical Development of Pritelivir, a Novel Treatment Option for Acyclovir-Resistant Herpes Simplex Virus Infections

Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients

A Cutting‐Edge View on the Current State of Antiviral Drug Development

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